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Review article, impact of vaccines; health, economic and social perspectives.
- 1 Department of Zoology, University of Oxford, Oxford, United Kingdom
- 2 Department of Paediatric Infectious Diseases, St George’s University Hospitals NHS Foundation Trust, London, United Kingdom
- 3 Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, United States
In the 20th century, the development, licensing and implementation of vaccines as part of large, systematic immunization programs started to address health inequities that existed globally. However, at the time of writing, access to vaccines that prevent life-threatening infectious diseases remains unequal to all infants, children and adults in the world. This is a problem that many individuals and agencies are working hard to address globally. As clinicians and biomedical scientists we often focus on the health benefits that vaccines provide, in the prevention of ill-health and death from infectious pathogens. Here we discuss the health, economic and social benefits of vaccines that have been identified and studied in recent years, impacting all regions and all age groups. After learning of the emergence of SARS-CoV-2 virus in December 2019, and its potential for global dissemination to cause COVID-19 disease was realized, there was an urgent need to develop vaccines at an unprecedented rate and scale. As we appreciate and quantify the health, economic and social benefits of vaccines and immunization programs to individuals and society, we should endeavor to communicate this to the public and policy makers, for the benefit of endemic, epidemic, and pandemic diseases.
“The impact of vaccination on the health of the world’s peoples is hard to exaggerate. With the exception of safe water, no other modality has had such a major effect on mortality reduction and population growth” ( Plotkin and Mortimer, 1988 ).
The development of safe and efficacious vaccination against diseases that cause substantial morbidity and mortality has been one of the foremost scientific advances of the 21st century. Vaccination, along with sanitation and clean drinking water, are public health interventions that are undeniably responsible for improved health outcomes globally. It is estimated that vaccines have prevented 6 million deaths from vaccine-preventable diseases annually ( Ehreth, 2003 ). By 2055, the earth’s population is estimated to reach almost 10 billion ( United Nations Department of Economic and Social Affairs, 2019 ), a feat that in part is due to effective vaccines that prevent disease and prolong life expectancy across all continents. That said, there is still much to be done to ensure the financing, provision, distribution, and administration of vaccines to all populations, in particular those which are difficult to reach, including those skeptical about their protective value and those living in civil disruption. Agencies including the World Health Organization (WHO), United Nations Children’s Fund (UNICEF), Gavi, the Vaccine Alliance, The Bill & Melinda Gates Foundation, and the Coalition for Epidemic Preparedness Initiative (CEPI), with their multiple funding streams have been instrumental in expanding vaccine benefits to all. These importance of these organizations in global co-operation and participation was essential in the setting of the 2019 global pandemic of SARS-CoV-2, in light of the health and economic impact of COVID-19 on societies in high-, middle- and low-income countries. This review will highlight the benefits of vaccinations to society from the perspectives of health, economy, and social fabric ( Figure 1 ), which need to be considered in the overall assessment of impact to ensure that vaccines are prioritized by those making funding decisions.
Figure 1. The impact of vaccines according to their health, economic or social benefit.
Brief History of Vaccine Development
Human use of preparations to prevent specific infections have been described since 1500 AD, beginning in China ( Needham, 2000 ) where smallpox was prevented by variolation, which is the introduction of material from scabs into the skin. In 1796 in the United Kingdom, Edward Jenner observed the immunity to smallpox of milkmaids having previously had natural infection with cowpox ( Jenner, 1798 ). He determined that inoculating small amounts of pus from the lesions of cowpox, presumably containing a virus related to vaccinia, into susceptible hosts rendered them immune to smallpox. The vaccine against smallpox was developed in 1798. The next phase of scientific developments involving the manipulation of infectious agents to extract suitable vaccine antigens took almost a century of research. Louis Pasteur’s work with attenuation by oxygen or heat led to live-attenuated chicken cholera, inactivated anthrax and live-attenuated rabies vaccines at the turn of the 20th century ( Pasteur, 1880 , 1881 , 1885 ). Alternative methods of attenuation using serial passage of Mycobacterium bovis led to the live Bacille Calmette-Guerin (BCG) ( Calmette, 1927 ) vaccine, still in use today for the prevention of tuberculosis. Serial passage was also used in the development of yellow fever vaccines ( Theiler and Smith, 1937a ) which are grown in chicken embryo tissues ( Theiler and Smith, 1937b ). Whole cell killed bacterial vaccines were developed when methods to treat and kill bacteria through heat or chemicals were established and whole cell typhoid, cholera and pertussis vaccines resulted at the end of the 19th Century. In 1923, Alexander Glenny and Barbara Hopkins developed methods to inactivate bacterial toxins with formaldehyde, leading to the diphtheria and tetanus toxoid vaccines ( Glenny and Hopkins, 1923 ).
Advances in virus culture in vitro allowed viral pathogens to be studied in greater detail and attenuation methods due to cultivation in artificial conditions led to the live oral polio, measles, rubella, mumps and varicella virus vaccines. In the 1960’s at the Walter Reed Army Institute of Research, vaccines were developed using capsular polysaccharides ( Gold and Artenstein, 1971 ; Artenstein, 1975 ), of encapsulated organisms including meningococci and later pneumococci ( Austrian, 1989 ) and Haemophilus influenzae type b (Hib) ( Anderson et al., 1972 ). To protect against multiple serotype variants of polysaccharide capsules, polyvalent vaccines were developed and later conjugated to carrier proteins to enhance their efficacy in infants in particular by recruiting T-cell mediated help to induce memory B-cells ( Schneerson et al., 1980 ). Vaccines made solely from proteins were rare, with the exception of the toxoid vaccines, but the acellular pertussis vaccine containing five protein antigens, was developed to mitigate the unwanted effects of the whole cell vaccine ( Sato and Sato, 1999 ).
The end of the 20th century marked a revolution in molecular biology and provided insights into microbiology and immunology allowing a greater understanding of pathogen epitopes and host responses to vaccination. Molecular genetics and genome sequencing has enabled the development of vaccines against RNA viruses possessing multiple variants of epitopes, such as the live and inactivated influenza vaccines ( Maassab and DeBorde, 1985 ) and live rotavirus vaccines ( Clark et al., 2006 ). DNA manipulation and excision allowed the use of surface antigen for hepatitis B viral vectors ( Plotkin, 2014 ). The human papilloma virus (HPV) vaccine benefits from enhanced immunogenicity due to the formation of virus-like particles by the L1 antigen of each virus contained in the vaccine ( Kirnbauer et al., 1992 ). Bacterial genome sequencing has provided in depth analysis of meningococcal antigens, to identify potential proteins for meningococcal B vaccines ( Serruto et al., 2012 ).
Vaccine development was tested in 2020 when a novel coronavirus, SARS-CoV-2, emerged from China causing a severe acute respiratory illness, which subsequently spread globally. Within 5 months of the discovery of this virus (7th January 2020) ( Zhu et al., 2020 ) and person-person transmission ( Chan et al., 2020 ), 5,697,334 cases had been identified, with orders of magnitude likely not measured and almost no country escaped the pandemic. Owing to the previous advances in vaccinology, by 8th April 2020, there were 73 vaccine candidates under pre-clinical investigation ( Thanh Le et al., 2020 ). Of these, six were in Phase 1 or 1/2 trials and one was in Phase 2/3 trials by 28th May 2020. The rapidity of this response demonstrated the ability to harness existing technologies including: RNA vaccine platforms (NCT04283461), DNA vaccine platforms (NCT04336410), recombinant vector vaccines (NCT04313127, NCT04324606) and adjuvants. The regulation, manufacturer and distribution of these vaccines will require expedition given the global public health need, from a period of many years to a matter of months. The efficacy and health impact of these vaccines is yet to be established, but if they are effective, then vaccines need to be made available for all global regions affected by SARS-CoV-2. The funding of this endeavor will prove challenging in a global context of national social and economic lockdown and massive government borrowing, but the justification for this provision will be through the multiple benefits to society that will need healthy citizens to rebuild economies in the decades post-COVID-19.
The history of vaccination is not complete without describing the public health intervention that led to the routine use of these vaccines for children globally. The Expanded Program of Immunization (EPI) was founded by WHO in 1974 with the aim of providing routine vaccines to all children by 1990 ( World Health Assembly, 1974 ). In 1977, global policies for immunization against diphtheria, pertussis, tetanus, measles, polio, and tuberculosis were set out. The EPI includes hepatitis B, Hib, and pneumococcal vaccines in many areas and by 2017, 85% of the world’s children (12–23 months of age) received diphtheria, pertussis, tetanus, and measles vaccines ( World Bank, 2019 ).
Health Benefits of Vaccination
Reduction in infectious diseases morbidity and mortality.
The most significant impact of vaccines has been to prevent morbidity and mortality from serious infections that disproportionately affect children. Vaccines are estimated to prevent almost six million deaths/year and to save 386 million life years and 96 million disability-adjusted life years (DALYs) globally ( Ehreth, 2003 ). The traditional measures of vaccine impact include: vaccine efficacy, the direct protection offered to a vaccinated group under optimal conditions e.g., trial settings; or vaccine effectiveness, the direct and indirect effect of vaccines on the population in a real-life setting ( Wilder-Smith et al., 2017 ). Providing a numerical measure of vaccine impact therefore involves estimating the extent of morbidity and mortality prevented. In the United States in 2009, amongst an annual birth cohort vaccinated against 13 diseases it was estimated that nearly 20 million cases of disease and ∼42,000 deaths were prevented ( Zhou et al., 2009 ). Infectious diseases that accounted for major mortality and morbidity in the early 20th century in the United States all showed over a 90% decline in incidence by 2017 from the pre-vaccine peak incidence ( Roush and Murphy, 2007 ), due to high vaccine uptake of over 90% for the DTaP (diphtheria, tetanus, and acellular pertussis), MMR (measles, mumps, and rubella) and polio vaccines ( World Health Organisation, 2019a ; Table 1 ). A similar pattern of infectious diseases reduction was seen across other high-income countries, demonstrating the efficacy of vaccines when available and accessible.
Table 1. Vaccine impact in United States comparing the incidence of diseases prior to the implementation of vaccine ( Roush and Murphy, 2007 ), described as the pre-vaccine era and the vaccine coverage ( Hill et al., 2017 ) and disease incidence ( Centers for Disease Control and Prevention, 2017 ) in 2017, as reported by the Centers for Disease Control and Prevention.
Globally, the provision of vaccines is more challenging in many low- and middle- income countries (LMIC), as evidenced by the failure to make the EPI vaccines available to every child by 1990, irrespective of setting ( Keja et al., 1988 ). Central to this is limited financial resources, but other barriers to vaccine introduction include: underappreciation of the value of vaccines locally/regionally though insufficient relevant data on disease burden, vaccine efficacy, or cost-effectiveness; inadequate healthcare infrastructure for vaccine handling, storage, programmatic management, and disease surveillance; and lack of global, regional or local policy-making and leadership ( Munira and Fritzen, 2007 ; Hajjeh, 2011 ). In 2018, the global uptake of three doses of DTaP reached 86% which corresponded to 116,300,000 infants ( World Health Organisation, 2019a ). The vaccine coverage is, however, variable between low-, middle- and high-income countries because of a combination of economic and political circumstances as well as variable access to non-governmental support from Gavi, the Vaccine Alliance ( Turner et al., 2018 ; Figure 2 ). Nevertheless, there has been a decrease in the global burden of diseases caused by vaccine-preventable pathogens ( Figure 3 ) enabling healthier lives for many millions of children. A further benefit following vaccination, is the evidence that although vaccines may not always prevent an infection, for example VZV or pertussis, a milder disease course may follow ( Andre et al., 2008 ; Bonanni et al., 2015 ).
Figure 2. Vaccine uptake across different regions defined by economic status by the World Bank into high- (solid line), middle- (dashed line), and low-income countries (dotted line) for the past 20 years. Data from the World Health Organization and UNICEF dataset “Coverage Estimates Series” ( World Health Organization [WHO] and United Nations Children’s Fund [UNICEF], 2019 ).
Figure 3. Reduction in infectious diseases globally. Across all world regions, data from the WHO, for the last 20 years showing the control of diphtheria and tetanus and the decline in rubella and congenital rubella syndrome (data not shown). Data from the World Health Organization dataset “Reported cases of vaccine-preventable diseases” ( World Health Organisation, 2019c ).
Eradication of Infectious Diseases
Global disease eradication can be achieved for pathogens that are restricted to human reservoirs. For eradication of infectious diseases, high levels of population immunity are required globally, to ensure no ongoing transmission in our well-connected world ( Andre et al., 2008 ). Furthermore, surveillance systems must be in place to monitor the decline in disease, with accurate and reliable diagnostic testing to monitor ongoing cases. At the time of writing, the only infectious disease that has been eradicated in humans by vaccination is smallpox. This disease had afflicted humans for millenia, with the earliest evidence found in Egyptian mummies from 1000 BC ( Geddes, 2006 ). Jenner’s successful development of the smallpox vaccine using vaccinia virus ( Jenner, 1798 ) led to the ultimate eradication of the disease through ring vaccination as announced by the World Health Assembly in 1980 ( Strassburg, 1982 ), which was an historic public health achievement. The second example of eradication was of the rinderpest virus in livestock, an infection that indirectly led to human loss of life through loss of agriculture leading to humanitarian crises through famine and poverty. Rinderpest virus infects cattle, buffalo and numerous other domestic species, with widespread disease affecting large parts of Africa and Europe in the 19th century ( Roeder et al., 2013 ). The Plowright tissue culture rinderpest vaccine, developed during the 1950s, was used for mass vaccination campaigns, alongside other public health measures, leading to eradication in 2011 ( Morens et al., 2011 ).
The next infection targeted for eradication is wild polio virus. This devastating paralytic disease routinely afflicted children and adults in both industrialized and developing settings, prior to the development of vaccines. Two polio vaccines, the inactivated polio vaccine (IPV) and the live-attenuated oral polio vaccine (OPV) became available in 1955 and 1963, respectively ( Plotkin, 2014 ), both able to protect against all three wild types of polio virus. Both vaccines have been used globally, with live-attenuated OPV much cheaper and easier to administer but carrying the risk of causing circulating vaccine-derived poliovirus (cVDPV) owing to back-mutation and re-acquisition of neurovirulence. Hence, due to its safety IPV was preferred in industrialized regions and those where the polio incidence was low. In 1998, the Global Polio Eradication Initiative, the largest public-private partnership led by national governments in partnership with the WHO, Rotary International, United States Centers for Disease Control and Prevention (CDC), and UNICEF was launched with the aim of global polio eradication by 2000. Although this target was not met due to lack of funding, political will, and competing health initiatives, there was a 99% reduction in polio incidence by 2000 ( Lien and Heymann, 2013 ). By 2003, there were only six endemic countries with new cases: Egypt, Niger, India, Nigeria, Afghanistan, and Pakistan, of which only the latter four had new cases by 2005. Eradication in India was problematic due to the high birth rates and poor sanitation amongst densely populated regions with marginalized communities and high population mobility ( Thacker et al., 2016 ). India was declared polio free in 2014. Wild polio virus type 2 was eradicated in 2015, the last case of wild type 3 was in 2012 and eradication announced in 2019, with wild type 1 virus remaining in two countries, Pakistan and Afghanistan ( World Health Organisation, 2019b ). In 2019, Nigeria was declared 3 years free of wild polio, the last country in Africa to declare any cases. In the first 6 months of 2020, there were 51 and 17 cases of wild type 1 polio reported in Pakistan and Afghanistan respectively ( Global Polio Eradication Initiative, 2019 ). Ongoing programs to roll out universal vaccination in both countries remain hindered by armed conflict, political instability, remote communities and underdeveloped infrastructure. The risk of the OPV recipients developing cVDPV disease, with transmission through the faeco-oral route to cause outbreaks of vaccine-derived paralytic poliomyelitis remains a concerning obstacle in the eradication process, requiring intensive surveillance.
The overriding health benefit perceived by most vaccine recipients is their personal, direct, protection. The added value of vaccination, on a population level, is the potential to generate herd immunity. Where a sufficiently high proportion of the population are vaccinated, transmission of the infecting agent is halted thereby protecting the unvaccinated, who may be those too young, too vulnerable, or too immunosuppressed to receive vaccines. Highly successful vaccination programs have been in place as part of the routine EPI, against encapsulated bacteria that are carried asymptomatically in the oropharynx but that can invade and cause septicemia and meningitis in all age groups. Vaccines against Neisseria meningitidis ( Gold and Artenstein, 1971 ), Streptococcus pneumoniae ( Austrian, 1989 ), and Hib ( Anderson et al., 1972 ) were developed in the 1960s, 1970s, and 1980s, respectively, using their polysaccharide capsules as vaccine antigens, which successfully induced protective immunity (direct protection). Conjugation of these polysaccharides to carrier proteins in the 1990s improved their efficacy by not only ensuring a T cell response and immune memory, but by reducing acquisition of pharyngeal carriage of these organisms, thus providing indirect protection and thereby preventing ongoing transmission ( Pollard et al., 2009 ). This was first observed in national carriage studies in the United Kingdom in 1999–2001 during a mass vaccination campaign against serogroup C N. meningitidis ( Maiden et al., 2008 ) and was a major contributing factor to the declining disease thereafter.
Herd (population) immunity requires high levels of vaccine uptake, to limit the number of unvaccinated people and the opportunity for pathogen transmission between them. The proportion of a given population required to induce herd immunity through vaccination is lower for the bacterial infections and conjugate polysaccharide vaccines, as their basic reproductive number (R 0 ) is lower than viral infections like measles, varicella or polio ( Table 2 ). Measles virus can cause devastating disease ranging from acute presentations with pneumonia or encephalitis, to immune amnesia and long-term complications such as subacute sclerosing panencephalitis ( Mina et al., 2015 , 2019 ; Moss, 2017 ; Petrova et al., 2019 ). The live-attenuated measles vaccine is highly efficacious and the first dose is recommended at 9–12 months of age. To protect those who cannot receive live vaccines (younger infants, pregnant women, the immunosuppressed) from acquiring measles in the community, at least 93–95% of the population is required to be vaccinated with two doses in order to interrupt measles virus transmission. In many countries in Europe and in the United States, this level of vaccination uptake is falling ( Wise, 2018 ), due to a combination of reduced accessibility to health services and vaccine misinformation. As a result, some countries, including the United Kingdom and United States, where elimination of measles had been declared have had a resurgence of disease ( Wise, 2019 ). For high-risk individuals who are unable to be vaccinated, herd immunity represents a life-saving protection strategy against many infections. An alternative strategy, cocooning, has been employed with limited success for pertussis and influenza ( Grizas et al., 2012 ), where their close/household contacts are vaccinated to prevent transmission.
Table 2. Vaccines with the potential to induce herd immunity, with the infectious agent, vaccine type, and thresholds of population vaccination needed for herd immunity ( Peltola et al., 1999 ; Whitney et al., 2003 ; Donaghy et al., 2006 ; Fine and Griffiths, 2007 ; Maiden et al., 2008 ; Curns et al., 2010 ; Paulke-Korinek et al., 2011 ; Plans-Rubio, 2012 ; Daugla et al., 2014 ; Tabrizi et al., 2014 ; Funk et al., 2019 ; Palmer et al., 2019 ).
Herd immunity has been observed for gastrointestinal infections with vaccines against cholera (oral cholera vaccine) and rotavirus (oral rotavirus vaccines). Early adopters of rotavirus vaccines included the United States (2006) and Austria (2007) where there were dramatic reductions in disease observed in the vaccinated infant cohort, and also in the older age groups of children and adults ( Curns et al., 2010 ; Paulke-Korinek et al., 2011 ), suggesting that the reduction in disease and shedding of virus in the stool stopped transmission to healthy household contacts. For the OPV, herd protection may also be induced through vaccine virus shedding and spread to unvaccinated people ( Fine and Griffiths, 2007 ).
Reduction in Secondary Infections That Complicate Vaccine-Preventable Diseases
Vaccines can prevent diseases beyond the specific infection they are designed to target. Infections with pathogens, in particular viruses, can predispose to the acquisition of other bacterial infections. For example, influenza virus infection, both seasonal and pandemic, is frequently complicated by bacterial pneumonia and acute otitis media (OM), and infrequently Aspergillus pneumonia/pneumonitis. During the influenza pandemic of 1918–19, secondary bacterial bronchopneumonia with S. pneumoniae, Streptococcus pyogenes , H. influenzae , and Staphylococcus aureus identified at autopsy, likely contributed to the excess mortality observed amongst healthy children and adults ( Morens and Fauci, 2007 ). Influenza vaccinations can be beneficial in preventing these complications and also morbidity including acute OM in children; a systematic review demonstrated influenza vaccine efficacy against OM of 51% (21–70%) ( Manzoli et al., 2007 ). Further, there is evidence that inactivated influenza vaccines administered to pregnant women can reduce the hospital admission with acute respiratory illnesses in their infants up to 6 months of age ( Regan et al., 2016 ). Amongst pregnant, HIV-negative women in South Africa, infants (<3 months) were protected against hospitalization with all-cause lower respiratory tract infections with a vaccine efficacy of 43% ( p = 0.05), including primary viral and secondary bacterial causes ( Nunes et al., 2017 ). Additionally, in children pneumococcal conjugate vaccines were observed to reduce the incidence of influenza-associated hospital admissions in United States ( Simonsen et al., 2011 ), Spain ( Dominguez et al., 2013 ), and South Africa ( Madhi et al., 2004 ; Abadom et al., 2016 ), through the prevention of secondary bacterial infections following primary influenza infection.
The introduction of the live-attenuated measles vaccine in the 1970s was observed to reduce both measles and non-measles mortality in children ( Aaby et al., 2003 ). Measles causes severe pneumonia, encephalitis, and the long-term sequel of subacute sclerosing panencephalitis ( Moss, 2017 ), but the decline in mortality was not limited to preventing these alone ( Aaby et al., 2003 ). Mathematical modeling of vaccination and immunological research demonstrated that measles causes an immunological amnesia, eliminating B cell populations and thus immune memory, leaving measles survivors susceptible to all the infective agents they had previously developed immunity against; it is estimated to take 3 years for immune recovery to occur ( Mina et al., 2015 ).
Prevention of Cancer
Historically, vaccines were developed against very severe infections with major morbidity and mortality from acute disease. As non-communicable diseases, including cancer, become the most frequent causes of death in industrialized countries and some developing countries, vaccines are being used to prevent these too, when the infectious agents are involved in carcinogenesis. Hepatitis B prevalence is high in regions of East Asia, sub-Saharan Africa, and the Pacific Islands. Chronic hepatitis B infection can lead to liver cirrhosis and hepatocellular carcinoma ( Bogler et al., 2018 ). Vertical transmission of hepatitis B is problematic as 70–90% of babies born to HbsAg and HbeAg positive mothers will become infected without prophylaxis administered to babies; with ∼90% of infants developing chronic hepatitis ( Borgia et al., 2012 ; Gentile and Borgia, 2014 ). The chronic hepatitis B carriage status of mothers is routinely checked at the start of pregnancy, in order to assess the need to vaccinate the infant after birth. The use of both hepatitis B vaccine, containing hepatitis B surface antigen, and immunoglobulin containing hepatitis B antibody can be used to minimize vertical transmission, with evidence from a 20-year-long study in Thailand demonstrating 100% prevention of transmission ( Poovorawan et al., 2011 ).
The sexually transmitted HPV is responsible for genital tract and oropharyngeal infections as a precursor to causing oncological disease affecting the cervix, vagina, vulva, penis, anal tract, and pharynx in both men and women. Cervical cancer is the fourth most common cancer globally, with 528,000 new cases annually and peak incidence in young women aged 25–34 years ( Ferlay et al., 2012 ). The HPV serotypes 16 and 18 carry a high-risk for cervical cancer ( Wang et al., 2018 ) and vaccination against these specific serotypes has been available since 2006 through bivalent (16 and 18), quadrivalent (6, 11, 16, and 18), and nonavalent (6, 11, 16, 18, 31, 33, 45, 52, 58) vaccines, which are now available to individuals from the age of 9 years ( Gupta et al., 2017 ). A vaccination program started in the United Kingdom in 2008, and at the time of writing over 10.5 million doses had been given to girls ( Public Health England, 2018 ), with the aim of preventing primary infection with HPV. The vaccine coverage was 83.8% for 13–14 year old girls in England in 2017/18 ( Public Health England, 2019 ). In July 2018, the vaccine was approved for use in boys ( Public Health England, 2019 ). After a decade of use, there has been an observed decline in the genital infections caused by serotypes 16 and 18 ( Public Health England, 2018 ), with further time needed to observe the fall in cervical cancer incidence. However, the incidence of pre-invasive cervical diseases has been reduced by 79–89% in Scottish women over 20 who were vaccinated with bivalent HPV vaccine when aged 12–13 years, with evidence of herd protection ( Palmer et al., 2019 ), offering a promising outlook for the reduction of cervical cancer in the future. An additional benefit of HPV vaccines, is their impact on neonatal morbidity and mortality, through the reduction in surgical treatment of cervical neoplasias, and the related preterm births and complications ( Soergel et al., 2012 ).
Preventing Antibiotic Resistance
The rise in antimicrobial resistance (AMR) is a universal threat. The use of antibiotics in humans, exposes the bacteria that reside in our microbiota to selection pressures resulting in the development of AMR. As the bacteria constituting the host microbiota are frequently responsible for invasive diseases such as: meningitis, pneumonia, urinary tract, or abdominal infections, the risk of developing infections that are difficult or eventually impossible to treat is fast becoming a reality ( Brinkac et al., 2017 ). In regions where resistant pathogens are circulating at high frequency, such as India or regions of Europe ( Logan and Weinstein, 2017 ), patients will be faced with choosing between having elective surgical procedures or chemotherapy for malignancy, and the risk of acquiring potentially untreatable, multi-drug resistant bacterial infections ( Liu et al., 2016 ). Vaccination is crucial in mitigating this risk, by preventing people from developing viral and bacterial infections in the first instance, and therefore reducing the antibiotic burden to which their microbiota are exposed. The development of AMR in bacteria is a cumulative process with frequent, repeated exposure to broad spectrum antibiotics as a major driver. Children and the elderly who are at particular risk of infection can benefit from vaccines against common primary and secondary infections such as: pneumonia (prevented by PCV, PPSV, influenza, and measles vaccines), OM (PCV, Hib, and measles vaccines), cellulitis secondary to VZV (VZV vaccine), and typhoid fever (typhoid vaccine) which alleviates the need for antibiotics being prescribed or bought ( Kyaw et al., 2006 ; Palmu et al., 2014 ). The extent to which vaccination contributes to antimicrobial stewardship was highlighted by its inclusion in vaccine cost-effectiveness analyses as part of national United Kingdom policy ( Bonanni et al., 2015 ).
Vaccines are highly beneficial on a population level and also cost-effective ( Shearley, 1999 ) in comparison to other public health interventions ( Bloom et al., 2005 ). Government departments are required to perform systematic economic analyses of vaccines and vaccine programs to justify their purchase in view of pressure on public and private finances globally, this was exacerbated by the 2008 financial crash. A vaccination program has clear direct costs including: vaccine purchase, infrastructure to run the program and maintain the cold chain, and healthcare/administration personnel. Governments, sometimes supported by charities and non-governmental organizations, invest in these with the intention of improving health. The reduction in morbidity and mortality associated with successful vaccine programs, through a combination of direct and indirect protection, has led to reduced incidence of diseases and their associated treatments and healthcare costs ( Deogaonkar et al., 2012 ). This potentially leads to economic growth, with less money spent owing to the costs averted through fewer medical tests, procedures, treatments and less time off work by patients/parents. Additionally, the use of combination vaccines e.g., DTaP/IPV/Hib/HepB provides protection against an increased number of diseases, with no additional infrastructure costs i.e. the same number of injections per child within existing immunization programs.
The cost-effectiveness analyses of vaccination programs demonstrate that they are overwhelmingly worth the investment, with most programs costing less than $50 per life gained, orders of magnitude less than prevention of diseases like hypertension ( Ehreth, 2003 ; Bloom et al., 2005 ). The returns on investment in vaccines, given their increasing provision through Gavi, have been estimated at 12–18% ( Bloom et al., 2005 ), but this is likely an underestimate. The monetary advantages of vaccination programs are important both to industrialized nations, such as the United States which obtains a net economic benefit of $69 billion, but also in 94 LMIC where investment of $34 billion, resulted in savings of $586 billion from the direct illness costs ( Ozawa et al., 2016 ; Orenstein and Ahmed, 2017 ). The net economic impact of eradication of disease has been estimated for both smallpox and polio. For smallpox, the eradication costs were over 100 million USD, but there are cost savings of 1.35 billion USD annually, with elimination of polio estimated to save 1.5 billion USD annually ( Barrett, 2004 ; Bloom et al., 2005 ). A less well-considered economic saving, not captured in cost-effectiveness or cost-benefit analyses, is from the prevention of long-term morbidity following acute infections ( Bloom et al., 2005 ), for example hearing impairment following pneumococcal meningitis or limb amputation following meningococcal disease, along with broader productivity gains ( Deogaonkar et al., 2012 ), which could have a major impact on LMIC adoption of vaccine programs.
The relationship between health and the economy is bidirectional, whereby economic growth enables funding in investments that improve health; and a healthy population contributes to and enhances an economy. These benefits of vaccinations and other public health interventions including sanitation, clean water, and antibiotics, are important for social as well as economic reasons. It has been suggested that the economic impact of vaccines should be considered more broadly than just the averted healthcare costs from prevented illness episodes and associated carer costs ( Deogaonkar et al., 2012 ; Barnighausen et al., 2014 ; Bonanni et al., 2015 ; Gessner et al., 2017 ; Wilder-Smith et al., 2017 ). Bärnighausen et al. (2011) , set out a framework to consider productivity gains measured by: outcome and behavior; community health and economic externalities; risk reduction; and health gains. Healthy children demonstrate improved educational attainment at school through better attendance and better cognitive performance ( Barham and Calimeria, 2008 ; Bloom et al., 2011 ; Deogaonkar et al., 2012 ). The impact of hearing loss from mumps, rubella or pneumococcal infections, or visual impairment from measles may require specific educational support, whereas the cognitive deficits from those childhood infections may require substantial remedial input. As more children survive to adulthood, a larger adult workforce is available, who when healthy can work for longer and more productively both physically and mentally ( Bloom and Canning, 2000 ; Bloom et al., 2005 ); though to date this has been observed largely following other health improvements, not vaccination specifically ( Jit et al., 2015 ). As a result of vaccination healthy and economically successful populations have lower fertility rates and smaller families ( Sah, 1991 ; Andre et al., 2008 ). With improved health and therefore life expectancy, there is a wider effect on families who may choose to invest more money in their future, for example to enhance their education or through savings ( Jit et al., 2015 ). Overall, vaccine programs should be viewed as an investment in human capital, providing enduring impact on economies worldwide.
Minimizing the Impact on Family
The economic impact of adult illness is evident from loss of productivity and pay for the duration of the illness and recovery period. The impact of childhood illness falls primarily on their adult carers, generally parents. In most industrialized regions, two-parent families are reliant on both parents undertaking at least part-time or full-time work. Therefore, when a child is unwell with childhood illnesses, which may or may not necessitate admission to hospital, the parent will invariably have to forego their paid employment to care for the child. In seven European countries one parent or carer required time off work in 39–91% of rotavirus gastroenteritis cases ( Van der Wielen et al., 2010 ). This loss of productivity in the parental workforce tends to disproportionately affect women, but loss of either parental attendance at work reduces overall employer productivity and in the short-term is rarely replaced. This argument was made for the impact of chicken pox on children, whereby the exclusion from school mandates parental caring at home for a period until the lesions are crusted over. VZV vaccines are estimated to have had a similar impact as rotavirus vaccine in United States studies ( Lieu et al., 1994 ). In many regions, mothers are still the primary carers, spending their days at home caring for children and maintaining the household; in these settings, the impact on this unpaid work is harder to determine.
It is of paramount importance to quantify and include productivity gains and the wider effects in analyses of impact for vaccines with only moderate efficacy, as calculated using traditional metrics. Vaccines such as the RTS,S/AS01 malaria vaccine, CYD-TDV dengue vaccine and rotavirus vaccine used in LMIC all have limited ability to broadly protect populations over a long duration but the public health benefits were important in vaccine implementation decisions in those countries ( Wilder-Smith et al., 2017 ). This suggests a paradigm for alternative regulatory requirements with a focus on public health outcomes ( Gessner et al., 2017 ).
Cost-Effective Preparedness for Outbreaks
As human populations grow and their use of the finite land resources increases, we are in increasingly close association with other living creatures, voluntarily or involuntarily. This interaction with natural reservoirs of potential infectious diseases increases the risk of zoonotic transmission of new infectious pathogens e.g., SARS, MERS-CoV, or known infectious pathogens with increased virulence e.g., influenza. Emerging infectious diseases disproportionately affect developing regions, where health infrastructure and surveillance are likely to be less well-established and robust. There were 1,307 epidemics of infectious diseases between 2011 and 2017, which cumulatively cost $60 billion annually to manage ( GHRF Commission, 2016 ). The unpredictability of outbreaks was highlighted by the Ebola epidemic in Western African countries of Liberia, Sierra Leone, and Guinea in 2014, which occurred in a period when public health was supposedly at its most advanced in recent history. However, a catalog of areas including: outbreak planning infrastructure; disease surveillance; local health services; escalation to international agencies were found to be lacking ( GHRF Commission, 2016 ). Although the WHO received criticism for its lack of escalation, in reality the global and interconnected infrastructure to prevent such epidemics taking lives and devastating societies is insufficient at the present time. The Zika virus epidemic in Latin America in 2015, first observed through an unexpectedly high incidence of microcephaly amongst newborns in Brazil’s northern regions ( Heukelbach et al., 2016 ), provide another example of how epidemics can have lasting impact, with the virus causing significant neurological damage to surviving infants ( Russo et al., 2017 ). The SARS-CoV-2 pandemic which began in 2019, was, at the time of writing, the largest infectious disease pandemic since the influenza pandemic of 1918/9. This global public health crisis highlighted stark societal inequalities persistent in many high-, middle- and low-income countries with direct and indirect impact on health outcomes from this infection. The cost-effectiveness of a vaccine in this setting was unquestionable, with economies and societies shut down for months in early 2020 and likely again in future. As it is not feasible or practical to be able to predict the location or nature of the next emerging threat, investment of an estimated $4.5 billion/year in healthcare systems could help speed up responses to infectious epidemics by prompt identification of the agent and effective control measures to limit the spread and consequences of disease ( GHRF Commission, 2016 ). The importance of this planning within the political landscape and the ongoing threat that infectious disease pose, may be appreciated more widely after 2020.
Establishing Programs for Vaccine Development
One effective infection control method is the use of vaccines in the course of an epidemic to halt transmission and to induce immunity to those as yet unaffected. The cost of vaccine development is a major challenge as there is little incentive for industry to invest in the design, testing and manufacture of vaccines that may never be needed, have a limited market, and, as previously eluded to, may be required in LMIC which cannot afford the upfront costs as an epidemic unfolds. The estimated costs for funding the development of infectious diseases vaccines for epidemics through phase 2a clinical trials are a minimum of $2.8-3.7 billion ( Gouglas et al., 2018 ). The CEPI alliance was established at the Davos World Economic Forum in 2017 as a global partnership between public, private and philanthropic organizations. In response to the conclusion that “a coordinated, international, and intergovernmental plan was needed to develop and deploy new vaccines to prevent future epidemics,” CEPI have identified the most important known global infectious threats and invested in the development of vaccines, stockpiling, and policies to allow equitable access to these ( Plotkin, 2017 ). Further, the establishment of research and development infrastructure pipelines will allow production of suitable vaccine candidates within 16 weeks of identification of a new pathogen antigen. The broader aims including: improving global epidemic responses; capacity building; and global regulation of outbreak management strategies are also within the remit of CEPI’s work. It is these types of preparedness plans that assisted vaccine development and global health collaborations to address the COVID-19 pandemic, though many regions of high-, middle-, and low-income countries alike were slow or resistant to pre-empt and prepare for this type of infectious disease threat.
Equity of healthcare.
As a result of the combined effects of poverty, malnutrition, poor hygiene and sanitation, overcrowding, discrimination and poorer access to health-care, the underprivileged in society are disproportionately afflicted by infectious diseases. Over the 20th century, it has become a moral standpoint and a human right for every individual to be provided with access to safe vaccines. The provision of vaccination as part of the EPI on a national and international scale ( World Health Assembly, 1974 ) acted as a great leveler to start reducing the impact of infectious diseases to all, regardless of other disadvantages. Over the 15 years of the EPI, the vaccine coverage in developing countries increased from 5% to ∼80% ( Levine and Robins-Browne, 2009 ). The EPI was revolutionary for its time, an ambitious public health program that aimed to improve children’s life chances despite the country and situation in which they were born. The administration of vaccines by UNICEF was deemed so important that there have been at least seven ceasefires in civil conflicts to allow this to happen ( Hotez, 2001 ).
The impact of vaccines on the inequity of those living in poverty is marked. A study of over 16,000 children during the phased introduction of the measles vaccine in Bangladesh in 1982, demonstrated improved health outcome equity when measured by under-5 mortality ( Bishai et al., 2003 ). Further, modeling of the impact of the rotavirus vaccine in India across social strata, which are closely aligned to wealth, suggested that the vaccine program would provide the poor with both health and financial benefits ( Verguet et al., 2013 ). Including such equity impact in the health economic modeling of vaccines would allow policy decisions to be targeted to the most vulnerable in society ( Riumallo-Herl et al., 2018 ). Additional cost-effective benefits observed after the implementation of combined public health initiatives ( Deogaonkar et al., 2012 ; Gessner et al., 2017 ) include provision of vaccines, facilitation of healthcare, reduction of indoor air pollution and improvement of nutrition to prevent childhood pneumonia ( Niessen et al., 2009 ).
Strengthening Health and Social Care Infrastructure
To provide the EPI universally to infants and children, a significant degree of healthcare infrastructure is required ranging from primary care to public health. An example of the multiple facets of a successful vaccine program were outlined in the Mission Indradhanush in India, which planned to make life-saving vaccines available to all children and pregnant women by 2020 through programs with (i) national, (ii) state, (iii) district, and (iv) block/urban level input ( Hinman and McKinlay, 2015 ). National programs require governments to provide financial resources and set out policy for implementation. States needed to obtain the vaccines and to store them appropriately whilst eligible children were identified through public health messaging and outreach. Districts and urban areas recruited staff trained in vaccine delivery and communication to administer vaccines and to provide the aftercare where required. Establishing this degree of nationwide infrastructure to reach those in urban and rural areas, provides the basis for the provision of other health and social care services for all members of the community, in particular improving maternal and infant mortality in developing regions and in the elderly in industrialized regions ( Shearley, 1999 ). Public health infrastructure and personnel could be used to promote other important messages and health education ( Shearley, 1999 ), relating to malnutrition, hygiene and sanitation and preventable diseases such as malaria and HIV infection. Global drivers are also key, as demonstrated by the establishment of the EPI in 1974, when all countries were directed to provide these vaccines, thereby developing their primary- and public health-care infrastructure, with benefit beyond the vaccine program. Vaccination contributes to the UN Millennium Development Goals and later Sustainable Development Goals for achievement by 2030. Gavi, the Vaccine Alliance, has been an important provider of funds, vaccines and support for countries whose gross national income per capita was <£1000/year ( Hinman and McKinlay, 2015 ). The partnerships forged through the development of vaccine programs in LMIC, can be long-lasting and beneficial through other health and social care endeavors ( Shearley, 1999 ).
Impact of Life Expectancy and Opportunity
Vaccination programs provide a degree of social mobility, as poverty and the associated ill-health and mortality from infectious diseases are no longer the determinants of one’s life chances. Vaccine recipients have the potential for improved life-expectancy largely demonstrated by, but not confined to, infants and children ( Andre et al., 2008 ). It has become increasingly recognized that an aging population goes through the process of immunosenescence ( Fulop et al., 2017 ), and increased incidence and severity of infectious diseases. In many countries, therefore, older people are offered vaccines to prevent infections with high mortality and morbidity, including the influenza, pneumococcal, herpes zoster, and pertussis vaccines ( Bonanni et al., 2015 ). These prevent the development of pneumonia, admission to hospital and the subsequent associated risks of death from cardiac failure, as observed in Sweden ( Christenson et al., 2004 ).
The global and interconnected world of the 21st century provides opportunity to discover new cultures, new environments and their resident microbes. The safety of global travel has been greatly enhanced by the availability of vaccines that provide protection against organisms that are different to those in a person’s home setting. Movement of people may be through necessity when fleeing war and conflict, in the search of better life opportunities, or for leisure purposes. For mass movements of refugees vaccines are crucial to the aid and relief efforts to support these individuals ( Hermans et al., 2017 ), as measles and cholera can be highly problematic in refugee camps. Global mass cultural or religious gatherings, such as the Hajj pilgrimage ( Yezli et al., 2018 ) or the Chinese New Year ( Chen et al., 2018 ) have been implicated in the spread of meningococcal disease outbreaks. Pre-travel vaccines offer the optimal level of protection for those with scheduled travel plans and include protection against: yellow fever, hepatitis A and B, rabies, Japanese encephalitis, tick-borne encephalitis, typhoid, and cholera.
Empowerment of Women
The empowerment of women is both a driver and effect of vaccination programs. The degree of education, literacy and independence of girls and women varies considerably across the world and within countries. Where women have the information and autonomy to make health-related decision for their children, childhood immunization rates improve. In a study in Bihar State in rural India involving an empowerment program, where participating women were educated about health and hygiene, there was a higher rate of DTP, measles and BCG vaccination in their children compared to the non-participants in the villages running the program ( Janssens, 2011 ). Further, this information and autonomy served to improve the rates of vaccination in children of non-participants in the villages running the program compared to control villages not running the education program, through social or formal ongoing dialogue within the village community. A separate public health initiative in Haryana, India conducted between 2005 and 2012 to reduce maternal and child health inequalities, involved improving access and provision of health resources to rural areas, the poor in society, women and children. One significant outcome of this initiative was the equitable provision of immunizations to girls and boys, despite the male-favored disparity prior to starting the public health initiative ( Gupta et al., 2016 ).
By improving infant and childhood mortality from infection, more children will survive to adulthood with the potential to have productive and healthy lives. This has led to healthy and economically secure women having fewer children and less peripartum morbidity and mortality ( Sah, 1991 ; Shearley, 1999 ). Thus, women are able to spend more time with their children and on their development ( Shearley, 1999 ) as well as their own education and contribution to the workforce. The strategy of maternal vaccination has demonstrated great success at preventing diseases that afflict infants too young to be vaccinated against pertussis, influenza and tetanus ( Marchant et al., 2017 ). Factors influencing the uptake of maternal vaccination include women’s previous experiences with healthcare and vaccines, so it is crucial to provide the access and support required to enable them to make informed choices during their pregnancy ( Wilson et al., 2019 ).
The impact of vaccines is broad and far-reaching, though not consistently quantifiable, analyzed or communicated. Traditionally, the perceived benefits of vaccination were to reduce morbidity and mortality from infections, and those remain the drivers for the innovation of new vaccines, in particular in preparation for outbreaks or against infections that afflict the most disadvantaged in society. However, an increasing appreciation for the economic and social effects of vaccines is being included in the development and assessment of vaccine programs, potentially realizing a greater benefit to society and resulting in wider implementation. There remain challenges to delivering vaccines to all children and vulnerable people worldwide, in particular those in communities that are difficult to reach geographically, politically and culturally and these challenges can only be overcome with the continued commitment and dedication to this endeavor on an international, national and individual scale.
SP conceptualized and designed the study. CR prepared the manuscript and figures. CR and SP contributed to literature search and revision and review of the final manuscript. Both authors contributed to the article and approved the submitted version.
Conflict of Interest
SP consults for many major vaccine manufacturers and biotechnology companies but this article was unfunded.
The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Keywords : immunization, vaccines, infectious diseases, infection, children, health economics
Citation: Rodrigues CMC and Plotkin SA (2020) Impact of Vaccines; Health, Economic and Social Perspectives. Front. Microbiol. 11:1526. doi: 10.3389/fmicb.2020.01526
Received: 09 April 2020; Accepted: 12 June 2020; Published: 14 July 2020.
Copyright © 2020 Rodrigues and Plotkin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Stanley A. Plotkin, [email protected]
This article is part of the Research Topic
Old And New Challenges In The Development Of Vaccines To Protect Against Infectious Diseases
Vaccine Safety Publications
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CDC’s Immunization Safety Office monitors the safety of licensed and authorized vaccines and conducts high-quality vaccine safety research. This research is peer-reviewed and published in reputable scientific outlets.
The vaccine safety articles and studies listed on this page include a full citation, a short summary, and a link to the free PMC article, when available.
- Vaccine Adverse Event Reporting System (VAERS)
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Shimabukuro T, Nair N. Allergic Reactions Including Anaphylaxis After Receipt of the First Dose of Pfizer-BioNTech COVID-19 Vaccine JAMA 2021 Feb 23;325(8):780-781 doi: 10.1001/jama.2021.0600.
Pfizer-BioNTech COVID-19 vaccine was authorized by the Food and Drug Administration (FDA) for emergency use in December 2020. CDC and FDA immediately began safety monitoring in the Vaccine Adverse Event Reporting System (VAERS). One health outcome in particular that CDC and FDA monitored for was severe allergic reaction, or anaphylaxis. From December 14–23, 2020, 1.89 million first doses of Pfizer-BioNTech COVID-19 vaccine were administered. The most commonly reported non-anaphylaxis allergic reactions included: rash, itchy skin, itchy and scratchy sensations in the throat, and mild respiratory symptoms. Safety monitoring identified 21 anaphylaxis reports, corresponding to an estimated rate of 11.1 cases per million doses administered; 17 (81% ) had a history of allergies or allergic reactions. No deaths from anaphylaxis were reported. CDC has guidance on the use of mRNA COVID-19 vaccines and management of anaphylaxis.
Shimabukuro T, Cole M, Su JR. Reports of Anaphylaxis After Receipt of mRNA COVID-19 Vaccines in the US—December 14, 2020-January 18, 2021. JAMA 2021 Feb 12; doi:10.1001/jama.2021.1967. Epub ahead of print.
In December 2020, FDA issued Emergency Use Authorizations for two mRNA-based vaccines for prevention of COVID-19 disease: Pfizer-BioNTech COVID-19 vaccine (December 11) and Moderna COVID-19 vaccine (December 18). After implementation of the vaccines, cases of anaphylaxis following both vaccines were reported. Anaphylaxis is a severe, life-threatening allergic reaction that can occur after vaccination. During December 14, 2020 through January 18, 2021, over 9.9 million doses of Pfizer-BioNTech vaccine and over 7.5 million doses of Moderna vaccine were administered. In this same time, CDC identified 66 anaphylaxis cases reported to VAERS: 47 following Pfizer-BioNTech vaccine (rate of 4.7 cases per million doses) and 19 following Moderna vaccine (rate of 2.5 cases per million doses). There were no deaths from anaphylaxis reported after either vaccine. Continued safety monitoring of mRNA COVID-19 vaccines has confirmed anaphylaxis following vaccination is a rare event.
CDC COVID-19 Response Team Allergic Reactions Including Anaphylaxis After Receipt of the First Dose of Moderna COVID-19 Vaccine— United States, December 21, 2020-January 10, 2021 MMWR Morb Mortal Wkly Rep. 2021 Jan 22:70(4);125-129.
On December 18, 2020, FDA issued an Emergency Use Authorization for Moderna COVID-19 vaccine to prevent COVID-19. As of January 10, 2021, over 4 million first doses of the vaccine had been administered. Many people did not have any side effects after COVID-19 vaccination. However, some serious adverse reactions were reported, such as the life-threatening allergic reaction, anaphylaxis. From December 21, 20201 through January 10, 2021, VAERS received 108 reports following Moderna vaccine identified as possible allergic reaction, including anaphylaxis. Through case review of medical reports, 10 cases were determined to be anaphylaxis (a rate of 2.5 cases of anaphylaxis per million doses). Of the 10 cases, 9 had a history of allergies or allergic reaction, including 5 who had a history of anaphylaxis. Anaphylaxis following Moderna vaccine appears to be a rare event. CDC and FDA will continue to monitor for anaphylaxis following COVID-19 vaccines.
CDC COVID-19 Response Team Allergic Reactions Including Anaphylaxis After Receipt of the First Dose of Pfizer-BioNTech COVID-19 Vaccine — United States, December 14-23, 2020 MMWR Morb Mortal Wkly Rep. 2021 Jan 15:70(2);46-51.
On December 11, 2020, FDA issued an Emergency Use Authorization for Pfizer-BioNTech COVID-19 vaccine to prevent COVID-19. As of December 23, 2020, over 1.8 million first doses of the vaccine had been administered. During this time, CDC and FDA were notified through multiple channels of suspected cases of anaphylaxis following vaccination. Anaphylaxis is a severe, life-threatening allergic reaction that occurs rarely after vaccination. From December 14-23, 2020, VAERS received 175 reports identified as possible allergic reaction, including anaphylaxis. Through case review of medical reports, 21 cases were determined to be anaphylaxis (a rate of 11.1 cases of anaphylaxis per million doses). Most anaphylaxis cases (81%) occurred in persons with a history of allergies or allergic reactions. Anaphylaxis following Pfizer-BioNTech vaccine appears to be a rare event. CDC and FDA will continue to monitor for anaphylaxis following COVID-19 vaccines.
Tompkins LK, Baggs J, Myers TR, Gee JM, Marquez PL, Kennedy SB, Peake D, Dua D, Hause AM, Strid P, Abara W, Rossetti R, Shimabukuro TT, Shay DK. Association between history of SARS-CoV-2 infection and severe systemic adverse events after mRNA COVID-19 vaccination among U.S. adults . Vaccine . 2022 Nov 1;S0264-410X(22)01342-1. Online ahead of print.
This study, published in December 2022, found that after receiving the first of two doses of an mRNA COVID-19 vaccine, patients who had previously tested positive for COVID-19 were somewhat more likely to have a severe systemic reaction to the vaccine compared to those who had not had COVID-19 previously. Though these reactions were rare, people who received the Moderna vaccine had a slightly higher risk of complications compared to participants who received the Pfizer-BioNTech vaccine. The study reviewed data from patients 18 years of age and older who had received a COVID-19 vaccination within the previous seven days and registered on CDC’s V-safe. V-safe is a web-based tool that uses text messages, emails, and web surveys to provide personalized health check-ins for people after receiving a new vaccine.
Tartof SY, Malden DE, Liu ILA, Sy LS, Lewin BJ, Williams JTB, Hambidge SJ, Alpern JD, Daley MF, Nelson JC, McClure D, Zerbo O, Henninger ML, Fuller C, Weintraub E, Saydeh S, Qian L. Health Care Utilization in the 6 Months Following SARS-CoV-2 Infection . JAMA Network . 2022 Aug 12 ;5(8):e2225657. doi:10.1001/jamanetworkopen.2022.25657.
This August 2022 publication presents a study on healthcare use in the six months immediately following COVID-19 infection. Data from the Vaccine Safety Datalink found that COVID-19 infections led to a 4% increase in healthcare use that included a mix of virtual encounters and emergency department visits. This increase shows the potential excess strain on the healthcare system and provides insight into long-term resource planning for patients who were previously infected with COVID-19.
Twentyman E, Wallace M, Roper LE, Anderson TC, Rubis AB, Fleming-Dutra KE, Hall E, Hsu J, Rosenblum HG, Godfrey M, Archer WR, Moulia DL, Daniel L, Brooks O, Talbot HK, Lee GM, Bell BP, Daley M, Meyer S, Oliver SE. Interim Recommendation of the Advisory Committee on Immunization Practices for Use of the Novavax COVID-19 Vaccine in Persons Aged ≥18 years — United States, July 2022 . MMWR Morb Mortal Wkly Rep . 2022 Aug 5;71(31);988–992.
The U.S. Food and Drug Administration issued an Emergency Use Authorization for the Novavax COVID-19 vaccine on July 13, 2022. On July 19, 2022, the Advisory Committee on Immunization Practices (ACIP) made recommendations for the use of the Novavax vaccine in adults ages 18 years and older as a primary series. Since June 2020, ACIP has reviewed data related to COVID-19 and the use of COVID-19 vaccines, including the Novavax vaccine. Data were used from a randomized double blind clinical trial based in the United States and Mexico that enrolled 29,945 participants ages 18 years and older during December 27, 2020, through September 27, 2021. Participants were given doses of either the Novavax vaccine or a saline placebo. Results showed the effectiveness of the Novavax vaccine in adults ages 18 years and older. Additional data sources from the United Kingdom, South Africa, and Australia were considered when looking at the benefits and risks of the Novavax vaccine. Novavax COVID-19 vaccine is an additional option for unvaccinated adults, increasing flexibility for the public and for vaccine providers to prevent severe COVID-19 illness.
Hause AM, Baggs J, Marquez P, Abara WE, Baumblatt J, Blanc PG, Su JR, Hugueley B, Parker C, Myers TR, Gee J, Shimabukuro TT, Shay DK. Safety Monitoring of COVID-19 mRNA Vaccine Second Booster Doses Among Adults Aged ≥50 Years — United States, March 29, 2022–July 10, 2022 . MMWR Morb Mortal Wkly Rep . 2022 Jul 29;71(30);971–976.
This analysis, published July 2022, reviewed vaccine safety data from V-safe and the Vaccine Adverse Event Reporting System after receipt of a second COVID-19 mRNA (Pfizer-BioNTech or Moderna) booster dose among adults ages 50 years and older from March 29–July 10, 2022. Vaccine safety experts identified no new safety concerns following the second mRNA booster dose in this age group. Local (itching, pain, redness, and/or swelling at the injection site) and systemic (fever, headache, joint pain) reactions were observed, and serious adverse events were rare. These findings are consistent with known adverse events after receipt of first booster doses and with the existing body of evidence that mRNA COVID-19 vaccines are safe.
Hause AM, Zhang B, Yue X, Marquez P, Myers TR, Parker C, Gee J, Su J, Shimabukuro TT, Shay DK. Reactogenicity of Simultaneous COVID-19 mRNA Booster and Influenza Vaccination in the US. . JAMA Netw Open . 2022 Jul 1;5(7):e2222241. doi: 10.1001/jamanetworkopen.2022.22241.
A review of vaccine safety data from September 22, 2021, through January 16, 2022, looked at reported reactions following vaccination with both influenza (flu) and an mRNA-based COVID-19 booster dose (third dose administered ≥ 5 months after second dose) during the same healthcare visit. The review found that people who received a booster and flu vaccine simultaneously were slightly more likely to report systemic reactions (i.e., headache, fatigue, and muscle pain) than people who received just the COVID-19 booster. Data were collected and reviewed from V-safe, a web-based tool that uses text messages, emails, and web surveys to provide personalized health check-ins for people after receiving a new vaccine.
Hanson KE, Goddard K, Lewis N, Fireman B, Myers TR, Bakshi N, Weintraub E, Donahue JG, Nelson JC, Xu S, Glanz JM, Williams JTB, Alpern JD, Klein NP. Incidence of Guillain-Barré Syndrome After COVID-19 Vaccination in the Vaccine Safety Datalink. . JAMA Netw Open . 2022 Apr 26; 5(4):e228879. doi: 10.1001/jamanetworkopen.2022.8879.
Post-authorization monitoring of COVID-19 vaccines in large populations may detect rare adverse events (AEs) that were not identified during clinical trials, such as Guillain-Barré syndrome (GBS). This cohort study, published April 2022, was conducted to look at data from the Vaccine Safety Datalink during December 13, 2020, through November 13, 2021, to assess the risk of GBS after COVID-19 vaccination with J&J/Janssen and mRNA (Pfizer-BioNTech or Moderna) vaccines. Data from 10,158,003 COVID-19 vaccine recipients who were at least aged 12 years were analyzed. The study found that cases of GBS were higher among those who received the J&J/Janssen vaccine, which is no longer used in the United States as of May 2023.
Xu S, Hong V, Sy LS, Glenn SC, Ryan DS, Morrissette KL, Nelson JC, Hambidge SJ, Crane B, Zerbo O, DeSilva MB, Glanz JM, Donahue JG, Lile E, Duffy J, Qian L. Changes in incidence rates of outcomes of interest in vaccine safety studies during the COVID-19 pandemic . Vaccine . 2022 April 18;S0264-410X922)00464-9. Online ahead of print.
The COVID-19 pandemic led to increased use of telehealth. Moving from in-person care to telehealth made it harder to identify outcomes in vaccine safety studies that are normally assessed during in-person health visits. Data from eight Vaccine Safety Datalink sites between January 1, 2017, and December 31, 2020, were used to determine changes in incidence rates for 21 outcomes that are traditionally assessed in in-person settings. The study, published May 2022, found that rates of some clinical outcomes changed during the pandemic and should not be used as background rates in vaccine safety studies. Data from 2020 were split into four periods: pre- to early pandemic (January–June), middle (July–September), and later pandemic (October–December). Four corresponding time periods (ranges of months) were used for each year during 2017–2019. Results showed that incidence rates for encephalomyelitis, encephalitis/myelitis/encephalomyelitis/meningoencephalitis, and thrombotic thrombocytopenic purpura cases did not change significantly during 2020. Incidence rates of acute myocardial infarction, anaphylaxis, appendicitis, convulsions/seizures, Guillain-Barré syndrome, immune thrombocytopenia (ITP), narcolepsy/cataplexy, hemorrhagic stroke, ischemic stroke, and venous thromboembolism decreased, and incidence rates of Bell’s palsy, ITP, and narcolepsy/cataplexy were higher. The higher incidence rates of these conditions suggest that telehealth visits should be considered for vaccine studies involving Bell’s palsy, ITP, and narcolepsy/cataplexy.
Kenigsberg TA, Hause AM, McNeil MM, Nelson JC, Shoup JA, Goddard K, Lou Y, Hanson KE, Glenn SC, Weintraub E. Dashboard development for near real-time visualization of COVID-19 vaccine safety surveillance data in the Vaccine Safety Datalink . Vaccine . 2022 May 1;40(22):3064-3071. Epub 2022 Apr 8.
The Vaccine Safety Datalink (VSD) conducts vaccine safety monitoring and vaccine safety research studies. When COVID-19 vaccinations began in the U.S. in December 2020, VSD helped with near real-time safety surveillance. Investigators developed a dashboard to show data metrics on vaccine safety. Dashboard visualizations provide situational awareness on vaccination coverage and the status of safety analysis. This May 2022 report describes the development and implementation of the COVID-19 Vaccine Dashboard, including metrics used to develop the dashboard, which may have application across various public health settings.
Rosenblum HG, Gee JM, Liu R, Marquez PL, Zhang B, Strid P, Abara WE, McNeil MM, Myers TR, Hause AM, Su JR, Baer B, Menschik D, Markowitz LE, Shimabukuro TT, Shay DK. Safety monitoring of mRNA vaccines administered during the initial 6 months of the US COVID-19 vaccination programme: an observational study of reports to Vaccine Adverse Events Reporting System and v-safe Lancet Infect Dis .2022 Mar 7;S1473-3099(22)0054-8. Online ahead of print.
In December 2020, two mRNA COVID-19 vaccines were authorized for emergency use in the United States. Clinical trials showed these vaccines to be safe, and post-authorization monitoring is necessary to evaluate their safety in larger and diverse populations. VAERS and v-safe are two national systems CDC uses to monitor COVID-19 vaccine safety. During the first six months of the COVID-19 vaccination program (December 14, 2020 through June 14, 2021) over 298 million doses of mRNA vaccines were administered in the U.S. In that period, over 7.9 million people enrolled in v-safe. Local (pain, redness, swelling at injection site) and systemic (fever, fatigue, and headache) reactions were reported more frequently following dose 2 compared to dose 1. The majority of symptoms were reported as mild, peaked on day 1 following vaccination, and were short-lived. Of the 340,000 adverse event reports to VAERS, the majority (92%) were classified as non-serious (similar to the local and systemic reactions reported to v-safe); 6.6% serious, non-death; 1.3% deaths. An in-depth review of reports of death found rates of death reported to VAERS were lower than expected background rates by age group. This analysis reinforces the safety of COVID-19 vaccines.
Hause AM, Bags J, Myers TR, Su JR, Blanc PG, Girwa Baumblatt JA, Woo EJ, Gee J, Shimabukuro TT, Shay DK. Safety Monitoring of COVID-19 Vaccine Booster Doses Among Adults — United States, September 22, 2021-February 6, 2022 MMWR Morb Mortal Wkly Rep 2022 Feb 11;71. Early Release.
In this February 2022 report, CDC reviewed the safety of a third dose of mRNA COVID-19 vaccine administered ≥ 5 months after the second dose. Safety data on adults ages 18 and older from V-safe and the Vaccine Adverse Event Reporting System showed no unexpected patterns of adverse events and found that for people who received the same mRNA COVID-19 vaccine for dose 3 as they received for doses 1 and 2, local and systemic reactions (such as pain, fatigue, and headache) were less frequently reported after dose 3 than after dose 2. Myocarditis was rarely reported following mRNA COVID-19 vaccine dose 3.
Oliver SE, Wallace M, See I, Mbaeyi S, Godfrey M, Hadler SC, Jatlaoui TC, Twentyman E, Hughes MM, Rao AK, Fiore A, Su JR, Broder KR, Shimabukuro T, Lale A, Shay DK, Markowitz LE, Wharton M, Bell BP, Brooks O, McNally V, Lee GM, Talbot HK, Daley MF. Use of the Janssen (Johnson & Johnson) COVID-19 Vaccine: Updated Interim Recommendations from the Advisory Committee on Immunization Practices – United States, December 2021. Morb Mortal Wkly Rep. 2022 Jan 20;71(3):90-95.
After a thorough review of available vaccine safety and effectiveness data during an emergency meeting in December 2021, the Advisory Committee on Immunization Practices (ACIP) recommended preferential use of mRNA COVID-19 vaccines (Pfizer-BioNTech/Comirnaty and Moderna) over the viral vector COVID-19 vaccine (Johnson & Johnson’s Janssen) for everyone ages 18 years and older in the U.S. CDC endorsed the committee’s decision and updated its recommendations for the prevention of COVID-19, stating a preference for mRNA COVID-19 vaccines over viral vector COVID-19 vaccines, if they are available. The mRNA COVID-19 vaccines are preferred over the viral vector COVID-19 vaccine for primary and booster vaccination. Since the January 2022 publication of this report, the J&J/Janssen COVID-19 vaccine is no longer available for use in the U.S.
Moro PL, McNeil MM. Successes of the CDC monitoring systems in evaluating post-authorization safety of COVID-19 vaccines [Editorial] . Expert Rev Vaccines. 2022 Mar;21(3):284-284. Epub 2022 Jan 5.
The U.S. Food and Drug Administration authorized the first two mRNA COVID-19 vaccines, Pfizer-BioNTech and Moderna, in mid-December 2020, along with the Johnson & Johnson Janssen (J&J/Janssen) vaccine at the end of February 2021, for emergency use in the United States. During pre-emergency use of these vaccines, adverse events consisted of local and systemic reactions. CDC uses three systems to monitor the safety of each of these COVID-19 vaccines in the United States: the Vaccine Adverse Event Reporting System, V-safe, and the Vaccine Safety Datalink. In addition to monitoring the safety of COVID-19 vaccines, these systems provide early safety data for very rare and serious adverse events of anaphylaxis, TTS, myocarditis/pericarditis, and Guillain-Barre syndrome—giving updated information for healthcare providers and vaccine recipients. These are complementary systems that continue to provide critical data about the safety of COVID-19 vaccines. Since the publication of this report, the J&J/Janssen COVID-19 vaccine is no longer available for use in the United States.
Lipkind HS, Vazquez-Benitez G, DeSilva M, Vesco KK, Ackerman-Banks C, Zhu J, Boyce TG, Daley MF, Fuller CC, Getahun D, Irving SA, Jackson LA, Williams JTB, Zerbo O, McNeil MM, Olson CK, Weintraub E, Kharbanda KO. Receipt of COVID-19 Vaccine During Pregnancy and Preterm or Small-for-Gestational-Age at Birth — Eight Integrated Health Care Orgnizations, United States, December 15, 2020-July 22, 2021. MMWR Morb Mort Wkly Rep. 2022 Jan 4:71 Early release.
Pregnant people with COVID-19 are at higher risk for severe illness and adverse birth outcomes such as pre-term and small-for-gestational-age birth, yet many remain reluctant to be vaccinated. COVID-19 vaccines are recommended for pregnant people to prevent maternal morbidity and adverse birth outcomes. This study, published January 2022, analyzed the risk for severe morbidity associated with COVID-19 in pregnancy, along with risk for pre-term birth or small-for-gestational-age at birth babies. Results show that receiving a COVID-19 vaccine during pregnancy was not linked with increased risk for pre-term birth or small-for-gestational-age birth. Risk for severe morbidity associated with COVID-19 disease in pregnancy was low; however, people with symptomatic COVID-19 during pregnancy were at increased risk for intensive care admission, with a 70% increased risk for death, compared with non-pregnant people with symptomatic infections. Results confirm the recommendations and benefits of receiving the COVID-19 vaccine during pregnancy.
Abara WE, Gee J, Mu Y, Deloray M, Ye T, Shay DK, Shimabukuro T. Expected Rates of Select Adverse Events following Immunization for COVID-19 Vaccine Safety Monitoring J Infect Dis. 2021 Dec 27;jiab628. Online ahead of print.
Chapin-Bardales J, Myers T, Gee J, Shay DK, Marquez P, Baggs J, Zhang B, Licata C, Shimabukuro TT. Reactogenicity within 2 weeks after mRNA COVID-19 vaccines: Findings from the CDC v-safe surveillance system. Vaccine 2021 Nov 26;39(48):7066-7073. Epub 2021 Oct 16.
In this review of v-safe vaccine safety data, researchers analyzed surveys of people who received their mRNA vaccine from December 14, 2020, through March 14, 2021. V-safe is a vaccine safety monitoring system that uses text messages and web surveys to collect information on health impacts reported after receipt of COVID-19 vaccines. During this time period, more than 4.7 million participants received one dose of an mRNA vaccine (Pfizer-BioNTech or Moderna), and over 2.9 million received a second dose. Most participants reported either a local reaction at the injection site (68.5% after dose 1; 72.9% after dose 2) or a systemic reaction, such as fever, headache, muscle ache and fatigue (50.6% after dose 1; 69.5% after dose 2). Researchers found that these side effects were reported more frequently among those who received Moderna than those who received Pfizer-BioNTech. An analysis of surveys reported on day 14 after vaccination indicated that new or worsening local and systemic reactions were uncommon during the second week following both dose 1 and dose 2. CDC will continue to closely monitor the safety of COVID-19 vaccines.
Hause AM, Baggs J, Gee J, Marquez P, Myers TR, Shimabukuro TT, Shay DK. Safety Monitoring of an Additional Dose of COVID-19 Vaccine — United States, August 12-September 19, 2021 MMWR Morb Mortal Wkly Rep. epub 2021 Sep 28.
On August 12, 2021, the Food and Drug Administration (FDA) expanded the Emergency Use Authorizations for Pfizer-BioNTech and Moderna (mRNA) COVID-19 vaccines to include an additional dose following the 2-dose vaccination series to those with compromised immune systems. From August 12 through September 19, over 22,000 v-safe enrollees reported an additional COVID-19 dose after completing the primary 2-dose mRNA vaccination series, most with the same vaccine. Among those who completed surveys for all 3 doses, local reactions (like pain or swelling where the shot was given) were reported slightly more after dose 3 compared with after dose 2 (79% vs. 78%), while reported systemic reactions (tiredness, headache) were slightly less common after dose 3 (74% vs. 77%). These side effects were mostly mild to moderate and short-lived. These findings did not show unexpected patterns of adverse events following an additional dose of COVID-19 vaccines. CDC will continue to monitor the safety of additional doses of COVID-19 vaccines and provide data to guide recommendations and protect the public’s health.
Klein NP, Lewis N, Goddard K, Fireman B, Zerbo Q, Hanson KE, Donahue JG, Kharbanda EO, Naleway A, Clark Nelson J, Xu S, Yih WK, Glanz JM, Williams JTB, Hambridge SJ, Lewin BJ, Shimabukuro TT, DeStefano F, Weintraub ES. Surveillance for Adverse Events After COVID-19 mRNA Vaccination JAMA 2021 Sept 3. Doi:10.1001/jama.2021.15072.
The Vaccine Safety Datalink (VSD) has conducted weekly near real-time monitoring, or Rapid Cycle Analysis (RCA), of Pfizer-BioNTech and Moderna mRNA COVID-19 vaccines since those vaccines received emergency use authorization from the Food and Drug Administration in December 2020. Between December 14, 2020 through June 25, 2021, over 11.8 million doses of mRNA were administered to 6.2 million people in the VSD network; 57% received Pfizer-BioNTech and 43% received Moderna. During that time period, VSD monitored 23 pre-specified health outcomes, including myocarditis/pericarditis and anaphylaxis. Researchers identified 34 cases of myocarditis/pericarditis in people ages 12 to 39 years; a majority (85%) were males. Among this age group, there is an increased risk of 6.3 additional myocarditis cases per million mRNA vaccinations administered in the first week following vaccination. The rate of anaphylaxis following vaccination was 4.8 cases per million doses of Pfizer-BioNTech and 5.1 per million doses of Moderna vaccination. VSD monitoring did not detect safety signals for any other pre-specified outcomes. Additional research is ongoing. Getting vaccinated remains the best way to protect against COVID-19 infection.
Rosenblum HG, Hadler SC, Moulia D, Shimabukuro TT, Su JR, Tepper NK, Ess KC, Woo EJ, Mba-Jonas A, Alimchandani M, Nair N, Klein NP, Hanson KE, Markowitz LE, Wharton M, McNally VV, Romero JR, Talbot K, Lee GM, Daley MF, Mbaeyi SA, Oliver SE. Use of COVID-19 Vaccines After Reports of Adverse Events Among Adult Recipients of Janssen (Johnson & Johnson) and mRNA COVID-19 Vaccines (Pfizer-BioNTech and Moderna): Update from the Advisory Committee on Immunization Practices — United States, July 2021 MMWR Morb Mortal Wkly Rep. 2021 Aug 10.
On July 22, 2021, CDC’s Advisory Committee on Immunization Practices (ACIP) reviewed a benefit-risk analysis of Guillain-Barré syndrome (GBS) following Johnson & Johnson’s Janssen (J&J/Janssen) vaccine, as well as the latest information on thrombosis with thrombocytopenia syndrome (TTS) following J&J/Janssen vaccination and myocarditis following mRNA vaccination (Pfizer-BioNTech and Moderna vaccines). As of June 30, 2021, about 12.6 million doses of Janssen vaccine had been administered and 141 million 2nd mRNA vaccine doses had been administered. Overall, there were 7.8 cases of GBS per million J&J/Janssen doses; 3 cases of TTS per million J&J/Janssen doses and 3.5 cases of myocarditis per million 2nd mRNA vaccine doses. After assessing the data, ACIP concluded that the benefits of COVID-19 vaccination in preventing COVID-19 illness, associated hospitalizations, ICU admissions, and death outweigh serious but rare risks of GBS, TTS, and myocarditis.
Pingali C, Meghani M, Razzaghi H, , Lamias MJ, Weintraub E, Kenigsberg TA, Klein NP, Lewis N, Fireman B, Zerbo O, Bartlett J, Goddard K, Donahue J, Hanson K, Naleway A, Kharbanda EO, Yih K, Clark Nelson J, Lewin BJ, Williams JTB, Glanz JM, Singletom JA, Patel SA. COVID-19 Vaccination Coverage Among Insured Persons Aged ≥ 16 years, by Race/Ethnicity and Other Selected Characteristics — Eight Integrated Health Care Organizations, United States, December 14, 2020-May 15, 2021 . MMWR Morb Mortal Wkly Rep. 2021 Jul 16;70(28):985-990.
Data has shown that non-Hispanic Black and Hispanic people have experienced higher COVID-19–associated deaths and serious outcomes; however, COVID-19 vaccination coverage has been lower in these groups. To look into these disparities further, researchers from CDC analyzed data collected from the Vaccine Safety Datalink (VSD) from December 14, 2020, through May 15, 2021. During that time, over 9.6 million people ages 16 years and older were enrolled in the VSD; 48.3% of the population had received at least one vaccine dose and 38.3% were considered fully vaccinated. In non-Hispanic Black and Hispanic populations, only 40.7% and 41.1% had received at least one COVID-19 vaccine dose, respectively. By comparison, non-Hispanic White people and non-Hispanic Asian people had higher coverage rates (54.6% and 57.4%, respectively). CDC will continue its ongoing efforts to improve vaccination coverage in all populations, especially among populations that are most greatly affected by COVID-19.
Gubernot D, Jazwa A, Niu M, Baumblatt J, Gee J, Moro P, Duffy J, Harrington T, McNeil MM, Broder K, Su J, Kamidani S, Olson CK, Panagiotakopoulos L, Shimabukuro T, Forshee R, Anderson S, Bennet S. U.S. Population-Based background incidence rates of medical conditions for use in safety assessment of COVID-19 vaccines Vaccine 2021 Jun 23;39(28):3666-3677. Epub 2021 May 14.
The COVID-19 vaccination campaign is the largest international collaboration of modern times. One aspect of vaccination campaigns that needs consideration is possible side effects or adverse events following vaccination. Serious health outcomes linked to vaccinations are rare, and some outcomes may occur incidentally in the vaccinated population. In this large-scale compilation of U.S. background rates for medical conditions, researchers reviewed scientific literature and calculated the background rates of specific medical conditions that are generally monitored following vaccination. For COVID-19 vaccine safety surveillance, experts at CDC and the Food and Drug Administration assembled a list of 22 potential adverse events that could be monitored following COVID-19 vaccination, including neurological, autoimmune, and cardiovascular conditions, and compiled estimates of the U.S. background rates through scientific literature review gathered from PubMed and other publicly available data. These rates may be useful for future studies that assess adverse events following COVID-19 vaccination.
Hause AM, Gee J, Johnson T, Jazwa A, Marquez P, Miller E, Su J, Shimabukuro TT, Shay DK. Anxiety-Related Adverse Event Cluster After Janssen COVID-19 Vaccination — Five U.S. Mass Vaccination Sites, April 2021 MMWR Morb Mortal Wkly Rep. 2021 April 20. Epub ahead of print.
From April 7-9, 2021, 5 weeks after the J&J/Janssen COVID-19 vaccine was authorized by FDA for emergency use, clusters of anxiety-related events after Janssen vaccination were reported to CDC. The reports came from 5 mass vaccination sites in different states; 4 closed temporarily to investigate the cases. Of the 8,624 Janssen vaccine recipients, there were 64 reports of anxiety-related events, including 17 reports of fainting. Commonly reported symptoms were light-headedness/dizziness (56%), excessive sweating (31%), fainting (27%), nausea or vomiting (25%) and low blood pressure (16%). Additionally, CDC reviewed all reports to VAERS of fainting after Janssen vaccine between March 2 through April 11, 2021 and identified 653 reports out of 8 million doses administered. Review of reports found that fainting occurs in 8 per 100,000 doses administered. Vaccine providers should observe individuals for 15 minutes after COVID-19 vaccination for signs of immediate anxiety-related reactions or fainting.
Shay DK, Gee J, Su JR, Myers TR, Marquez P, Liu R, Zhang B, Licata C, Clark TA, Shimabukuro TT. Safety Monitoring of the Janssen (Johnson & Johnson) COVID-19 Vaccine — United States, March-April 2021 . MMWR Morb Mortal Wkly Rep. 2021 April 30. Epub ahead of print.
Johnson & Johnson’s Janssen COVID-19 vaccine was authorized by FDA for emergency use on February 27, 2021. By April 21, nearly 8 million doses of the Janssen COVID-19 vaccine had been administered. CDC researchers reviewed safety monitoring data from VAERS and the v-safe after-vaccination health checker, and found 97% of reported reactions after vaccination, such as headache, fever, chills, injection site pain, and fatigue, were nonserious and consistent with clinical trials data. CDC and FDA issued a pause of the Janssen vaccine April 12–23, 2021, after 6 cases of cerebral venous sinus thrombosis (CVST), a serious condition that involves blood clots in the brain, were identified in VAERS. By April 25, a total of 17 thrombotic (blood clots) events with thrombocytopenia (low platelet counts) were reported to VAERS, including 3 thrombotic events not occurring in the brain. CDC and FDA continue to monitor the safety of COVID-19 vaccines, analyzing the risks and benefits of continued use.
Shimabukuro TT, Kim SY, Myers TR, Moro PL, Oduyebo T, Panagiotakopoulos L, Marquez PL, Olson CK, Liu T, Chang KT, Ellington SR, Burke VK, Smoots AN, Green CJ, Licata C, Zhang BC, Alimchandani M, Mba-Jonas A, Martin SW, Gee JM, Meaney-Delman DM. Preliminary Findings of mRNA Covid-19 Vaccine Safety in Pregnant Persons N Engl J Med 2021 April 21. DOI: 10.1056/NEJMoa2104983 Epub ahead of print.
Pregnant people were not included in the messenger RNA (mRNA) COVID-19 vaccine clinical trials. Because of the increased risk of severe illness from COVID-19, CDC has provided guidance to pregnant people who may want to get a COVID-19 vaccine. The safety of mRNA vaccines in pregnant people is monitored through 3 systems: v-safe after vaccination health checker, the v-safe pregnancy registry and VAERS. From December 14, 2020 through February 28, 2021, 35,691 v-safe participants ages 16 to 54 identified as pregnant. Injection site pain was commonly reported. Of those, 3,958 enrolled in the v-safe pregnancy registry: 827 completed pregnancy; 712 (86.1%) had live births, with most vaccinations completed in the 3rd trimester. In the VAERS reports following mRNA vaccinations, 155 (70.1%) were nonpregnancy specific; 66 (29.9%) were pregnancy and neonatal specific events. The analysis of v-safe and VAERS data did not show any safety concerns among pregnant persons who received mRNA COVID-19 vaccines.
Chapin-Bardales J, Gee J, Myers T. Reactogenicity Following Receipt of mRNA-Based COVID-19 Vaccines JAMA Insights 2021 April 5. doi:10.1001/jama.2021.5374 Epub ahead of print.
CDC created v-safe, a smartphone-based tool, to monitor in near-real time the safety of COVID-19 vaccines authorized by FDA for emergency use. V-safe uses text messaging and web surveys to provide personalized health check-ins after COVID-19 vaccination. Researchers reviewed data collected from v-safe from December 14, 2020 to February 28, 2021, including side effects and reactions to the mRNA COVID-19 vaccines. Over 3.6 million v-safe participants completed at least one health check-in after the first dose and over 1.9 million after the second dose. Injection site pain was commonly reported after first (70%) and second doses (75%) of either mRNA vaccine. Systemic reactions, such as fatigue, headache, muscle pain, chills, fever, and joint pain were the top symptoms reported by participants after the first mRNA vaccine dose. These reports increased substantially after the second dose among both mRNA vaccines. People aged 65 years and older reported fewer reactions than younger people. While v-safe is voluntary and includes less than 10% of people vaccinated, reported reactions to the mRNA vaccines were consistent with results observed in clinical trials.
Gee J, Marquez P, Su J, Calvert GM, Liu R, Myers T, Nair N, Martin S, Clark T, Markowitz L, Lindsey N, Zhang B, Licata C, Jazwa A, Sotir M, Shimabukuro T. First Month of COVID-19 Vaccine Safety Monitoring — United States, December 14, 2020-January 13, 2021 MMWR Morb Mortal Wkly Rep. 2021 Feb 26;70;283-288.
The U.S. FDA authorized two COVID-19 vaccines for emergency use in December 2020: Pfizer-BioNTech and Moderna. During clinical trials, there were reports of local reactions where the shot was given, and systemic reactions affecting other parts of the body. Safety monitoring for these vaccines has been the most intense and comprehensive in U.S. history. From December 14, 2020 through January 13, 2021, almost 14 million vaccine doses were distributed. During that time, over 1.6 million vaccine recipients enrolled in v-safe, and VAERS received 6,994 reports of adverse events following vaccination. About 91% of VAERS reports were non-serious; commonly reported symptoms included headache (22.4%), fatigue (16.5%) and dizziness (16.5%). V-safe enrollees reported similar local and systemic reactions. While deaths were reported to VAERS, available documentation did not suggest a causal link between the vaccine and death. Overall, no unusual or unexpected reporting patterns were detected.
Malden DE, Gee J, Glenn S, Li Z, Mercado C, Ogun OA, Kim S, Lewin BJ, Ackerson BK, Jazwa A, Weintraub ES, McNeil MM, Tartof S. Reactions following Pfizer-BioNTech COVID-19 mRNA vaccination and related healthcare encounters among 7,077 children aged 5-11 years within an integrated healthcare system . Vaccine. 2023 Jan 9; https://doi.org/10.1016/j.vaccine.2022.10.079. Online ahead of print.
Xu S, Huang R, Sy LS, Hong V, Glenn SC, Ryan DS, Morrissette K, Vazquez-Benitez G, Glanz JM, Klein NP, Fireman B, McClure D, Liles EG, Weintraub ES, Tseng HF, Qian L. A Safety Study Evaluating non-COVID-19 Mortality Risk Following COVID-19 Vaccination . Vaccine . 2022 Dec 20; https://doi.org/10.1016/j.vaccine.2022.12.036 Online ahead of print.
A study evaluating the risk of non-COVID-19 mortality after COVID-19 vaccination found that for each vaccine and across age, sex, and race/ethnicity groups, COVID-19 mortality rates were lower among those vaccinated compared to people who were unvaccinated. The study, published December 2022, used data from seven Vaccine Safety Datalink sites from December 14, 2020, through August 31, 2021. Three separate analyses were conducted for each of the three COVID-19 vaccines used in the United States.
Xu S, Huang R, Sy LS, Glenn SC, Ryan DS, Morrissette K, Shay DS, Vazquez-Benitez G, Glanz JM, Klein NP, McClure D, Liles EG, Weintraub ES, Tseng HF, Qian L. COVID-19 Vaccination and Non-COVID-19 Mortality Risk — Seven Integrated Health Care Organizations, United States, December 14, 2020-July 31, 2021 MMWR Morb Mortal Wkly Rep. epub 2021 Oct 22.
Since COVID-19 vaccinations have become available in December 2020, an estimated 182 million people in the United States were fully vaccinated against COVID-19 by September 21, 2021. However, since April 2021, the number of people starting to get COVID-19 vaccines has decreased. People have cited vaccine safety concerns as deterrents to getting a COVID-19 vaccine, concerns that include deaths following COVID-19 vaccination. Although deaths after COVID-19 vaccination have been reported to VAERS, there have been few studies done to evaluate the mortality not associated with COVID-19 among vaccinated and unvaccinated groups. To analyze this, researchers conducted a study using the Vaccine Safety Datalink, comparing those who received COVID-19 vaccines and those who did not between December 2020 through July 2021. This study included data from 11 million people; 6.4 million received either Pfizer-BioNTech, Moderna or Janssen COVID-19 vaccine and 4.6 were unvaccinated. The analysis showed that those who received COVID-19 vaccinations had lower rates of mortality for non-COVID-19 causes than those unvaccinated. These findings provide evidence that COVID-19 vaccines are safe and support current vaccination recommendations.
Cortese MM, Taylor AW, Akinbami LJ, Thames-Allen A, Yousaf AR, Campbell AP, Maloney SA, Harrington TA, Anyalechi EG, Munshi D, Kamidani S, Curtis CR, McCormick DW, Staat MA, Edwards KM, Creech CB, Museru O, Marquez P, Thompson D, Su JR, Schlaudecker EP, Broder KR. Surveillance For Multisystem Inflammatory Syndrome in US Children Aged 5-11 Years Who Received Pfizer-BioNTech COVID-19 Vaccine, November 2021 through March 2022 . J Infect Dis . 2023 Feb 23;jiad051. Online ahead of print.
Haq K, Anyalechi EG, Schlaudecker EP, McKay R, Kamidani S, Manos C, Oster ME. Multiple MIS-C Readmissions and Giant Coronary Aneurysm After COVID-19 Illness and Vaccination: A Case Report . The Pediatric Infectious Disease Journal . 2022 Dec 16; DOI: 10.1097/INF.0000000000003801. Online ahead of print.
Multisystem inflammatory syndrome in children (MIS-C) rarely involves delayed giant coronary aneurysms, hospital readmissions, or symptom occurrence after COVID-19 vaccination. In this case report, the authors describe a child with all 3 of these unusual features. The authors discuss his clinical presentation and medical management, review the current literature, and review CDC guidance recommendations regarding further vaccinations. A 5-year-old boy began to show symptoms of MIS-C 55 days after COVID-19 illness and 15 days after receiving the first COVID-19 vaccine dose. This is the only reported case of a patient admitted to the hospital three times for MIS-C complications after COVID-19 vaccination. Whether the child’s MIS-C complications were related to his receiving a COVID-19 vaccine after having COVID-19 illness remains unknown. After consultation with the CDC-funded Clinical Immunization Safety Assessment Project, the patient’s care team decided against further COVID-19 vaccination until at least three months after normalization of inflammatory markers.
Yousaf AR, Cortese MM, Taylor AW, Broder KR, Oster ME, Wong JM, Guh AY, McCormick DW, Kamidani S, Schlaudecker EP, Edwards K, Creech CB, Staat MA, Belay ED, Marquez P, Su JR, Salzman MB, Thompson D, Campbell AP, MIS-C Investigation Authorship Group. Reported cases of multisystem inflammatory syndrome in children aged 12-20 years in the USA who received a COVID-19 vaccine, December, 2020, through August, 2021: a surveillance investigation . Lancet Child Adolesc Health . 2022 May;6(5):303-312. Epub 2022 Feb 23.
Multisystem inflammatory syndrome in children (MIS-C), a condition in children where the heart, liver, kidneys, or other organs of the body become inflamed, is a rare but serious complication of COVID-19 disease in people ages less than 21 years. Because this inflammatory illness occurs after COVID-19 infection, scientists wondered if this same type of inflammatory illness might occur after COVID-19 vaccination. In this report, published May 2022, investigators found that reported cases of MIS-C occurring at some point during the surveillance period after receiving a COVID-19 vaccine were rare; they identified 21 cases in people ages 12–20 years during a period when more than 21 million people these ages had received at least one vaccine dose. Most of the people who developed MIS-C also had laboratory evidence showing past or recent COVID-19 infection. Whether COVID-19 vaccination contributed in any way to them developing MIS-C remains unknown. CDC will continue to monitor reports of MIS-C and report findings, particularly in children and adolescents now authorized to receive the COVID-19 vaccine.
Belay ED, Godfred Cato S, Rao AK, Abrams J, Wilson WW, Lim S, Newton-Cheh C, Melgar M, DeCuir J, Webb B, Marquez P, Su JR, Meng L, Grome HN, Schlaudecker E, Talaat K, Edwards K, Barnett E, Campbell AP, Broder KR, Bamrah Morris S. Multisystem Inflammatory Syndrome in Adults after SARS-CoV-2 infection and COVID-19 vaccination . Clin Infect Dis. 2021 Nov 28;cia963. Online ahead of print.
Multisystem inflammatory syndrome in adults (MIS-A) is a rare but serious complication of COVID-19 disease. Because of the association with COVID-19 illness, MIS-A was included in the list of adverse events to monitor following COVID-19 vaccination. Researchers reviewed reports of MIS-A from December 14, 2020, to April 30, 2021. These MIS-A reports came from different sources, including treating clinicians, state health departments and as well as the Vaccine Adverse Event Reporting System (VAERS). During the analysis period, there were 20 patients who met the CDC case definition for MIS-A. All 20 patients had confirmed past or current COVID-19 infection. Most patients reported gastrointestinal and cardiac issues, low blood pressure, and shock. Seven patients received a COVID-19 vaccine before MIS-A onset, typically 10 days before MIS-A symptoms began; 3 patients received a second COVID-19 vaccine dose 4, 17, and 22 days before MIS-A onset. All vaccinated patients had underlying COVID-19 infection prior to MIS-A onset. MIS-A has not been reported following vaccination alone. Clinicians should report suspected MIS-A cases following COVID-19 vaccination to VAERS.
Grome HN, Threlkeld M, Threlkeld S, Newman C, Brasil Martines R, Reagan-Steiner S, Whitt MA, Gomes-Solecki M, Nair N, Fill MM, Jones TF, Schaffner W, Dunn J. Fatal Multisystem Inflammatory Syndrome in Adult after SARS-CoV-2 Natural Infection and COVID-19 Vaccination . EID Journal . 2021 Sept 24; 27 (11) 2914-2918. doi:10.3201/eid2711.211612.
Goddard K, Hanson KE, Lewis N, Weintraub E, Fireman B, Klein NP. Incidence of Myocarditis/Pericarditis Following mRNA COVID-19 Vaccination Among Children and Younger Adults in the United States. . Annals of Internal Medicine. 2022 Oct 4. doi.org/10.7326/M22-2274.
Vaccine safety monitoring systems have reported cases of myocarditis and pericarditis after mRNA-based COVID-19 vaccination, especially among younger males 0 to 7 days after receiving the second vaccine dose. Using data from the Vaccine Safety Datalink, a population-based surveillance study was conducted on pre-specified outcomes after COVID-19 vaccination among people ages 5 to 39 years. Researchers identified potential cases of myocarditis and pericarditis in emergency department and inpatient settings 1 to 98 days after vaccination and validated initial findings by reviewing medical records. Results found that during December 14, 2020, through May 31, 2022 (among people ages 18–39 years), and through August 20, 2022 (among people ages 5–17 years), there were 320 potential cases of myocarditis or pericarditis after 6,992,340 people were vaccinated. Of 320 potential cases, 224 cases were verified, with 137 cases of myocarditis or pericarditis occurring 0 to 7 days after vaccination: 18 cases after the first dose and 119 cases after the second dose. Adolescent males were shown to have higher incidence of myocarditis and pericarditis. Given the known risk of complications after COVID-19 disease (including myocarditis), the findings of this study support that the benefits of mRNA vaccination outweigh the risks.
Kracalik I, Oster ME, Broder KR, Cortese MM, Glover M, Shields K, Creech CB, Romanson B, Novosad S, Soslow J, Walter EB, Marquez P, Dendy JM, Woo J, Valderrama AL, Ramirez-Cardenas A, Assefa A, Campbell MJ, Su JR, Magill SS, Shay DK, Shimabukuro TT, Basavaraju SV. Outcomes at least 90 days onset of myocarditis after mRNA COVID-19 vaccination in adolescents and young adults in the USA: a follow-up surveillance study . Lancet Child Adolesc Health . 2022 Nov 6;6(11):788-798. Epub 2022 Sept 22.
CDC collected data on individuals with myocarditis after mRNA COVID-19 vaccination through follow-up surveys of people ages 12–29 years for whom a report of myocarditis after mRNA COVID-19 vaccination was made to the Vaccine Adverse Event Reporting System (VAERS) during December 2020 through November 2021. Clinical outcomes and quality of life at least 90 days since onset of myocarditis after mRNA COVID-19 vaccination in adolescents and young adults were assessed. This study, published November 2022, found that approximately 80% of patients diagnosed with myocarditis after receiving an mRNA COVID-19 vaccine were considered recovered by healthcare providers at least 90 days after the onset of myocarditis. CDC is continuing to follow up with patients who have not been considered recovered since myocarditis symptom onset to better understand longer-term outcomes.
Goddard K, Lewis N, Fireman B, Weintraub E, Shimabukuro T, Zerbo O, Boyce TG, Oster ME, Hanson KE, Donahue JG, Ross P, Naleway A, Nelson JC, Lewin B, Glanz JM, Williams JTB, Kharbanda EO, Yih WK, Klein NP. Risk of myocarditis and pericarditis following BNT162b2 and mRNA-1273 COVID-19 vaccination . Vaccine 2022 Aug 19; 40(35):5153-5159. Epub 2022 Jul 12.
Evidence indicates that mRNA COVID-19 vaccination is associated with the risk of myocarditis and possibly pericarditis, especially among adolescent and young adult males. It is unclear if risk differs between mRNA-1273 (Moderna) and BNT162b2 (Pfizer-BioNTech). This study, published August 2022, reviewed health records among a diverse population to see if there is a clear difference in risk of myocarditis associated with receiving an mRNA-1273 versus BNT162b2 vaccine. During December 14, 2020, through January 15, 2022, 41 cases of myocarditis and pericarditis were reported after 2,891,498 doses of BNT162b2, and 38 cases of myocarditis and pericarditis were reported after 1,803,267 doses of mRNA-1273. Cases had similar demographic and clinical characteristics. In most cases, patients were hospitalized for one day or less; none required intensive care. Risk of myocarditis and pericarditis was higher after mRNA-1273 vaccine than after BNT162b2 vaccine during the 0–7 days after receiving either vaccine. Both vaccines were associated with increased risk of myocarditis and pericarditis among young males ages 18–39 years.
Weintraub ES, Oster ME, Klein NP. Myocarditis or Pericarditis Following mRNA COVID-19 Vaccination . JAMA 2022 Jun 24; 5(6):e2218512. doi:10.1001/jamanetworkopen.2022.18512
This commentary, published June 2022, discusses a study presenting evidence that a longer time interval between dose 1 and dose 2 of an mRNA COVID-19 vaccine might lower the risk of myocarditis or pericarditis. The commentary also includes data from the Vaccine Safety Datalink, including reported rates of myocarditis or pericarditis after receiving an mRNA COVID-19 vaccine (Moderna or Pfizer-BioNTech). Reported rates of myocarditis or pericarditis were higher after receipt of the Moderna vaccine than the Pfizer-BioNTech vaccine and were higher following dose 2. Vaccine safety monitoring has been ongoing globally, and the risk of myocarditis appears highest among adolescents and young adult males following dose 2 of the primary series. However, the risk of myocarditis after COVID-19 disease remains greater than after COVID-19 vaccination, which remains the most effective way to prevent serious complications from COVID-19 infection.
Block JP, Boehmer TK, Forrest CB, Carton TW, Lee GM, Ajani UA, Christakis DA, Cowell LG, Draper C, Ghildayal N, Harris AM, Kappelman MD, Ko JY, Mayer KH, Nagavedu K, Oster ME, Paranjape A, Puro J, Ritchey MD, Shay DK, Thacker D, Gundlapalli AV. Cardiac Complications After SARS-CoV-2 Infection and mRNA COVID-19 Vaccination — PCORnet, United States, January 2021–January 2022 . MMWR Morb Mortal Wkly Rep. 2022 Apr 8; 71(14);517-523.
Data from 40 U.S. healthcare systems participating in PCORnet, the National Patient-Centered Research Network, were analyzed to identify people ages 5 years and older who developed heart complications after COVID-19 disease or after getting an mRNA COVID-19 vaccination during January 1, 2021, through January 31, 2022. The risk for heart complications after mRNA COVID-19 vaccination was highest among teen boys ages 12–17 years and young men ages 18–29 years after getting the second dose of vaccine. However, the risk of heart complications was higher after COVID-19 disease than after a second dose of vaccine—specifically, 2 to 6 times as high for teen boys and 7 to 8 times as high for young men. These findings support the continued use of recommended mRNA COVID-19 vaccines among all eligible people ages 5 years and older.
Oster ME, Shay DK, Su JR, Gee J, Creech CB, Broder KR, Edwards K, Soslow JH, Dendy JM, Schlaudecker E, Lang SM, Barnett ED, Ruberg FL, Smith MJ, Campbell MJ, Lopes RD, Sperling LS, Baumblatt JA, Thompson DL, Marquez PL, Strid P, Woo J, Pugsley R, Reagan-Steiner S, DeStefano F, Shimabukuro TT. Myocarditis Cases Reported After mRNA-Based COVID-19 Vaccination in the US From December 2020 to August 2021 . JAMA 2022 Jan 25; 327(4):331-34. Online ahead of print.
A review of vaccine safety data reported during December 2020–August 2021 found that there was a small but increased risk for myocarditis, or inflammation of the heart muscle, following mRNA COVID-19 vaccination (Pfizer-BioNTech and Moderna). After a review of reports submitted to the Vaccine Adverse Event Reporting System, scientists found that the risk of myocarditis was highest following receipt of the second vaccine dose among adolescent and young adult males. This risk should be considered within the context of the significant benefits of COVID-19 vaccination in preventing COVID-19 infection and potential serious complications from COVID-19. The benefits of COVID-19 vaccination continue to outweigh any potential risks, including myocarditis.
Paddock CD, Reagan-Steiner S, Su JR, Oster ME, Martines RB, Bhatnagar J, Shimabukuro TT. Autopsy Histopathologic Cardiac Findings in Two Adolescents Following the Second COVID-19 Vaccine Dose . Arch Pathol Lab Med 2022 Apr 11. Doi: 10.5858/arpa.2022-0084-LE. Online ahead of print.
This letter to the editor, published April 2022, responds to a report describing an investigation of autopsy findings for two adolescents who died after COVID-19 vaccination. The letter to the editor points out that the authors of the original manuscript omitted key findings by CDC. Investigation by CDC found evidence that death was related to C septicum sepsis. C septicum sepsis is a fatal infection that can present with non-specific signs and symptoms. C septicum sepsis is lethal in 60–70% of cases, and death typically occurs within 12–48 hours of symptoms. Information reported to the Vaccine Adverse Event Reporting System showed that the patients described flu-like symptoms for two days before death. The original investigation, by omitting CDC’s additional findings, could be interpreted as evidence that the COVID-19 vaccine was the cause of death.
Oster ME, Shay DK, Su JR, Gee J, Creech B, Broder KR, Edwards K, Soslow JH, Dendy JM, Schlaudecker E, Lang SM, Barnett ED, Ruberg FL, Smith MJ, Campbell MJ, Lopes RD, Sperling LS, Baumblatt JA, Thompson DL, Marquez PL, Strid P, Woo J, Puglsey R, Reagan-Steiner S, DeStefano F, Shimabukuro TT. Myocarditis Cases Reported After mRNA-Based COVID-19 Vaccination in the US from December 2020 to August 2021 JAMA. 2022 Jan 18;327(4):331-340. Online ahead of print.
Since mRNA-based COVID-19 vaccines were authorized for emergency use in December 2020, there have been reports of myocarditis, or inflammation of the heart muscle, following vaccination. To see if there was an association between mRNA COVID-19 vaccination and myocarditis, researchers reviewed reports submitted to the Vaccine Adverse Event Reporting Systems (VAERS) from December 2020 through August 31, 2021. In that time, more than 192 million people ages 12 years and older have received at least one dose of mRNA COVID-19 vaccines. From this population, VAERS received 1,626 myocarditis reports that met case definition. The review found the rates myocarditis were highest following the second dose of mRNA vaccine among adolescent and young adult males. Myocarditis is a rare but serious adverse event that can occur following mRNA COVID-19 vaccination. The benefits of COVID-19 vaccination continue to outweigh any potential risks, including myocarditis.
Gargano JW, Wallace M, Hadler SC, Langley G, Su JR, Oster ME, Broder KR, Gee J, Weintraub E, Shimabukuro T, Scobie HM, Moulia D, Markowitz LE, Wharton M, McNally VV, Romero JR, Keipp Talbot H, Lee GM, Daley MF, Oliver SE. Use of mRNA COVID-19 Vaccine After Reports of Myocarditis Among Vaccine Recipients: Update from the Advisory Committee on Immunization Practices — United States, June 2021 MMWR Morb Mortal Wkly Rep. 2021 Jul 9;70:977-982.
Two mRNA COVID-19 vaccines were given emergency use authorization (EUA) by the Food and Drug Administration (FDA) in December 2020: Pfizer-BioNTech and Moderna COVID-19 vaccines. Pfizer-BioNTech was authorized for individuals 16 years and older, and Moderna for adults 18 years and older. In May 2021, FDA expanded Pfizer-BioNTech vaccine’s authorization to include adolescents aged 12 to 15 years. After reported myocarditis/pericarditis among mRNA vaccine recipients, mostly in younger males after the 2nd dose, the Advisory Committee on Immunization Practices (ACIP) held a meeting to review these reports and conduct a risk-benefit assessment of mRNA COVID-19 vaccination in the U.S. Evidence presented showed that the highest rates of myocarditis were reported in males aged 12-17 and 18-24 (62.8 and 50.5 reported cases of myocarditis per million 2nd mRNA doses administered, respectively). On June 23, after reviewing all the available information, ACIP determined that the benefits of mRNA COVID-19 vaccination under EUA outweighed the risks of myocarditis in all populations. CDC and FDA will continue to monitor cases of myocarditis among mRNA COVID-19 vaccine recipients.
Shay DK, Shimabukuro, TT, DeStefano F. Myocarditis Occurring After Immunization with mRNA-Based COVID-19 Vaccines: Editorial . JAMA Cardiol. Published online June 29, 2021. doi:10.1001/jamacardio.2021.2821.
CDC researchers reviewed several case reports of acute myocarditis occurring in people following mRNA-based COVID-19 vaccinations (Pfizer BioNTech or Moderna). The first report included 4 cases of myocarditis developed 1 to 5 days after getting dose 2 of mRNA-based COVID-19 vaccine. Second report included 23 cases of acute myocarditis within 4 days of vaccination, mostly after dose 2. The last report included 7 cases in adolescents, ages 14-19. All presented with myocarditis or myopericarditis (heart muscle and lining inflammation) within 4 days of dose 2. The review of these cases showed clinical similarities and there were no other known causes for their acute myocarditis, suggesting a likely association with vaccination. Myocarditis following COVID-19 vaccination is rare. Researchers will continue to look into myocarditis following COVID-19 vaccination.
Goddard K, Hanson KE, Lewis N, Weintraub E, Fireman B, Klein NP. Incidence of Myocarditis/Pericarditis Following mRNA COVID-19 Vaccination Among Children and Younger Adults in the United States . Annals of Internal Medicine. 2022 Oct 4. doi.org/10.7326/M22-2274.
Hause AM, Marquez P, Zhang B, Myers TR, Gee J, Su JR, Parker C, Thompson D, Panchanathan SS, Shimabukuro TT, Shay DK. COVID-19 mRNA Vaccine Safety Among Children Aged 6 Months–5 Years — United States, June 18, 2022–August 21, 2022 . MMWR Morb Mortal Wkly Rep. 2022 Sep 2;71(35);1115-1120.
This study, published September 2022, found that among children ages 6 months to 5 years who received mRNA COVID-19 vaccines, local and systemic reactions were mostly mild or moderate. Serious reports of adverse events were rare. Safety data from the Vaccine Adverse Event Reporting System and V-safe were used to look at reported reactions in this age group. Most reported reactions—such as injection site pain, irritability, crying, and sleepiness—were consistent with those observed during the vaccines’ preauthorization clinical trials. This study reinforces the safety profile of mRNA COVID-19 vaccination among children in this age group.
Hause AM, Baggs J, Marquez P, Abara WE, Baumblatt JG, Thompson D, Su JR, Myers TR, Gee J, Shimabukuro TT, Shay DK. Safety Monitoring of Pfizer-BioNTech COVID-19 Vaccine Booster Doses Among Children Aged 5–11 Years — United States, May 17–July 31, 2022 . MMWR Morb Mortal Wkly Rep. 2022 Aug 19;71(33);1047–1051.
A CDC study published August 2022 found that among children ages 5–11 years who received a booster dose of Pfizer-BioNTech’s mRNA COVID-19 vaccine (third dose administered ≥5 months after the second dose), serious reports of adverse events were rare. Data from V-safe and the Vaccine Adverse Event Reporting System were used to look at adverse events reported in this age group. Data showed children that received a third dose had similar adverse events to those reported after receiving a first or second dose. Most reported adverse events—such as injection site pain and headache—were considered mild. The findings are consistent with those observed during the vaccine’s clinical trial and reinforces the safety of mRNA COVID-19 booster dose vaccination among children ages 5–11 years.
Hause AM, Baggs J, Marquez P, Abara WE, Baumblatt JG, Thompson D, Su JR, Myers TR, Gee J, Shimabukuro TT, Shay DK. Safety Monitoring of COVID-19 mRNA Vaccine First Booster Doses Among Persons Aged ≥12 Years with Presumed Immunocompromise Status — United States, January 12, 2022–March 28, 2022 . MMWR Morb Mortal Wkly Rep. 2022 Jul 15; 71(28);899–903.
Immunocompromised people are at risk for severe COVID-19 disease, and additional doses of COVID-19 vaccine are recommended for this population. To characterize the safety of first booster doses among immunocompromised persons ages 12 years and older, CDC reviewed adverse events (AEs) reported to V-safe and the Vaccine Adverse Event Reporting System (VAERS) during the week after receipt of an mRNA COVID-19 first booster dose (fourth dose administered ≥ 3 months after the third) during January 12, 2022–March 28, 2022. Safety data identified no unusual or unexpected patterns of AEs. Mild to moderate reactions, such as injection site pain, fatigue, headache, and muscle pain following a booster dose were similar to those among non-immunocompromised people. Local and systemic reactions were less common following dose 4 compared to dose 3. These findings support evidence that mRNA COVID-19 vaccines are safe for immunocompromised people.
Fleming-Dutra KE, Wallace M, Moulia DL, Twentyman E, Roper LE, Hall E, Link-Gelles R, Godfrey M, Woodworth KR, Anderson TC, Rubis AB, Shanley E III, Jones JM, Morgan RL, Brooks O, Talbot HK, Lee GM, Bell BP, Daley M, Meyer S, Oliver SE. Interim Recommendations of the Advisory Committee on Immunization Practices for Use of Moderna and Pfizer-BioNTech COVID-19 Vaccines in Children Aged 6 Months–5 Years — United States, June 2022 . MMWR Morb Mortal Wkly Rep. 2022 Jul 1; 71(26);859–868.
Vaccination remains the best protection against COVID-19-related hospitalization and death. On June 17, 2022, the U.S. Food and Drug Administration (FDA) granted Emergency Use Authorization for the Moderna COVID-19 vaccine for children ages 6 months–5 years and for the Pfizer-BioNTech COVID-19 vaccine for children ages 6 months–4 years. The Advisory Committee on Immunization Practices (ACIP) determined that the benefits of vaccination for these age groups outweigh the risks. To guide recommendations on the use of vaccines, ACIP used the Evidence to Recommendation Framework. The framework considered the importance of COVID-19 as a public health problem, the benefits and risks of using each vaccine, and parents’ values regarding the use of vaccines in this age group. Studies for each vaccine were conducted as a randomized double-blind study. In both studies, participants in this age group received either two doses of the vaccine (Moderna or Pfizer-BioNTech) or saline placebo. Results showed that both vaccines are safe and effective to prevent severe COVID-19 illness in this age group.
Hause AM, Shay DK, Klein NP, Abara WE, Baggs J, Cortese MM, Fireman B, Gee J, Glanz JM, Goddard K, Hanson KE, Hugueley B, Kenigsberg T, Kharbanda EO, Lewin B, Lewis N, Marquez P, Myers T, Naleway A, Nelson JC, Su JR, Thompson D, Olubajo B, Oster ME, Weintraub ES, Williams JTB, Yousaf AR, Zerbo O, Zhang B, Shimabukuro TT. Safety of COVID-19 Vaccination in United States Children Ages 5 to 11 Years . Pediatrics . 2022 Jul 14. https://doi.org/10.1542/peds.2022-057313.
This study, published July 2022, reviewed adverse events observed following the Pfizer two-dose vaccine administered to children ages 5–11 years and found mild-to-moderate events within the first day or two of vaccination. Researchers analyzed data from three U.S. safety monitoring systems during four months of vaccine administration among children ages 5–11 years to provide insight on adverse events. Among 48,795 children ages 5–11 years enrolled in V-safe—a web-based tool that uses text messages, emails, and web surveys to provide personalized health check-ins for people after receiving a new vaccine—most reported events were mild to moderate, were most frequently reported the day after vaccination, and were more common after the second dose. The most common events reported were injection site pain, fatigue, headache, fever, and muscle soreness. The study also evaluated data from the Vaccine Adverse Events Reporting System (VAERS), the national spontaneous reporting system co-managed by CDC and the U.S. Food and Drug Administration, and the Vaccine Safety Datalink (VSD), an active surveillance system that monitors electronic health records for pre-specified events including myocarditis. VAERS received 7,578 adverse event reports; 97% were non-serious. Reviewing 194 serious VAERS reports, 15 myocarditis cases were verified; 8 occurred in males after dose 2. In VSD, no safety signals were detected in weekly sequential monitoring after administration of 726,820 doses. The authors concluded that the vaccine is safe for children ages 5–11 years and that adverse events are usually clinically mild and resolve quickly.
Paddock CD, Reagan-Steiner S, Su JR, Oster ME, Martines RB, Bhatnagar J, Shimabukuro TT. Autopsy Histopathologic Cardiac Findings in 2 Adolescents Following the Second COVID-19 Vaccine Dose . Arch Pathol Lab Med. 2022 Apr 8; 146 (8): 921–923.
Hause AM, Baggs J, Marquez P, Abara WE, Olubajo B, Myers TR, Su JR, Thompson D, Gee J, Shimabukuro TT, Shay DK. Safety Monitoring of COVID-19 Vaccine Booster Doses Among Persons Aged 12-17 Years — United States, December 9, 2021-February 20, 2022 . MMWR Morb Mortal Wkly Rep . 2022 Mar 4;71(9):347-351.
CDC reviewed safety data for a third dose of Pfizer-BioNTech COVID-19 vaccine administered ≥ 5 months after the second dose among adolescents ages 12–17 years. This review, published March 2022, identified no unusual or unexpected patterns of adverse events. Data from V-safe and the Vaccine Adverse Event Reporting System were used to characterize adverse events reported among this age group. Reactions such as injection site pain, fatigue, headache, and muscle pain following dose 3 vaccinations were mostly mild to moderate in severity and were most frequently reported the day after vaccination. Myocarditis was less frequently reported following a third dose than a second dose. Parents should be advised that local and systemic reactions are expected among adolescents following Pfizer-BioNTech vaccine dose 3 and that serious adverse events, including myocarditis, are rare.
Yousaf AR, Cortese MM, Taylor AW, Broder KR, Oster ME, Wong JM, Guh AY, McCormick DW, Kamidani S, Schlaudecker EP, Edwards K, Creech CB, Staat MA, Belay ED, Marquez P, Su JR, Salzman MB, Thompson D, Campbell AP, MIS-C Investigation Authorship Group. Reported cases of multisystem inflammatory syndrome in children aged 12-20 years in the USA who received a COVID-19 vaccine, December, 2020, through August, 2021: a surveillance investigation . Lancet Child Adolesc Health . 2022 May;6(5):303-312. Epub 2022 Feb 23.
DeSilva MB, Haapal J, Vazquez-Benitez G, Daley MF, Nordin JD, Klein NP, Henninger ML, Williams JTB, Hambidge SJ, Jackson ML, Donahue JG, Qian L, Lindley MC, Gee J, Weintraub ES, Kharbanda EO. Association of the COVID-19 Pandemic with Routine Childhood Vaccination Rates and Proportion Up to Date with Vaccinations Across 8 US Health Systems in the Vaccine Safety Datalink . JAMA Pediatr. 2022 Jan 1;176(1):68-77. Doi: 10.1001/jamapediatrics.2021.4251.
Routine vaccinations in the United States and globally have been affected by the COVID-19 pandemic. This study, published January 2022, used data from eight health systems in California, Oregon, Washington, Colorado, Minnesota, and Wisconsin in the Vaccine Safety Datalink to compare trends in pediatric vaccination before and during the pandemic and to evaluate the proportion of children who were up to date with routine vaccinations in February, May, and September 2020. Children from age groups younger than 24 months and ages 4–6, 11–13, and 16–18 years were included if they had at least 1 week of health system enrollment from January 5, 2020, through October 3, 2020. Results show that as of September 2020, childhood vaccination rates and proportion of children who were up to date on routine vaccinations remained lower than 2019 levels and that intervention measures must be made to promote catch-up vaccinations.
Hause AM, Baggs J, Marquez P, Myers TR, Gee J, Su JR, Zhang B, Thompson D, Shimabukuro TT, Shay DK. COVID-19 Vaccine Safety in Children Ages 5-11 years — United States, November 3-December 19, 2021 . MMWR Morb Mort Wkly Rep. 2021 Dec 31:70(5152);1755-1760.
On October 29, 2021, the FDA expanded emergency use authorization (EUA) for the Pfizer-BioNTech COVID-19 vaccine to include children ages 5-11 years. Once the EUA was in place, researchers began reviewing vaccine safety data for this age group, collected through the Vaccine Adverse Event Reporting System (VAERS) and v-safe. From November 3 through December 19, 2021, around 8.7 million doses of Pfizer vaccine were administered to children ages 5-11 years. During that time, VAERS received 4,249 reports of adverse events following vaccination for children in that age group, 98% of which were non-serious. There were 11 verified cases of myocarditis. Of the over 42,000 children enrolled in v-safe, 70% recorded a second dose. Local reactions (symptoms around the injection site) and systemic reactions (fever, headache, fatigue) following dose 2 of Pfizer vaccination among this age group were reported less frequently than reactions reported among children ages 12-15 years. The initial safety findings showed no unusual patterns of adverse events and that the benefits of COVID-19 vaccination continue to outweigh the risks. CDC and FDA will continue to monitor COVID-19 vaccine safety, communicate findings, and use vaccine safety data to inform vaccination recommendations.
Hause AM, Gee J, Baggs J, Abara WE, Marquez P, Thompson D, Su JR, Licata C, Rosenblum HG, Myers TR, Shimabukuro TT, Shay DK. COVID-19 Vaccine Safety in Adolescents—United States, December 14, 2020—July 16, 2021 . MMWR Morb Mortal Wkly Rep. 2021 Jul 30.
As of July 2021, Pfizer-BioNTech COVID-19 Vaccine (Pfizer-BioNTech) is the only COVID-19 vaccine authorized for use in adolescents (people aged 12–17 years). To evaluate the safety of Pfizer-BioNTech in adolescents, researchers reviewed data collected from VAERS and v-safe between December 14, 2020 through July 16, 2021. Over 8.9 million Pfizer-BioNTech doses were administered to adolescents ages 12-17. VAERS received 9,246 reports of adverse events in adolescents; over 90% of reports were non-serious. Myocarditis was reported in 4.3% (397) of all VAERS reports. Of the 129,000 adolescents who enrolled in v-safe, the most frequently reported side effects included injection site pain, fatigue, headache, and weakness. With the exception of myocarditis, the safety findings were similar to what was observed during preauthorization trials. CDC and FDA are actively monitoring the safety of COVID-19 vaccines. Serious adverse events after COVID-19 vaccination are rare, and CDC continues to recommend everyone 12 years and older get vaccinated as soon as possible to help protect against COVID-19.
Kharbanda EO, Haapala J, Lipkind HS, DeSilva MB, Zhu J, Vesco KK, Daley MF, Donahue JG, Getahun D, Hambidge SJ, Irving SA, Klein NP, Nelson JC, Weintraub ES, Williams JTB, Vazquez-Benitez G. COVID-19 Booster Vaccination in Early Pregnancy and Surveillance for Spontaneous Abortion . JAMA Network Open. 2023 May 19;6(5):e2314350.
Vazquez-Benitez G, Haapala J, Lipkind HS, DeSilva MB, Zhu J, Daley MF, Getahun D, Klein NP, Vesco KK, Irving SA, Nelson JC, Williams JTB, Hambidge SJ, Donahue J, Fuller CC, Weintraub ES, Olson C, Kharbanda EO. COVID-19 Vaccine Safety Surveillance in Early Pregnancy in the United States: Design Factors Affecting the Association Between Vaccine and Spontaneous Abortion . American Journal of Epidemiology. 2023 Mar 16;kwad059. Online ahead of print.
Moro PL, Olson CK, Zhang B, Marquez P, Strid P. Safety of Booster Doses of Coronavirus Disease 2019 (COVID-19) Vaccine in Pregnancy in the Vaccine Adverse Event Reporting System . Obstet Gynecol. 2022 Sept 1; 40(3):421-427.
A review of reports to the Vaccine Adverse Event Reporting System (VAERS) showed that adverse events (AEs) reported after booster dose mRNA COVID-19 vaccination among pregnant people were similar to AEs reported after primary series mRNA COVID-19 vaccination among pregnant people. During September 22, 2021, through March 24, 2022, VAERS received 323 reports of AEs among pregnant people who received the Pfizer-BioNTech or the Moderna COVID-19 booster dose. The most common pregnancy-specific AE reported after receipt of a booster dose was miscarriage, which is relatively common during pregnancy. This study, published September 2022, did not identify any new or unexpected AEs after receipt of a booster dose of mRNA COVID-19 vaccine among pregnant people.
DeSilva M, Haapala J, Vazquez-Benitez G, Vesco KK, Daley MF, Getahun D, Zerbo O, Naleway A, Nelson JC, Williams JTB, Hambidge SJ, Boyce TG, Fuller CC, Lipkind HS, Weintraub E, McNeil MM, Kharbanda EO. Evaluation of Acute Adverse Events after Covid-19 Vaccination during Pregnancy . N Engl J Med. . 2022 Jun 22. DOI: 10.1056/NEJMc2205276. Epub ahead of print.
Pregnant people with COVID-19 symptoms have a higher risk of adverse outcomes than people who are not pregnant. A retrospective study published June 2022 and focusing on pregnant people ages 16–49 years who were either vaccinated or unvaccinated between December 15, 2020, and July 1, 2021, was conducted to show the safety of COVID-19 vaccines and the occurrence of adverse events (AEs). There were 45,232 pregnant people identified in the study who received one or two doses of a COVID-19 vaccine. Less than 1% of pregnant people had to be hospitalized for AEs. There were no serious AEs that occurred more frequently among vaccinated versus unvaccinated pregnant people, showing that the COVID-19 vaccine is not linked to serious AEs in this population.
Razzaghi H, Meghani M, Crane B, Ellington S, Naleway AL, Irving SA, Patel SA. Receipt of COVID-19 Booster Dose Among Fully Vaccinated Pregnant Individuals Aged 18 to 49 Years by Key Demographics . JAMA . 2022 Apr 22; .2354-2351 (23) 327 doi:10.1001/jama.2022.6834.
Data from the Vaccine Safety Datalink showed that fewer than half of pregnant people who were up to date with their COVID-19 vaccines received a COVID-19 booster dose by February 2022. Researchers assessed vaccination trends over time among pregnant people ages 18–49 years beginning the week of August 13, 2021, when additional vaccine doses were authorized, through the week ending February 26, 2022. Out of 71,745 people who were pregnant during the study period, 49,072 were fully vaccinated, with 25,321 of those having received a booster dose. Receipt of a booster dose was highest among pregnant people ages 35–49 years, Asian people, and non-Hispanic White people. Booster dose rates were lower among pregnant people ages 18–24 years, non-Hispanic Black people, and Hispanic people. These findings can help inform methods to increase booster dose vaccinations.
Moro PL, Olson CK, Clark E, Marquez P, Strid P, Ellington S, Zhang B, Mba-Jonas A, Alimchandani M, Cragan J, Moore C. Post-authorization surveillance of adverse events following COVID-19 vaccines in pregnant persons in the Vaccine Adverse Event Reporting System (VAERS), December 2020-October 2021 . Vaccine . 2022 May 26;40(24):3389-3394. Epub 2022 Apr 12.
A CDC study published May 2022 and looking at more than 10 months of vaccine safety data from people who were pregnant and received a COVID-19 vaccine found no concerning patterns of health problems related to vaccination. These findings add to a growing body of evidence that COVID-19 vaccines are safe for people who are pregnant. These findings also reaffirm CDC’s recommendation for pregnant people to get vaccinated to protect themselves and their babies from severe COVID-19 illness.
During December 14, 2020, through October 31, 2021, CDC scientists analyzed more than 3,000 reports that were submitted to the Vaccine Adverse Event Reporting System (VAERS), a passive vaccine safety monitoring system co-managed by CDC and the U.S. Food and Drug Administration (FDA). The study evaluated and summarized reports to VAERS about people who were pregnant and received a COVID-19 vaccine to assess for potential safety problems with the vaccines. Scientists found no concerning patterns of negative outcomes among people who were pregnant and vaccinated or among their babies.
Lipkind HS, Vazquez-Benitez G, DeSilva M, Vesco KK, Ackerman-Banks C, Zhu J, Boyce TG, Daley MF, Fuller CC, Getahun D, Irving SA, Jackson LA, Williams JTB, Zerbo O, McNeil MM, Olson CK, Weintraub E, Kharbanda KO. Receipt of COVID-19 Vaccine During Pregnancy and Preterm or Small-for-Gestational-Age at Birth — Eight Integrated Health Care Organizations, United States, December 15, 2020-July 22, 2021 . MMWR Morb Mort Wkly Rep. 2022 Jan 4:71(1);26-30. Early release.
Moro PL, Panagiotakopoulos L, Oduyebo T, Olson CK, Myers T. Monitoring the safety of COVID-19 vaccines in pregnancy in the US. Human Vaccines & Immunotherapies. 2021 Nov 10. doi.org/10.1080/21645515.2021.1984132.
Zauche LH, Wallace B, Smoots AN, Olson CK, Oduyebo T, Kim SY, Petersen EE, Ju J, Beauregard J, Wilcox AJ, Rose CE, Meaney-Delman DM, Ellington SR, CDC v-safe COVID-19 Pregnancy Registry Team. Receipt of mRNA COVID-19 Vaccines and Risk of Spontaneous Abortion N Engl J Med. 2021 Sept 8. Dpo: 10.1056/NEJMc2113891.
Although pregnant people are at increased risk for severe illness from COVID-19, the COVID-19 vaccination rate among pregnant people has been much lower than that of the general U.S. population. Data about vaccination during pregnancy was initially limited because pregnant participants were excluded from COVID-19 vaccine clinical trials. To evaluate the safety of mRNA vaccines in pregnant people, researchers analyzed data on miscarriage, or a pregnancy loss that occurs before 20 weeks of pregnancy, collected from v-safe COVID-19 Vaccine Pregnancy Registry participants. Over 2,400 registry participants received at least one dose of an mRNA COVID-19 vaccine just before pregnancy or within the first 20 weeks of pregnancy. The cumulative risk of miscarriage among those who received an mRNA COVID-19 vaccine was similar (14.1%) to previously published background rates (11 to 16%) . Therefore, this study demonstrated no increased risk of miscarriage following receipt of COVID-19 mRNA vaccine in early pregnancy. Research will continue on the safety of COVID-19 vaccines in pregnant people.
Kharbanda EO, Haapala J, DeSilva M, Vazquez-Benitez G, Vesco KK, Naleway AL, Lipkind HS. Spontaneous Abortion Following COVID-19 Vaccination During Pregnancy JAMA 2021 Sep 8. Doi:10.1001/jama.2021.15494
Although pregnant people are at increased risk for severe illness from COVID-19, the COVID-19 vaccination rate among pregnant people has been much lower than that of the general U.S. population. Data about vaccination during pregnancy was initially limited because pregnant participants were excluded from vaccine clinical trials. Researchers within the Vaccine Safety Datalink, a collaboration between CDC and 9 health systems, representing approximately 3% of the U.S. population, analyzed data from 8 health systems from December 15, 2020 through June 28, 2021 to evaluate whether there’s an association between COVID-19 vaccine and miscarriage (pregnancy loss that occurs before 20 weeks of pregnancy). This analysis included over 105,000 pregnancies. About 14% received one or more doses of one of the 3 available COVID-19 vaccines during pregnancy before 20 weeks’ gestational age. The analysis found that people who were currently pregnant at the time of COVID-19 vaccination and those who became pregnant after vaccination did not have an increased risk of miscarriage. Research will continue on the safety of COVID-19 vaccines in pregnant people.
Razzaghi H, Meghani M, Pingali C, Crane B, Naleway A, Weintraub E, Kenigsberg TA, Lamias MJ, Irving SA, Kauffman TL, Vesco KK, Daley MF, DeSilva M, Donahue J, Getahun D, Glee S, Hambidge SJ, Jackson LJ, Lipkind HS, Nelson J, Zerbo O, Oduyebo T, Singleton JA, Patel SA. COVID-19 Vaccination Coverage Among Pregnant Women During Pregnancy — Eight Integrated Health Care Organizations, United States, December 14, 2020-May 8, 2021 . MMWR Morb Mortal Wkly Rep . 2021 Jun 18;70(24):895-899.
Pregnant people are at increased risk for severe illness and death from COVID-19; however, current data about vaccination coverage and safety in pregnant people are limited. Researchers reviewed safety data collected from the Vaccine Safety Datalink (VSD) on COVID-19 vaccination among pregnant people. From December 14, 2020 to May 8, 2021, 135,968 pregnant people were identified in the VSD network. Of those, only 16.3% received at least one dose of a COVID-19 vaccine. Researchers identified Hispanic (11.9%) and non-Hispanic Black women (6%) ages 18 to 24 years old as among the groups of pregnant people with the lowest vaccination rate. Non-Hispanic Asian women were the group with the highest vaccination rate (24.7%). Overall, pregnant women ages 35 to 49 years had a high vaccination rate (22.7%). CDC recommends COVID-19 vaccination for anyone who is pregnant or considering becoming pregnant to prevent serious outcomes from COVID-19 illness. Additional outreach, especially for younger pregnant individuals and those from racial and ethnic minority groups, could increase vaccine confidence and COVID-19 vaccination in these populations.
Shimabukuro TT, Kim SY, Myers TR, Moro PL, Oduyebo T, Panagiotakopoulos L, Marquez PL, Olson CK, Liu R, Chang KT, Ellington SR, Burkel VK, Smoots AN, Green CJ, Licata C, Zhang BC, Alimchandani M, Mba-Jonas A, Martin SW, Gee JM, Meaney-Delman DM, CDC v-safe COVID-19 Pregnancy Registry Team. Prelimiary Findings of mRNA COVID-19 Vaccine Safety in Pregnant Persons . N Engl J Med . 2021 Jun 17;384(24):2273-2282. Epub 2021 Apr 21.
Oliver SE, Wallace M, See I, Mbaeyi S, Godfrey M, Hadler SC, Jatlaoui TC, Twentyman E, Hughes MM, Rao AK, Fiore A, Su JR, Broder KR, Shimabukuro T, Lale A, Shay DK, Markowitz LE, Wharton M, Bell BP, Brooks O, McNally V, Lee GM, Talbot HK, Daley MF. Use of the Janssen (Johnson & Johnson) COVID-19 Vaccine: Updated Interim Recommendations from the Advisory Committee on Immunization Practices — United States, December 2021 . MMWR Morb Mortal Wkly Rep. 2022 Jan 21; 71(3);90–95.
See I, Lale A, Marquez P, Streiff MB, Wheeler AP, Tepper NK, Woo EJ, Broder KR, Edwards KM, Gallego R, Geller AI, Jackson KA, Sharma S, Talaat KR, Walter EB, Akpan IJ, Ortel TL, Urrutia VC, Walker S, Yui JC, Shimabukuro TT, Mba-Jonas A, Su JR, Shay DK. Case Series of Thrombosis with Thrombocytopenia Syndrome after COVID-19 vaccination—United States, December 2020 to August 2021 . Ann Intern Med. 2022 Jan 18. Doi: 10.7326/M21-4502 Online ahead of print.
Thrombosis with thrombocytopenia syndrome (TTS) is a rare but potentially life-threatening condition that causes blood clots in large blood vessels and low platelets (blood cells that help form clots). To describe surveillance data and reporting rates of all reported TTS cases after COVID-19 vaccination in the United States, researchers reviewed data from the Vaccine Adverse Event Reporting System (VAERS) reported during December 14, 2020, through August 31, 2021, for patients who reported TTS symptoms after receiving a COVID-19 vaccine. Results showed 57 confirmed TTS cases after receiving a J&J/Janssen, Pfizer-BioNTech, or Moderna vaccine. Reporting rates for TTS were 3.83 per million vaccine doses (Ad26.COV2.S) and 0.00855 per million vaccine doses (mRNA-based COVID-19 vaccines). Of the 3 TTS cases after mRNA-based COVID-19 vaccination (Pfizer-BioNTech or Moderna), two were in men older than 50 years and one was in a woman aged 50 to 59 years. All cases after J&J/Janssen vaccination involved hospitalization. Although rare, TTS is a serious adverse event associated with J&J/Janssen vaccination, which is no longer available in the U.S. as of May 2023.
MacNeil JR, Su JR, Broder KR, Guh AY, Gargano JW, Wallace M, Hadler SC, Scobie HM, Blain AE, Moulia D, Daley MF, McNally VV, Romero JR, Keipp Talbot H, Lee GM, Bell BP, Oliver SE. Updated Recommendations from the Advisory Committee on Immunization Practices for Use of Janssen (Johnson & Johnson) COVID-19 Vaccine After Reports of Thrombosis with Thrombocytopenia Syndrome Among Vaccine Recipients — United States, April 2021 . MMWR Morb Mortal Wkly Rep. 2021 Apr 30;70:651-656.
The Johnson & Johnson/Janssen (Janssen) COVID-19 vaccine was authorized for emergency use on February 27, 2021. On April 13, CDC and the Food and Drug Administration (FDA) recommended pausing the use of Janssen vaccine after thrombosis with thrombocytopenia syndrome (TTS) was reported among vaccine recipients. TTS is a rare syndrome that involves blood clots in large blood vessels with low platelets. The Advisory Committee on Immunization Practices (ACIP) held two emergency meetings to review reports of TTS following Janssen vaccine and conducted a risk-benefit assessment. The estimated reporting rate of TTS was 7 cases of TTS per million Janssen doses administered to women aged 18-49 years. After their review, on April 23, ACIP concluded that the benefits of resuming Janssen COVID-19 vaccination among persons aged 18 years and older outweighed the risks and reaffirmed its interim recommendation under FDA’s Emergency Use Authorization (EUA), which includes a new warning for rare clotting events, primarily in women aged 18-49 years. CDC and FDA will continue to closely monitor reports of TTS following Janssen vaccination.
See I, Su JR, Lale A, Woo EJ, Guh AY, Shimabukuro TT, Streiff MB, Rao AK, Wheeler AP, Beavers SF, Durbin AP, Edwards K, Miller E, Harrington TA, Mba-Jonas A, Nair N, Nguyen DT, Talaat KR, Urrutia VC, Walker SC, Creech B, Clark TA, DeStefano F, Broder KR. US Case Reports of Cerebral Venous Sinus Thrombosis With Thrombocytopenia After Ad26.COV2.S Vaccination, March 2 to April 21, 2021 JAMA 2021 April 30. Doi:10.1001/jama.2021.7517 Epub ahead of print.
Around 7 million doses of Johnson & Johnson’s Janssen (J&J/Janssen) COVID-19 vaccine were given between March 2–April 12, 2021. During this time, VAERS received reports following J&J/Janssen vaccination of cerebral venous sinus thrombosis (CVST) with thrombocytopenia, which involves blood clots in the brain with low platelet counts. By April 21, there were 12 reports of CVST and thrombocytopenia. This serious condition was reported in women between 18 and under 60 years. All were hospitalized; 10 were admitted to intensive care units (ICU). As of April 21, 4 patients were sent home, 2 were moved to hospital units outside of ICU, 3 continued ICU care, and 3 died. The review shows that U.S. cases of CVST and thrombocytopenia after J&J/Janssen vaccination were clinically similar to CVST cases in Europe after Oxford/AstraZeneca COVID-19 vaccination. Investigation of the potential relationship between J&J/Janssen vaccine and CVST with thrombocytopenia is ongoing.
These articles listed were posted on a pre-print server and are in the process of being submitted to a scientific or medical journal. Articles posted on a pre-print server contain preliminary data and are not peer reviewed (reviewed and evaluated by others in the same field but not involved in the study).
The purpose of posting studies on pre-print is to provide the most current data available to the public. When a manuscript is submitted to a peer review journal, additional data may become available and may alter the analysis of the data posted in the pre-print article.
Hause AM, Shay DK, Klein NP, Abara WE, Baggs J, Cortese MM, Fireman B, Gee J, Glanz JM, Goddard K, Hanson KE, Hugueley B, Kenigsberg K, Kharbanda EO, Lewin B, Lewis N, Marquez P, Myers T, Naleway A, Nelson JC, Su JR, Thompson D, Olubajo B, Oster ME, Weintraub ES, Williams JTB, Yousaf AR, Zerbo O, Zhang B, Shimabukuro TT. Safety of COVID-19 Vaccination in US Children Ages 5-11 Years Pediatrics . 2022 May 18. Doi.org/10.1542/peds.2022-057313 Online ahead of print.
Observational Maternal COVID-19 Vaccination Study Principal Investigators: Geeta K Swamy, Karen R Broder, Elizabeth Schlaudecker, Stephen I Pelton Locations: Centers for Disease Control and Prevention, Boston Medical Center, Duke University, Cincinnati Children’s Hospital Medical Center First Posted: April 1, 2021 Summary Recruitment Status: Recruiting
Safety of Simultaneous COVID-19 and IIV4 Vaccination Principal Investigators: Emmanuel B Walter, Kawsar Talaat, Elizabeth Schlaudecker, Karen R Broder Locations: Centers for Disease Control and Prevention, Duke University, Cincinnati Children’s Hospital Medical Center and Johns Hopkins University First Posted: August 31, 2021 Summary Recruitment Status: Recruiting
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Kenigsberg TA, Goddard K, Hanson KE, Lewis N, Klein N, Irving SA, Naleway AL, Crane B, Kauffman TL, Xu S, Daley MF, Hurley LP, Kaiser R, Jackson LA, Jazwa A, Weintraub ES. Simultaneous administration of mRNA COVID-19 bivalent booster and influenza vaccines . Vaccine . 2023 Sep 7; https://doi.org/10.1016/j.vaccine.2023.08.023. Online ahead of print.
Yih WK, Daley MF, Duffy J, Fireman B, McClure DL, Nelson JC, Qian L, Smith N, Vazquez-Benitez G, Weintraub E, Williams JTB, Xu S, Maro JC. Safety signal identification for COVID-19 bivalent booster vaccination using tree-based scan statistics in the Vaccine Safety Datalink . Vaccine . 2023 Aug 14; https://doi.org/10.1016/j.vaccine.2023.07.10 Online ahead of print.
Romanson B, Moro PL, Su JR, Marquez P, Nair N, Day B, DeSantis A, Shimabukuro TT. Notes from the Field: Safety Monitoring of Novavax COVID-19 Vaccine Among Persons Aged ≥ 12 Years – United States, July 13, 2022 – March 13, 2023 . MMWR Morb Mortal Wkly Rep . 2023 Aug 4. 72(31);850-851.
Moro PL, Zhang B, Marquez P, Reich J. Post-marketing Safety Surveillance of Hexavalent Vaccine in the Vaccine Adverse Event Reporting System . Journal of Pediatrics. 2023 Jul 28. Doi.org/10.1016/j.peds.2023.113643. Online ahead of print.
Woo EJ, Gee J, Marquez P, Baggs J, Abara WE, McNeil MM, Dimova RB, Su JR. Post-authorization safety surveillance of Ad.26.COV2.S vaccine: Reports to the Vaccine Adverse Event Reporting System and v-safe, February 2021-February 2022 . Vaccine . 2023 Jul 5; https://doi.org/10.1016/j.vaccine.2023.06.023 Online ahead of print.
Schmader KE, Liu CK, Flannery B, Rountree W, Auerbach H, Barnett ED, Schlaudecker EP, Todd CA, Poniewierski M, Staat MA, Harrington T, Li R, Broder KR, Walter EB. Immunogenicity of adjuvanted versus high-dose inactivated influenza vaccines in older adults: a randomized clinical trial . Immun Ageing . 2023 Jul 1; 20(1):30. doi: 10.1186/s12979-023-00355-7.
DeSilva MB, Haapla J, Vazquez-Benitez G, Boyce TG, Fuller CC, Daley MF, Getahun D, Hambidge SJ, Lipkind HS, Naleway AL, Nelson JC, Vesco KK, Weintraub ES, Williams JTB, Zerbo O, Kharbanda EO. Medically Attended Acute Adverse Events in Pregnant People After Coronavirus Disease 2019 (COVID-19) Booster Vaccination . Obstet Gynecol . 2023 Jul 1;142(1):125-129.
Zhou ZH, Cortese MM, Fang JL, Wood R, Hummell DS, Risma KA, Norton AE, KuKuruga M, Kirshner S, Rabin RL, Agarabi C, Staat MA, Halasa N, Ware RE, Stahl A, McMahon M, Browning P, Maniatis P, Bolcen S, Edwards KM, Su JR, Dharmarajan S, Forshee R, Broder KR, Anderson S, Kozlowski S. Evaluation of association of anti-PEG antibodies with anaphylaxis after mRNA COVID-19 vaccination . Vaccine . 2023 Jun 23; https://doi.org/10.1016/j.vaccine.2023.05.029 Online ahead of print.
Soon after mRNA COVID-19 vaccines became available for use in the United States, cases of anaphylaxis (an-uh-fuh-LAK-sis), or severe whole body allergic reactions, were reported in vaccine safety monitoring systems, raising concerns that rates of this severe allergic reaction were higher with mRNA vaccines than with other vaccines. Learning the cause of anaphylaxis following mRNA vaccination is important because multiple vaccine doses are required to be considered fully vaccinated against COVID-19. The mRNA COVID-19 vaccines contain polyethylene glycol (PEG), which has been associated with allergic reactions in some medical products. In this publication, authors share results of an evaluation to determine if PEG may cause anaphylaxis following mRNA vaccination. The study compared levels of anti-PEG Immunoglobin E (IgE), a type of antibody, in serum samples of patients who had anaphylaxis after mRNA COVID-19 vaccination to those of patients who did not have any allergic reaction after mRNA vaccination. The evaluation found that anti-PEG IgE antibodies were rare in people with anaphylaxis after mRNA vaccination and that low levels of the antibody were found in people who did not have an allergic reaction after mRNA vaccination. The results suggest that PEG allergy is not a common cause of anaphylaxis following mRNA COVID-19 vaccination.
Miller ER, Moro PL, Shimabukuro TT, Carlock G, Davis SN, Freeborn EM, Roberts AL, Gee J, Taylor AW, Gallego R, Suragh T, Su JR. COVID-19 vaccine safety inquiries to the centers for disease control and prevention immunization safety office . Vaccine . 2023 Jun 19; https://doi.org/10.1016/j.vaccine.2023.05.054 Online ahead of print.
Day B, Menschik D, Thompson D, Jankosky C, Su J, Moro P, Zinderman C, Welsh K, Dimova RB, Nair N. Reporting rates for VAERS death reports following COVID-19 vaccination, December 14, 2020-November 17, 2021 . Pharmacoepidemiol Drug Saf . 2023 Jul 9; 32(7):763-772. Online ahead of print.
Goddard K, Donahue JG, Lewis N, Hanson KE, Weintraub ES, Fireman B, Klein NP. Safety of COVID-19 mRNA Vaccination Among Young Children in the Vaccine Safety Datalink . Pediatrics . 2023 Jun 6. https://doi.org/10.1542/peds.2023-061894
Greenberg V, Vazquez-Benitez G, Kharbanda EO, Daley MF, Tseng HF, Klein NP, Naleway AL, Williams JTB, Donahue J, Jackson L, Weintraub E, Lipkind H, DeSilva MB. Tdap vaccination during pregnancy and risk of chorioamnionitis and related infant outcomes . Vaccine . 2023 May 23;41(22):3429-3435
Abara WE, Gee J, Marquez P, Woo J, Myers TR, DeSantis A, Baumblatt JAG, Woo EJ, Thompson D, Nair N, Su JR, Shimabukuro TT, Shay DK. Reports of Guillain-Barré Syndrome After COVID-19 Vaccination in the United States . JAMA Network. 2023 Feb 1;6(2):e2253845. doi:10.1001/jamanetworkopen.2022.53845.
Myers TR, Marquez PL, Gee JM, Hause AM, Panagiotakopoulos L, Zhang B, McCullum I, Licata C, Olson CK, Rahman S, Kennedy SB, Cardozo M, Patel CR, Maxwell L, Kallman JR, Shay DK, Shimabukuro TT. The v-safe after vaccination health checker: Active vaccine safety monitoring during CDC’s COVID-19 pandemic response . Vaccine . 2023 Jan 23; https://doi.org/10.1016/j.vaccine.2022.12.031 Online ahead of print.
Yih WK, Daley MF, Duffy J, Fireman B, McClure D, Nelson J, Qian L, Smith N, Vazquez-Benitez G, Weintraub E, Williams JTB, Xu S, Maro JC. A broad assessment of covid-19 vaccine safety using tree-based data-mining in the vaccine safety datalink . Vaccine . 2023 Jan 16; https://doi.org/10.1016/j.vaccine.2022.12.026 . Online ahead of print.
Xu S, Huang R, Sy LS, Hong V, Glenn SC, Ryan DS, Morrissette K, Vazquez-Benitez G, Glanz JM, Klein NP, Fireman B, McClure D, Liles EG, Weintraub ES, Tseng HF, Qian L. A safety study evaluating non-COVID-19 mortality risk following COVID-19 vaccination . Vaccine . 2023 Jan 16; https://doi.org/10.1016/j.vaccine.2022.12.036 . Online ahead of print.
Yih WK, Daley MF, Duffy J, Fireman B, McClure D, Nelson J, Qian L, Smith N, Vazquez-Benitez G, Weintraub E, Williams JTB, Xu S, Maro JC. Tree-based data mining for safety assessment of first COVID-19 booster doses in the Vaccine Safety Datalink . Vaccine . 2023 Jan 9; https://doi.org/10.1016/j.vaccine.2022.11.053 . Online ahead of print.
Moro PL, Zhang B, Ennulat C, Harris M, McVey R, Woody G, Marquez P, McNeil MM, Su JR. Safety of Co-administration of mRNA COVID-19 and seasonal inactivated influenza vaccines in the Vaccine Adverse Event Reporting System (VAERS) during July 1, 2021 – June 30, 2022 . Vaccine . 2023 Jan 9; https://doi.org/10.1016/j.vaccine.2022.12.069 Online ahead of print.
COVID-19 vaccines can be co-administered with other recommended vaccines, including seasonal flu vaccines. Vaccine Adverse Event Reporting System (VAERS) data were used to look at adverse events (AEs) following co-administration of mRNA COVID-19 and flu vaccines during July 1, 2021, through June 30, 2022. During this period, VAERS received 2,449 reports of AEs consisting of injection site reactions, headaches, pain, dyspnea, COVID-19 infection, and chest pain after co-administration of mRNA COVID-19 and flu vaccines. This review did not reveal unusual or unexpected patterns of AEs.
Malden DE, Gee J, Glenn S, Li Z, Mercado C, Ogun OA, Kim S, Lewin BJ, Ackerson BK, Jazwa A, Weintraub ES, McNeil MM, Tartof S. Reactions following Pfizer-BioNTech COVID-19 mRNA vaccination and related healthcare encounters among 7,077 children aged 5-11 years within an integrated healthcare system . Vaccine . 2023 Jan 9; https://doi.org/10.1016/j.vaccine.2022.10.079 . Online ahead of print.
Tompkins LK, Baggs J, Myers TR, Gee JM, Marquez PL, Kennedy SB, Peake D, Dua D, Hause AM, Strid P, Abara W, Rossetti R, Shimabukuro TT, Shay DK. Association between history of SARS-CoV-2 infection and severe systemic adverse events after mRNA COVID-19 vaccination among U.S. adults . Vaccine . 2022 Dec 12;S0264-410X(22)01342-1. Online ahead of print.
Goddard K, Hanson KE, Lewis N, Weintraub E, Fireman B, Klein NP. Incidence of Myocarditis/Pericarditis Following mRNA COVID-19 Vaccination Among Children and Younger Adults in the United States . Annals of Internal Medicine . 2022 Dec. doi.org/10.7326/M22-2274.
Hause AM, Marquez P, Zhang B, Myers TR, Gee J, Su JR, Blanc PG, Thomas A, Thompson D, Shimabukuro TT, Shay DK. Safety Monitoring of Bivalent COVID-19 mRNA Vaccine Booster Doses Among Persons Aged ≥ 12 Years – United States, August 31 – October 23, 2022 . MMWR Morb Mortal Wkly Rep. 2022 Nov 4; 71(44);1401–1406.
This CDC study, published November 2022, found that among people aged 12 years and older who received a bivalent mRNA COVID-19 vaccine booster dose, serious adverse events were rare. Common side effects were headache, fever, fatigue, pain where the shot was given, and chills. The study’s preliminary findings support the overall safety of bivalent mRNA COVID-19 vaccines. Health impacts associated with the original mRNA and the bivalent mRNA COVID-19 vaccines are less frequent and less serious than COVID-19 illness.
During August 31–October 23, 2022, approximately 4.7 million people aged 12 years and older received a dose of the Pfizer-BioNTech bivalent mRNA COVID-19 booster, and approximately 2.6 million people aged 18 years and older received a dose of the Moderna bivalent mRNA COVID-19 booster. CDC reviewed health impact assessments received by CDC’s V-safe and reviewed reports voluntarily submitted to the Vaccine Adverse Event Reporting System during August 31–October 23, 2022, to characterize the safety of bivalent mRNA COVID-19 booster vaccination among people in this age group. The initial safety findings for bivalent mRNA COVID-19 vaccines were generally like those from pre-authorization clinical trials. Data identified no unusual or unexpected patterns of adverse events following vaccination with the Pfizer-BioNTech or Moderna bivalent mRNA COVID-19 vaccines. Reports of serious adverse events following receipt of bivalent COVID-19 vaccine booster doses were rare. Commonly reported reactions such as headache, fever, fatigue, injection-site pain, and chills, were mild and like those reported following receipt of the monovalent mRNA COVID-19 booster dose.
Nelson JC, Ulloa-Perez E, Yu O, Cook AJ, Jackson ML, Belongia EA, Daley MF, Harpaz R, Kharbanda EO, Klein NP, Naleway AL, Tseng HF, Weintraub ES, Duffy J, Yih WK, Jackson LA. Active Post-Licensure Safety Surveillance for Recombinant Zoster Vaccine Using Electronic Health Record Data . Am J Epidemiol . 2022 Oct 4. doi: 10.1093/aje/kwac170. Online ahead of print.
Recombinant zoster vaccine (RZV) was licensed in 2017 to prevent herpes zoster and its complications in older adults. Vaccine Safety Datalink (VSD) electronic health records data were used to monitor adults ages 50 years and older who received care at VSD healthcare systems in the United States to identify increased risks of 10 pre-specified outcomes potentially related to RZV—including stroke, anaphylaxis, and Guillain-Barré syndrome (GBS). There were 647,833 RZV doses administered during January 2018 through December 2019. During this time, no increased risk of any of these outcomes was detected for RZV recipients who had received the Zoster Vaccine Live (ZVL), a live-attenuated virus vaccine, from 2013–2017, or for non-RZV vaccinated persons who had an annual check-up during the 2018–2019 study period. This study, published October 2022, provides additional reassurance of the safety of recombinant zoster vaccine.
Daley MF, Reifler LM, Glanz JM, Hambidge SJ, Getahun D, Irving SA, Nordin JD, McClure DL, Klein NP, Jackson ML, Duffy J, DeStefano F. Association Between Aluminum Exposure from Vaccines Before Age 24 Months and Persistent Asthma at Age 24-59 Months [PDF – 10 Pages] . Academic Pediatrics . 2022 Sept 27. Online ahead of print
This observational study suggests a possible association between exposure to aluminum in some childhood vaccines and development of persistent asthma in children. The study consisted of 326,991 children and found that cumulative exposure to aluminum from vaccines during the first two years of life was associated with a small increased risk of persistent asthma in children ages 2-5 years. There is overwhelming evidence of the benefits of vaccines. CDC is not changing the current routine childhood vaccination recommendations based on this single study. Small amounts of aluminum are included in many routine childhood vaccines to help the body build a stronger immunity from diseases. Further investigation is needed to explore the potential risk of aluminum exposure from routine childhood vaccines on the development of persistent asthma in children; efforts are underway.
Hause AM, Marquez P, Zhang B, Myers TR, Gee J, Su JR, Parker C, Thompson D, Panchanathan SS, Shimabukuro TT, Shay DK. COVID-19 mRNA Vaccine Safety Among Children Aged 6 Months–5 Years — United States, June 18, 2022–August 21, 2022 . MMWR Morb Mortal Wkly Rep . 2022 Sep 2;71(35);1115-1120.
Hause AM, Baggs J, Marquez P, Myers TR, Su JR, Hugueley B, Thompson D, Gee J, Shimabukuro TT, Shay DK. Safety Monitoring of Pfizer-BioNTech COVID-19 Vaccine Booster Doses Among Children Aged 5–11 Years — United States, May 17–July 31, 2022 . MMWR Morb Mortal Wkly Rep. 2022 Aug 19;71(33);1047–1051.
Goddard K, Lewis N, Fireman B, Weintraub E, Shimabukuro T, Zerbo O, Boyce TG, Oster ME, Hanson KE, Donahue JG, Ross P, Naleway A, Nelson JC, Lewin B, Glanz JM, Williams JTB, Kharbanda EO, Yih WK, Klein NP. Risk of myocarditis and pericarditis following BNT162b2 and mRNA-1273 COVID-19 vaccination . Vaccine . 2022 Aug 19; 40(35):5153-5159. Epub 2022 Jul 12.
Wong KK, Heilig CM, Hause A, Myers TR, Olson CK, Gee J, Marquez P, Strid P, Shay DK. Menstrual irregularities and vaginal bleeding after COVID-19 vaccination reported to v-safe active surveillance, USA in December, 2020-January, 2022: an observational cohort study . Lancet Digit Health . 2022 Aug 9; S2589-7500(22)00125-X. Online ahead of print.
In this study, published August 2022, CDC vaccine safety experts found that menstrual irregularities and vaginal bleeding have been reported among people who received COVID-19 vaccines. These reports were most often about menstrual cycle timing and the severity of menstrual symptoms. During December 14, 2020, through January 9, 2022, researchers analyzed data from V-safe, a web-based tool that uses text messages, emails, and web surveys to provide personalized health check-ins for people after receiving a new vaccine. Researchers identified 84,943 responses to open-ended survey questions related to menstruation or vaginal bleeding from 63,815 V-safe participants ages 18 years and older. Most respondents reported changes to the timing (i.e., cycle beginning earlier or later than expected, missed cycles, and spotting) and the severity (i.e., heavier flow, more painful than usual, or prolonged bleeding) of menstrual symptoms after COVID-19 vaccination. More respondents reported symptoms after their second vaccine dose compared with their first vaccine dose. While researchers acknowledge that an association between COVID-19 vaccination and menstrual irregularities is plausible, they also note that menstrual irregularities are common without COVID-19 vaccination and suggest that further studies are needed to assess clinical significance of menstrual irregularities after vaccination.
Hause AM, Baggs J, Marquez P, Abara WE, Baumblatt JG, Thompson D, Su JR, Myers TR, Gee J, Shimabukuro TT, Shay DK. Safety Monitoring of COVID-19 mRNA Vaccine First Booster Doses Among Persons Aged ≥12 Years with Presumed Immunocompromise Status — United States, January 12, 2022–March 28, 2022 .. MMWR Morb Mortal Wkly Rep . 2022 Jul 15; 71(28);899–903.
Fleming-Dutra KE, Wallace M, Moulia DL, Twentyman E, Roper LE, Hall E, Link-Gelles R, Godfrey M, Woodworth KR, Anderson TC, Rubis AB, Shanley E III, Jones JM, Morgan RL, Brooks O, Talbot HK, Lee GM, Bell BP, Daley M, Meyer S, Oliver SE. Interim Recommendations of the Advisory Committee on Immunization Practices for Use of Moderna and Pfizer-BioNTech COVID-19 Vaccines in Children Aged 6 Months–5 Years — United States, June 2022 . MMWR Morb Mortal Wkly Rep . 2022 Jul 1; 71(26);859–868.
Hause AM, Zhang B, Yue X, Marquez P, Myers TR, Parker C, Gee J, Su J, Shimabukuro TT, Shay DK. Reactogenicity of Simultaneous COVID-19 mRNA Booster and Influenza Vaccination in the US . JAMA Netw Open 2022 Jul 1;5(7):e2222241.doi: 10.1001/jamanetworkopen.2022.22241.
Weintraub ES, Oster ME, Klein NP. Myocarditis or Pericarditis Following mRNA COVID-19 Vaccination . JAMA . 2022 Jun 24; 5(6):e2218512. doi:10.1001/jamanetworkopen.2022.18512
DeSilva M, Haapala J, Vazquez-Benitez G, Vesco KK, Daley MF, Getahun D, Zerbo O, Naleway A, Nelson JC, Williams JTB, Hambidge SJ, Boyce TG, Fuller CC, Lipkind HS, Weintraub E, McNeil MM, Kharbanda EO. Evaluation of Acute Adverse Events after Covid-19 Vaccination during Pregnancy . N Engl J Med . 2022 Jun 22. DOI: 10.1056/NEJMc2205276. Epub ahead of print.
Moro PL, Olson CK, Clark E, Marquez P, Strid P, Ellington S, Zhang B, Mba-Jonas A, Alimchandani M, Cragan J, Moore C. Post-authorization surveillance of adverse events following COVID-19 vaccines in pregnant persons in the vaccine adverse event reporting system (VAERS), December 2020 – October 2021 . Vaccine . 2022 May 26; 40(24):3389-3394. Epub 2022 Apr 12.
Xu S, Hong V, Sy LS, Glenn SC, Ryan DS, Morrissette KL, Nelson JC, Hambidge SJ, Crane B, Zerbo O, DeSilva MB, Glanz JM, Donahue JG, Liles E, Duffy J, Qian L. Changes in incidence rates of outcomes of interest in vaccine safety studies during the COVID-19 pandemic . Vaccine . 2022 May 20;40(23):3150-3158. Epub 2022 Apr 18.
Kenigsberg TA, Hause AM, McNeil MM, Nelson JC, Shoup JA, Goddard K, Lou Y, Hanson KE, Glenn SC, Weintraub E. Dashboard development for near real-time visualization of COVID-19 vaccine safety surveillance data in the Vaccine Safety Datalink . Vaccine . 2022 May 11;40(22):3064-3071. Epub 2022 Apr 8.
Razzaghi H, Meghani M, Crane B, Ellington S, Naleway AL, Irving SA, Patel SA. Receipt of COVID-19 Booster Dose Among Fully Vaccinated Pregnant Individuals Aged 18 to 49 Years by Key Demographics . JAMA . 2022 Apr 22;327(23):2351-2354. doi:10.1001/jama.2022.683.
Zerbo O, Modaressi S, Goddard K, Lewis E, Fireman B, Daley MF, Irving SA, Jackson LA, Donahue JG, Qian L, Getahun D, DeStefano F, McNeil MM, Klein NP. Safety of measles and pertussis-containing vaccines in children with autism spectrum disorders . Vaccine . 2022 Apr 20; 40(18):2568-2573. Epub 2022 Mar 18.
This study, published April 2022, found no increased risk of adverse events (AEs) after measles or pertussis vaccination among children diagnosed with autism spectrum disorder (ASD) compared to children without an ASD diagnosis. The study included children born between 1995 and 2012 who were ages 4–7 years at the time of vaccination and included members of six healthcare delivery systems within the Vaccine Safety Datalink. The study included 14,947 children with ASD and 1,650,041 children without ASD. Results showed no differences between children with and without ASD for AEs such as fever or reactions that required emergency department visits following their measles or pertussis vaccination.
Paddock CD, Reagan-Steiner S, Su JR, Oster ME, Martines RB, Bhatnagar J, Shimabukuro TT. Autopsy Histopathologic Cardiac Findings in 2 Adolescents Following the Second COVID-19 Vaccine Dose . Arch Pathol Lab Med . 2022 Apr 8; 146 (8): 921–923.
Block JP, Boehmer TK, Forrest CB, Carton TW, Lee GM, Ajani UA, Christakis DA, Cowell LG, Draper C, Ghildayal N, Harris AM, Kappelman MD, Ko JY, Mayer KH, Nagavedu K, Oster ME, Paranjape A, Puro J, Ritchey MD, Shay DK, Thacker D, Gundlapalli AV. Cardiac Complications After SARS-CoV-2 Infection and mRNA COVID-19 Vaccination — PCORnet, United States, January 2021–January 2022 . Morb Mortal Wkly Rep . 2022 Apr 8; 71(14);517-523.
Hanson KE, Goddard K, Lewis N, Fireman B, Myers TR, Bakshi N, Weintraub E, Donahue JG, Nelson JC, Xu S, Glanz JM, Williams JTB, Alpern JD, Klein NP. Incidence of Guillain-Barré Syndrome after COVID-19 Vaccination in the Vaccine Safety Datalink . JAMA Network Open . 2022 Apr 26;5(4):e228879. doi: 10.1001/jamanetworkopen.2022.8879.
Sokolow AG, Stallings AP, Kercsmar C, Harrington T, Jimenez-Truquw N, Zhu Y, Sokolow K, Moody A, Schlaudecker EP, Walter EM, Allen Staat M, Broder KR, Creech CB. Safety of Live Attenuated Influenza Vaccine in Children with Asthma . Pediatrics . 2022 Apr 1;149(4):e2021055432. Epub 2022 Mar 28.
People ages 5 years and older with asthma should receive the quadrivalent live attenuated influenza vaccine (LAIV4) with caution because of concerns for wheezing events. This study, published in April 2022, compared the proportion of children with asthma who experienced asthma-related symptoms after receipt of LAIV4 to the proportion of children with asthma who experienced asthma-related symptoms after receipt of the quadrivalent inactivated influenza vaccine (IIV4) and found that LAIV4 was not associated with increased exacerbations, asthma-related symptoms, or decrease in expiratory flow rate compared with IIV4 among this age group. During two influenza seasons, 142 children with asthma ages 5–17 years were monitored for asthma symptoms for 42 days after IIV4 or LAIV4 vaccination. During the observation period, 18 (13%) of 142 participants had exacerbated symptoms: 8 (11%) who received the LAIV4 and 10 (15%) who received the IIV4 vaccine.
Rosenblum HG, Gee J, Liu R, Marquez PL, Zhang B, Strid P, Abara WE, McNeil MM, Myers TR, Hause AM, Su JR, Markowitz LE, Shimabukuro TT, Shay DK. Safety of mRNA vaccines administered during the initial 6 months of the US COVID-19 vaccination programme: an observational study of reports to the Vaccine Adverse Event Reporting System and v-safe . Lancet Infect Dis . 2022 Mar 7; S1473-3099(22)00054-8. Online ahead of print.
In a comprehensive analysis of mRNA COVID-19 vaccine data (i.e., Pfizer-BioNTech and Moderna), published June 2022, CDC scientists reviewed 6 months of safety data from the Vaccine Adverse Event Reporting System (VAERS), a passive vaccine safety surveillance system co-managed by CDC and the U.S. Food and Drug Administration (FDA), and V-safe, a web-based tool that uses text messages, emails, and web surveys to provide personalized health check-ins for people after receiving a new vaccine. During December 14, 2020, through June 14, 2021, more than 298 million doses of mRNA COVID-19 vaccine were administered. The review found that most reported reactions—such as headache, fatigue, and soreness at the injection site—were mild and short in duration and most reported adverse events were not serious (did not require hospitalization or cause disability, life-threatening illness, or death). These findings reinforce evidence that mRNA COVID-19 vaccines are safe and could reassure those who might be hesitant to get an mRNA vaccine because of safety concerns.
Hause AM, Baggs J, Marquez P, Abara WE, Olubajo B, Myers TR, Su JR, Thompson D, Gee J, Shimabukuro TT, Shay DK. Safety Monitoring of COVID-19 Vaccine Booster Doses Among Persons Aged 12–17 Years — United States, December 9, 2021–February 20, 2022 . MMWR Morb Mortal Wkly Rep . 2022 Mar 1;71(9);347–351.
Moro PL, McNeil MM. Successes of the CDC monitoring systems in evaluating post-authorization safety of COVID-19 vaccines [Editorial] . Expert Rev Vaccines. 2022 Mar;21(3):281-284. Epub 2022 Jan 5.
Irving SA, Groom HC, Dandamudi P, Daley MF, Donahue JG, Gee J, Hechter R, Jackson LA, Klein NP, Liles E, Myers TR, Stokley S. A decade of data: Adolescent vaccination in the vaccine safety datalink, 2007 through 2016 . Vaccine . 2022 Feb 23; 40(9):1246-1252. Epub 2022 Feb 4.
Between May 2005 and March 2007, three vaccines were recommended by the Advisory Committee on Immunization Practices for adolescents in the United States: meningococcal vaccine (MenACWY), pertussis vaccine (Tdap), and human papillomavirus vaccine (HPV). This study, published February 2022, was conducted regarding all vaccines administered to adolescents ages 11 to 18 years in the Vaccine Safety Datalink population during January 1, 2007, through December 31, 2016, to better understand vaccination coverage (the number of vaccine doses administered) for these vaccines. There were 4,884,553 vaccine visits among this age group during the study period. Vaccine coverage for Tdap, MenACWY, and HPV increased across the study period with a variety of vaccine combinations administered among both sexes. Vaccine administration in this population can provide a historical pattern to compare with future vaccination campaigns among this group.
Hause AM, Baggs J, Marquez P, Myers TR, Su JR, Blanc PG, Gwira Baumblatt JA, Woo EJ, Gee J, Shimabukuro TT, Shay DK. Safety Monitoring of COVID-19 Vaccine Booster Doses Among Adults — United States, September 22, 2021–February 6, 2022 . MMWR Morb Mortal Wkly Rep . 2022 Feb 18; 71(7);249–254.
Oster ME, Shay DK, Su JR, Gee J, Creech B, Broder KR, Edwards K, Soslow JH, Dendy JM, Schlaudecker E, Lang SM, Barnett ED, Ruberg FL, Smith MJ, Campbell MJ, Lopes RD, Sperling LS, Baumblatt JA, Thompson DL, Marquez PL, Strid P, Woo J, Puglsey R, Reagan-Steiner S, DeStefano F, Shimabukuro TT. Myocarditis Cases Reported After mRNA-Based COVID-19 Vaccination in the US from December 2020 to August 2021 JAMA . 2022 Jan 25;327(4):331-340. Online ahead of print.
Oliver SE, Wallace M, See I, Mbaeyi S, Godfrey M, Hadler SC, Jatlaoui TC, Twentyman E, Hughes MM, Rao AK, Fiore A, Su JR, Broder KR, Shimabukuro T, Lale A, Shay DK, Markowitz LE, Wharton M, Bell BP, Brooks O, McNally V, Lee GM, Talbot HK, Daley MF. Use of the Janssen (Johnson & Johnson) COVID-19 Vaccine: Updated Interim Recommendations from the Advisory Committee on Immunization Practices — United States, December 2021 . MMWR Morb Mortal Wkly Rep . 2022 Jan 21; 71(3);90–95.
Navarro RA, Lin CC, Colli B, Qian L, Liu ILA, Sy LS, Jacobsen SJ, Tartof SY. Safety of Influenza Vaccination During Orthopedic Surgery Hospitalizations J Am Acad Orthop Surg . 2022 Jan 15;30(2):e155-e163. Doi: 10.5435/JAAOS-D-21-00101.
Despite national recommendations, flu vaccination rates during hospitalizations remain low. Flu vaccination during hospitalization for orthopedic surgery was studied to address whether there is an increase for infection post discharge. Researchers conducted a study of patients ages ≥ 6 months who were hospitalized for orthopedic surgery between September 1, 2011, and March 31, 2014, to assess the association between flu vaccination during inpatient care for orthopedic surgery and rates of readmission for infections less than seven days post discharge. Results showed 2,395 hospitalizations with inpatient vaccination and 21,708 hospitalizations without inpatient vaccination. Those vaccinated during inpatient care did not show a significant increase in readmission for infection. Data supports the recommendation of vaccinating orthopedic surgery patients against influenza.
Woo EJ, Moro PL. Postmarketing safety surveillance of high-dose quadrivalent influenza vaccine: Reports to the Vaccine Adverse Event Reporting System . Vaccine. 2022 Jan 12. ISSN: 0264-410X. Online ahead of print.
On November 4, 2019, the U.S. Food and Drug Administration approved the high-dose flu vaccine (Fluzone High-Dose Quadrivalent; QIV-HD) for flu prevention in individuals ages 65 years and older. A clinical trial did not show major differences in adverse events (AEs) following vaccination with QIV-HD versus Fluzone High-Dose (trivalent). Researchers reviewed and summarized reports of AEs after QIV-HD vaccination to the Vaccine Adverse Event Reporting System (VAERS) to learn more. During July 30, 2020, through June 30, 2021, VAERS received 2,122 reports after vaccination with QIV-HD. The majority (95.1%) were non-serious and included events that had been observed in the clinical trial such as injection site reactions, fever, headache, and nausea. The most common serious events included Guillain-Barré syndrome, cellulitis or other local reactions, constitutional signs/symptoms (e.g., fever), and cardiovascular events. This review, published February 2022, did not reveal new safety concerns.
Lipkind HS, Vazquez-Benitez G, DeSilva M, Vesco KK, Ackerman-Banks C, Zhu J, Boyce TG, Daley MF, Fuller CC, Getahun D, Irving SA, Jackson LA, Williams JTB, Zerbo O, McNeil MM, Olson CK, Weintraub E, Kharbanda KO. Receipt of COVID-19 Vaccine During Pregnancy and Preterm or Small-for-Gestational-Age at Birth — Eight Integrated Health Care Organizations, United States, December 15, 2020-July 22, 2021 MMWR Morb Mort Wkly Rep. 2022 Jan 4:71 (1);26-30. Early release.
DeSilva MB, Haapal J, Vazquez-Benitez G, Daley MF, Nordin JD, Klein NP, Henninger ML, Williams JTB, Hambidge SJ, Jackson ML, Donahue JG, Qian L, Lindley MC, Gee J, Weintraub ES, Kharbanda EO. Association of the COVID-19 Pandemic with Routine Childhood Vaccination Rates and Proportion Up to Date with Vaccinations Across 8 US Health Systems in the Vaccine Safety Datalink JAMA Pediatr. 2022 Jan 1;176(1):68-77. Doi: 10.1001/jamapediatrics.2021.4251.
Woo EJ, Mba-Jonas A, Dimova RB, Alimchandani M, Zinderman CE, Nair N. Association of Receipt of the Ad26.COV2.S COVID-19 Vaccine With Presumptive Guillain-Barre Syndrome, February-July 2021 . Jama . 2021 Oct 26; 326(16):1606-1613. doi: 10.1001/jama.2021.16496.
Groom HC, Crane B, Naleway AL, Weintraub E, Daley MF, Wain K, Kurilo MB, Burganowski R, DeSilva MB, Donahue JG, Glenn SC, Goddard K, Jackson ML, Kharbanda EO, Lewis N, Lou Y, Lugg M, Scott E, Sy LS, Williams JTB, Irving SA. Monitoring vaccine safety using the Vaccine Safety Datalink: Assessing capacity to integrate data from Immunization Information Systems Vaccine . 2022 Jan 31;40(5):752-756. Epub 2021 Dec 31.
The Vaccine Safety Datalink (VSD) uses vaccination data collected from electronic health records at eight integrated health systems to monitor vaccine safety. To capture additional data about vaccines administered outside traditional health systems, however, vaccine safety researchers looked to the state and local Immunization Information Systems (IIS), which collects vaccination data from non-traditional health settings. Researchers conducted a survey from 2009-2010 to evaluate how VSD incorporates state and local IIS data. Results at that time showed that only three of the then seven VSD sites had received any state or local IIS data. To evaluate the current status of IIS data exchange with VSD, researchers surveyed the now eight VSD sites in January 2021. The survey shows that all eight receive and integrate COVID-19 vaccine data from IIS, which positions the VSD well for conducting quality assessments of vaccine safety.
Hause AM, Baggs J, Marquez P, Myers TR, Gee J, Su JR, Zhang B, Thompson D, Shimabukuro TT, Shay DK. COVID-19 Vaccine Safety in Children Ages 5-11 years — United States, November 3-December 19, 2021 . MMWR Morb Mort Wkly Rep. 2021 Dec 31:70(5152);1755-1760.
Abara WE, Gee J, Mu Y, Deloray M, Ye T, Shay DK, Shimabukuro T. Expected Rates of Select Adverse Events following Immunization for COVID-19 Vaccine Safety Monitoring J Infect Dis . 2021 Dec 27;jiab628. Online ahead of print.
Perez-Vilar S, Dores G, Marquez PL, Ng CS, Cano MV, Rastogi A, Lee L, Su JR, Duffy J. Safety surveillance of meningococcal group B vaccine (Bexsero®), Vaccine Adverse Event Reporting System, 2015-2018 . Vaccine . 2022 Jan 21;40(2):247-254. Epub 2021 Dec 7.
Glanz JM, Clarke CL, Daley MF, Shoup JA, Hambidge SJ, Williams JTB, Groom HC, Kharbanda EO, Klein NP, Jackson LA, Lewin BJ, McClure DL, Xu S, DeStefano F. The Childhood Vaccination Schedule and the Lack of Association with Type 1 Diabetes . Pediatrics. 2021 Dec 1;148(6):e2021051910. Doi: 10.1542/peds.2021-051910 Online ahead of print.
Goud R, Lufkin B, Duffy J, Whitaker B, Wong HL, Liao J, Lo AC, Weintraub E, Kelman JA, Forshee RA. Risk of Guillain-Barré Syndrome Following Recombinant Zoster Vaccine in Medicare Beneficiaries . JAMA Intern Med. 2021 Dec 1;181(12):1623-1630. Doi: 10.1001/jamainternmed.2021.6227. Online ahead of print.
Moro PL, Panagiotakopoulos L, Oduyebo T, Olson CK, Myers T. Monitoring the safety of COVID-19 vaccines in pregnancy in the US . Human Vaccines & Immunotherapies. 2021 Nov 10. doi.org/10.1080/21645515.2021.1984132.
Chapin-Bardales J, Myers T, Gee J, Shay DK, Marquez P, Baggs J, Zhang B, Licata C, Shimabukuro TT. Reactogenicity within 2 weeks after mRNA COVID-19 vaccines: Findings from the CDC v-safe surveillance system . Vaccine. 2021 Nov 26;39(48):7066-7073. Epub 2021 Oct 16.
Pingali C, Meghani M, Razzaghi H, , Lamias MJ, Weintraub E, Kenigsberg TA, Klein NP, Lewis N, Fireman B, Zerbo O, Bartlett J, Goddard K, Donahue J, Hanson K, Naleway A, Kharbanda EO, Yih K, Clark Nelson J, Lewin BJ, Williams JTB, Glanz JM, Singletom JA, Patel SA. COVID-19 Vaccination Coverage Among Insured Persons Aged ≥ 16 years, by Race/Ethnicity and Other Selected Characteristics — Eight Integrated Health Care Organizations, United States, December 14, 2020-May 15, 2021 . MMWR Morb Mortal Wkly Rep . 2021 Jul 16;70(28):985-990.
Shay DK, Shimabukuro TT DeStefano F. Myocarditis Occurring After Immunization with mRNA-Based COVID-19 Vaccines: Editorial . JAMA Cardiol. Published online June 29, 2021. doi:10.1001/jamacardio.2021.2821.
Razzaghi H, Meghani M, Pingali C, Crane B, Naleway A, Weintraub E, Kenigsberg TA, Lamias MJ, Irving SA, Kauffman TL, Vesco KK, Daley MF, DeSilva M, Donahue J, Getahun D, Glee S, Hambidge SJ, Jackson LJ, Lipkind HS, Nelson J, Zerbo O, Oduyebo T, Singleton JA, Patel SA. COVID-19 Vaccination Coverage Among Pregnant Women During Pregnancy — Eight Integrated Health Care Organizations, United States, December 14, 2020-May 8, 2021 . MMWR Morb Mortal Wkly Re p. 2021 Jun 18;70(24):895-899.
Naleway AL, Crane B, Irving SA, Bachman D, Vesco KK, Daley MF, Getahun D, Glenn SC, Hambidge SJ, Jackson LA, Klein NP, McCarthy NL, McClure DL, Panagiotakopoulos L, Panozzo CA, Vazquez-Benitez G, Weintraub E, Zerbo O, Kharbanda EO. Vaccine Safety Datalink infrastructure enhancements for evaluating the safety of maternal vaccination Ther Adv Drug Saf. 2021 Jun 14;12:20420986211021233. eCollection 2021.
Monitoring vaccine safety during pregnancy is important because pregnant women have historically been excluded from vaccine clinical trials. The Vaccine Safety Datalink (VSD) conducts near-real-time surveillance on vaccine safety. When data is collected, researchers use specific algorithms to identify particular subjects. Since 2012, VSD researchers have used an algorithm called Pregnancy Episode Algorithm (PEA) to identify medical records of people who have been vaccinated during pregnancy. In this study, researchers wanted to update and enhance the PEA to include the updated medical codes and incorporate sources of data about how far along the person is in the pregnancy. The researchers did so by developing the Dynamic Pregnancy Algorithm (DPA), which identifies people earlier in their pregnancies. The enhanced PEA and the new DPA will assist researchers in better evaluating the safety of current and future vaccinations administered during or around the time of pregnancy.
Xu S, Clarke Cl, Newcomer SR, Daley MF, Glanz JM. Sensitivity analyses if unmeasured and partially-measure confounders using multiple imputation in a vaccine safety study . Pharmacoepidemiol Drug Saf. 2021 Sept;30(9):1200-1213. Epub 2021 May 31.
Liles E, Irving SA, Dandamudi P, Belongia EA, Daley MF, DeStefano F, Jackson LA, Jacobsen SJ, Kharbanda E, Klein NP, Weintraub E, Naleway AL. Incidence of pediatric inflammatory bowel disease within the Vaccine Safety Datalink network and evaluation of association with rotavirus vaccination Vaccine . 2021 Jun 16;39(27):3614-3620. Epub 2021 May 26.
Multiple studies in the last 20 years have reported an increase of Inflammatory Bowel Disease (IBD) in children. IBD is when the intestines become inflamed, which causes abdominal pain, cramping, and chronic diarrhea. The rotavirus vaccine, a routine pediatric immunization, contains a weakened form of rotavirus that can inflame the lining of the gut. This inflammation could potentially trigger IBD. Researchers wanted to study if there was a connection between pediatric IBD and rotavirus vaccination. From 2007 through 2016, over 2.4 million children ages 10 years and younger from the Vaccine Safety Datalink were included in the analysis. Of the 2.4 million, 333 cases of IBD were identified with rates of IBD higher in children ages 5 to 9 years. The analyzed data suggests there is a small increase of IBD overall in pediatrics with no connection with the rotavirus vaccine. Parents should make sure their children receive their scheduled vaccinations and talk to a healthcare provider about specific concerns.
Gubernot D, Jazwa A, Niu M, Baumblatt J, Gee J, Moro P, Duffy J, Harrington T, McNeil MM, Broder K, Su J, Kamidani S, Olson CK, Panagiotakopoulos L, Shimabukuro T, Forshee R, Anderson S, Bennet S. U.S. Population-Based background incidence rates of medical conditions for use in safety assessment of COVID-19 vaccines . Vaccine. 2021 Jun 23;39(28):3666-3677. Epub 2021 May 14.
Daley MF, Reifler LM, Shoup JA, Narwaney KJ, Kharbanda EO, Groom HC, Jackson ML, Jacobsen SJ, McLean HQ, Klein NP, Williams JTB, Weintraub ES, McNeil MM, Glanz JM. Temporal Trends in Undervaccination: a Population-Based Cohort Study Am J Prev Med . 2021 Jul;61(1):64-72. Epub 2021 Apr 30.
Kharbanda EO, Vazquez-Benitez G, DeSilva MB, Naleway AL, Klein NP, Hechter RC, Glanz JM, Donahue JG, Jackson LA, Sheth SS, Greenberg V, Panagiotakopoulos L, Mba-Jonas A, Lipkind HS. Association of Inadvertent 9-Valent Human Papillomavirus Vaccine in Pregnancy with Spontaneous Abortion and Adverse Birth Outcomes JAMA Netw Open .2021 Apr 1;4(4):e214340.
Woo EK, Moro PL. Postmarketing safety surveillance of quadrivalent recombinant influenza vaccine: Reports to the vaccine adverse event reporting system. Vaccine. 2021 Mar 4;S0264-410X(21)00232-2. Epub ahead of print.
The recombinant hemagglutinin quadrivalent influenza vaccine (Flublok Quadrivalent; RIV4) was approved by FDA in October 2016 for persons 18 years and older to reduce the risk from flu and flu-related complications. To analyze the safety profile of RIV4 since its approval, researchers reviewed adverse events reported to VAERS. From July 1, 2017 through June 30, 2020, VAERS received 849 reports after RIV4 vaccination. A majority of reports (810; 95%) were non-serious; injection site reactions were reported most often. There were 131 reports of allergic reactions. A majority of allergic reactions (127) were reported as non-serious, but required immediate medical care. Reports of allergic reactions do not necessarily suggest that RIV4 is particularly allergenic; some individuals may have a hypersensitivity to drug or vaccine exposure. Among serious adverse event reports, there were 10 cases of Guillain-Barré syndrome. Overall, the analysis did not identify any new safety concerns of RIV4.
Perez-Vilar S, Hu M, Weintraub, Arya D, Lufkin B, Myers T, Woo EJ, Lo AC, Cho S, Swarr M, Liao J, Wernecke M, MaCurdy T, Kelman J, Anderson S, Duffy J, Forshee RA. Guillain-Barré Syndrome After High-Dose Influenza Vaccine Administration in the United States, 2018-2019 Flu Season J Infect Dis . 2021 Feb 13;223(3):416-425. Doi: 10.1093/infdis/jiaa543.
Su JR, McNeil MM, Welsh KJ, Marquez PL, Ng C, Yan M, Cano MV Myopericarditis after vaccination, Vaccine Adverse Event Reporting System (VAERS), 1990-2018 . Vaccine . 2021 Jan 29; 39(5):839-845. Epub 2021 Jan 6.
Myopericarditis, an inflammation of the heart muscle and tissue around the heart, has many causes including viral infections. While not confirmed as a cause, myopericarditis after vaccination has been periodically reported. Researchers identified reports of myopericarditis following vaccination submitted to the Vaccine Adverse Event Reporting System (VAERS) from 1990–2018. During 1990–2018, VAERS received a total 620,195 reports: 708 (0.1%) met the case definition or were physician-diagnosed as myopericarditis. Most (79%) reports described males, 69% were serious, and 72% had symptom onset within 2 weeks of vaccination. Overall, smallpox (59%) and anthrax (23%) vaccines were most commonly reported, with higher reporting rates only after smallpox vaccine. Myopericarditis remains rarely reported after vaccines licensed for use in the United States. In this analysis, myopericarditis was most commonly reported after smallpox vaccine, and less commonly after other vaccines.
Moro PL, Marquez P. Reports of cell-based influenza vaccine administered during pregnancy in the Vaccine Adverse Event Reporting System (VAERS), 2013-2020. Vaccine. 2021 Jan 22;39(4):678-681. Epub 2020 Dec 25
Flucelvax (ccIIV3 or ccIIV4; ccIIV) was approved by FDA for use in persons aged 18 years and older. There are limited data on the safety of ccIIV in pregnant women or their infants. To assess the safety of ccIIV given during pregnancy, researchers searched VAERS for reports of adverse events (AEs) from July 1, 2013 through May 31, 2020. During that time, VAERS received 4,852 reports following ccIIV, and 391 reports included pregnant women (8%). Of those, 24 (6.1%) were classified as serious. Two neonatal deaths were reported; no maternal deaths occurred. Among the 340 reports with trimester information, ccIIV was administered during the second trimester in 170 (50%). The most frequently reported pregnancy-specific AE was premature delivery (85; 21.7%). There were 62 reports (15.9%) of low birth weight of infants and 15 report of birth defects. While these results are different than previous pregnancy reviews after inactivated influenza vaccines (IIV), no safety concerns were identified.
Kharbanda EO, Vazquez-Benitez G, DeSilva MB, Spaulding AB, Daley MF, Naleway AL, Irving SA, Klein NP, Tseng HF, Jackson LA, Hambridge SJ, Olaiya O, Panozzo CA, Myers TR, Romitti PA. Developing Algorithms for Identifying Major Structural Birth Defects Using Automated Electronic Health Data. Pharmacoepidemiol Drug Saf. 2021 Feb;30(2):266-274. Epub 2020 Dec 3.
Vaccine Safety Datalink (VSD) researchers often rely on electronic health records when conducting observational studies. To improve case identification, researchers use algorithms to accurately identify diagnoses for particular conditions or diseases. Algorithms used in previous studies for selected birth defects were based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. In October 2015, the United States transitioned to the 10 th edition (ICD-10-CM). In this study, researchers updated, validated, and refined algorithms for use with ICD-10-CM codes. Final algorithms were applied to a group of live births delivered between October 2015 through September 2017 at 8 VSD sites and were compared to the original ICD-9-CM algorithms applied to a group of live births in 2004-2013. Results demonstrated that the new ICD-10-CM algorithms can be used for future studies of maternal vaccine safety.
Panagiotakopoulos L, McCarthy NL, Tepper NK, Kharbanda NK, Lipkind HS, Vazquez-Benitez G, McClure DL, Greenberg V, Getahun D, Glanz JM, Naleway AL, Klein NP, Nelson JC, Weintraub ES. Evaluating the Association of Stillbirths After Maternal Vaccination in the Vaccine Safety Datalink. Obstet Gynecol. 2020 Dec;136(6):1086-1094.
The Advisory Committee on Immunization Practices recommends women receive vaccinations against flu and tetanus, diphtheria, and acellular pertussis (Tdap) during each pregnancy. Despite reassuring safety data, pregnant women often have concerns about the safety of vaccines for them and their babies. Researchers used the VSD to evaluate whether vaccinations given during pregnancy were associated with stillbirth (fetal death occurring on or after 20 weeks gestation). The study compared 795 stillbirths (confirmed with medical record review) and 3,180 live birth controls between September 30, 2015 and January 1, 2020. Researchers found 51.7% of stillbirth cases and 52.9% live birth controls were exposed to vaccines during pregnancy, including flu and Tdap vaccines. The findings show that vaccination during pregnancy did not increase the risk of stillbirth, including recommended, non-recommended, and contraindicated vaccines. Overall, the study results support the safety of ACIP recommendations during pregnancy.
Haber P, Tate J, Marquez PL, Moro PL, Parashar U. Safety Profile of rotavirus vaccines among individuals aged ≥8 months of age, United States, vaccine adverse event reporting system (VAERS), 2006-2019. Vaccine. 2020 Nov 29;S0264-410X(20)31466-3. Online ahead of print.
Two live oral rotavirus vaccines, RotaTeq (RV5) and Rotarix (RV1), were introduced into the routine vaccination program in 2006 and 2008, respectively. RV1 is administered at ages 2 and 4 months and RV5 is administered at ages 2, 4, and 6 months. The series is recommended prior to 8 months of age to decrease the risk of intussusception (IS), an intestinal obstruction common in younger children. However, there is limited safety data on the vaccines when given to children older than 8 months. Researchers in the Vaccine Adverse Event Reporting System (VAERS) analyzed reports of adverse events (AEs) following rotavirus vaccination submitted January 2006 through December 2019. A total 344 reports were submitted: 309 reports included children 8 months to 5 years of age, and 35 reports included children 6 years and older. While known AEs were identified – diarrhea, fever and vomiting – no new or unexpected safety concerns were identified for those vaccinated beyond the recommended age.
Perez-Vilar S, Hu M, Weintraub E, Arya D, Lufkin B, Myers T, Woo EJ, Lo A, Chu S, Swarr M, Liao J, Wernecke M, MaCurdy T, Kelman J, Anderson S, Duffy J, Forshee RA. Guillain-Barré Syndrome After High-Dose Influenza Vaccine Administration in the United States, 2018–2019 Season J Infect Dis. 2020 Nov 2; jiaa543. Online ahead of print.
While an association between influenza vaccination and Guillain-Barré syndrome (GBS) was first noticed in 1976, studies in subsequent flu seasons have assessed the risk and found either no or small risk of GBS following influenza vaccination. Early during the 2018-2019 flu season, the Vaccine Safety Datalink (VSD) identified a statistical signal for an increased risk of GBS in days 1–42 following high-dose influenza vaccine (IIV3-HD) administration. The signal was rapidly evaluated using Medicare data by conducting early- and end-of-season analyses. The Medicare analyses, which included more than 7 million IIV3-HD vaccinations, did not detect a statistically significant increased GBS risk. The VSD end-of-season analysis also did not find an increased GBS risk among more than 600,000 IIV3-HD vaccinations. These analyses determined that if a GBS risk existed, it was similar to that from prior seasons.
Duffy J, Marquez P, Dores GM, Ng C, Su J, Cano J, Perez-Vilar S. Safety Surveillance of bivalent meningococcal group B vaccine, Vaccine Adverse Event Reporting System, 2014-2018. Open Forum Infec Dis. 2020 Oct 27. Online ahead of print.
Licensed in October 2014, MenB-FHbp was the first meningococcal group B vaccine approved for use in the United States. The Advisory Committee on Immunization Practices recommends the 3-dose series for individuals aged 10-25 years who are at an increased risk of meningococcal B disease. Researchers reviewed reports of adverse events (AEs) following MenB-FHbp submitted to the Vaccine Adverse Event Reporting System (VAERS) from October 2014 through December 2018. During this time period, VAERS received 2,106 reports involving MenB-FHbp, representing 698 reports per million doses distributed (over 3 million doses were distributed in this analysis period). The most common AEs reported were fever (27%), headache (25%), and pain (16%). Overall, the review did not identify any new safety issues. The most commonly reported AEs following MenB-FHbp were consistent with those identified in clinical trials as described in the package insert.
Miller ER, McNeil MM, Moro PL, Duffy J, Su JR. The reporting sensitivity of the Vaccine Adverse Event Reporting System (VAERS) for anaphylaxis and for Guillain-Barré syndrome. Vaccine. 2020 Nov 3;38(47)7458-7463. Epub 2020 Oct 7.
Underreporting is an important limitation that is common to passive surveillance systems. The number of adverse events (AEs) that occur after vaccination and the percentage of those that get reported to the Vaccine Adverse Event Reporting System (VAERS) is unknown. To determine the sensitivity of VAERS in capturing AE reports, researchers analyzed pre-specified outcomes – anaphylaxis and Guillain-Barré syndrome (GBS) – reported to VAERS and determined if they are similar to previous estimates for other severe AEs. These estimates used were obtained from published studies of the Vaccine Safety Datalink of anaphylaxis and GBS following vaccination. VAERS sensitivity for capturing anaphylaxis after seven different vaccines ranged from 13-76%; sensitivity for capturing GBS after three different vaccines ranged from 12-64%. For anaphylaxis and GBS, VAERS sensitivity is comparable to previous estimates for detecting important AEs following vaccination.
Panagiotakopoulos L, Myers TR, Gee J, Lipkind HS, Kharbanda EO, Ryan DO, Williams, JTB, Naleway AL, Klein NP, Hambridge SJ, Jacobsen SJ, Glanz JM, Jackson LA, Shimabukuro TT, Weintraub ES. SARS-CoV-2 Infection Among Hospitalized Pregnant Women: Reasons for Admission and Pregnancy Characteristics – Eight U.S. Health Care Centers, March 1-May 30, 2020. MMWR Morb Mortal Wkly Rep 2020;69:1355-1359. 2020 Sept 25.
As part of CDC surveillance of COVID-19 hospitalizations, Vaccine Safety Datalink researchers identified 105 pregnant women with SARS-CoV-2 infection from March 1 through May 30, 2020. Of those, 43 (41%) were admitted for COVID-19 illness (e.g., worsening respiratory status) and 62 (59%) were admitted for pregnancy-related treatment or procedures (e.g, delivery) and identified with SARS-CoV-2 infection. More pregnant women with prepregnancy obesity and gestational diabetes were hospitalized for the treatment of COVID-19 illness than pregnant women admitted for pregnancy-related reasons. Intensive care was required in 30% (13/43) of pregnant women admitted for COVID-19 illness, and one pregnant woman died from COVID-19. Adverse birth outcomes, such as preterm delivery and stillbirth, were more common among pregnant women with SARS-CoV-2 infection, regardless of symptoms. Pregnant women should take preventive measures to protect themselves against SARS-CoV-2 infection.
Mbaeyi SA, Bozio CH, Duffy J, Rubin LG, Hariri S, Stephens DS, MacNeil JR. Meningococcal Vaccination: Recommendations of the Advisory Committee on Immunization Practices, United States, 2020. MMWR Recomm Rep. 2020 Sept;69(No. RR-9):1-41.
This report compiles and summarizes all recommendations from CDC’s Advisory Committee on Immunization Practices (ACIP) for use of meningococcal vaccines in the United States; it is intended for use by clinicians and public health providers. A systematic literature search was completed to review all available evidence on the immunogenicity, effectiveness, and safety of U.S. licensed quadrivalent meningococcal conjugate (MenACWY) and serogroup B meningococcal (MenB) vaccines among age groups for which the vaccines were approved. To further assess vaccine safety, data were evaluated from the Vaccine Adverse Event Reporting System (VAERS) and the Vaccine Safety Datalink (VSD), two post-licensure surveillance systems for adverse events.
Myers TR, McNeil MM, NG CS, Li R, Marquez PL, Moro PL, Omer SB, Cano MV. Adverse Events Following Quadrivalent Meningococcal Diphtheria Toxoid Conjugate Vaccine (Menactra ®) Reported to the Vaccine Adverse Event Reporting System (VAERS), 2005-2016. Vaccine. 2020 Sep 11;38(40):6291-6298 Epub 2020 Jul 31.
Licensed in January 2005, Menactra was the first quadrivalent meningococcal conjugate vaccine approved to provide protection against invasive meningococcal disease. It is licensed for use in individuals aged 9 months through 55 years. Researchers reviewed reports of adverse events (AEs) after Menactra to the Vaccine Adverse Event Reporting System (VAERS) from 2005-2016, including serious reports, selected pre-specified outcomes, and use during pregnancy. From January 2005 thought June 2019, VAERS received 13,075 reports of AEs following Menactra vaccination. Most reports (94%) were classified as non-serious; commonly reported AEs included injection site redness and swelling, fever, headache, and dizziness. There were 36 reports of death following Menactra; researchers did not find any evidence to suggest the vaccine caused the deaths. This review did not reveal any new safety concerns and provides further reassurance regarding the safety of Menactra.
Moro PL, Woo EL, Marquez P, Cano M. Monitoring the safety of high-dose, trivalent inactivated influenza vaccine in the vaccine adverse event reporting system (VAERS), 2011-2019. Vaccine. 2020 Aug 18;38(37):5923-5926. Epub 2020 Jul 21.
Older adults are at higher risk of developing serious complications from flu. In December 2009, the high-dose trivalent influenza vaccine (IIV3-HD) was licensed for adults 65 years and older. Using the Vaccine Adverse Event Reporting System, researchers analyzed the 12,320 reports submitted after IIV3-HD vaccination from 2011-2019. Of the total, there were 61 reports of GBS and 13 of anaphylaxis. Nearly 6% of all reports were classified as serious (723). The most commonly reported serious events were fever (30.2%), weakness (28.9%), and shortness of breath (24.9%). There were 55 reports of death following IIV3-HD, and cause of deaths reported were typical for those in this age group with no evidence to suggest the vaccine caused the deaths. There were reports of 13 pregnant women and 59 children who inadvertently received IIV3-HD. Overall, this review of IIV3-HD did not reveal any new safety concerns among individual adults 65 years and older.
Wang SV, Stefanini K, Lewis E, Newcomer SR, Fireman B, Daley MF, Glanz JM, Duffy J, Weintraub E, Kulldorf M. Determining Which of Several Simultaneously Administered Vaccines Increase Risk of an Adverse Event Drug Saf. 2020 Oct;43(10):1057-1065. Epub 2020 Jul 1.
The CDC childhood immunization schedule recommends all children get vaccinated. Children may get multiple vaccinations on the same day. If a child has an adverse event after getting multiple vaccinations, it would be difficult to determine which vaccine, if any, caused the event. Using observed data from two Vaccine Safety Datalink sites, researchers developed a systematic process to determine which of the simultaneously administered vaccine(s) are most likely to have caused an observed increase in risk of an adverse event. From the five scenarios simulated, the process determined which of the vaccines contributed to the simulated excess risk. This process could be used again in the future to provide valuable information on the potential risk of adverse events following individual and simultaneous vaccinations.
Hesse EM, Navarro RA, Daley MF, Getahun D, Henninger ML, Jackson LA, Nordin J, Olson SC, Zerbo O, Zheng C, Duffy J. Risk for Subdeltoid Bursitis After Influenza Vaccination: A Population-Based Cohort Study Ann Intern Med. 2020 Aug 18;173(4):253-261. Epub 2020 Jun 23.
Subdeltoid bursitis, characterized by pain or loss of motion in the shoulder, has been reported as an adverse event following intramuscular vaccination in the upper arm, and most case reports involved the influenza vaccine. With over 160 million U.S. doses distributed annually and recommended to everyone over 6 months of age, researchers wanted to estimate the risk of subdeltoid bursitis following influenza vaccination. In this cohort study using data from 7 Vaccine Safety Datalink sites, researchers included people who received an inactivated influenza vaccine during the 2016–2017 flu season, totaling 2.9 million people. The analysis to calculate risk of bursitis compared cases that appeared 3 days following vaccination to a control period 30-60 days following vaccination. There were an estimated 7.78 (95% CI 2.19-13.38) additional cases of bursitis per one million people vaccinated. While an increased risk of bursitis following vaccination was present, the overall risk was small.
Hause AM, Panagiotakopoulos L, Weintraub E, Sy LS, Glenn SC, Tseng HF, McNeil MM. Adverse Outcomes in Pregnant Women Hospitalized with Respiratory Syncytial Virus Infection: A Case-Series Clin Infect Dis. 2020 Jun 2; ciaa668. Online ahead of print.
Respiratory syncytial virus (RSV) is a common respiratory virus that usually causes mild, cold-like symptoms and can be serious for infants and older adults. RSV infection in pregnant women has not been well described and can be clinically severe and result in hospitalization. CDC has emphasized the need to characterize RSV infection during pregnancy, including burden of the illness, risk factors for severe disease, and pregnancy and neonatal outcomes. In this study, researchers identified 25 pregnant women at Kaiser Permanente Southern California who tested positive for RSV. Ten of those women (40%) were hospitalized: five were diagnosed with pneumonia/atelectasis, two with respiratory failure (one requiring mechanical ventilation), and two with sepsis. Six women had a pregnancy complication during hospitalization, including one induced preterm birth. The information from this study may inform the benefits of maternal vaccination for an RSV vaccine intended to protect infants.
Suragh TA, Hibbs B, Marquez P, McNeil MM. Age inappropriate influenza vaccination in infants less than 6 months old, 2010-2018 Vaccine. 2020 May 6;38(21):3747-3751. Epub Apr 6.
Annual influenza (flu) vaccination is recommended for everyone 6 months or older, and vaccination in infants less than 6 months old is a vaccine error. There are few safety studies in this population. Researchers searched the Vaccine Adverse Event Reporting System (VAERS) for reports of adverse events (AEs) following flu vaccination in infants less than 6 months old from 2010-2018. A total of 114 reports were found; 21 reported a specific AE. Fever, irritability, crying and diarrhea were the most common symptoms. Researchers identified several risk factors: 1) individuals getting vaccinated together resulting in patient mix-ups, 2) healthcare provider not verifying the patient’s information, and 3) provider confusion due to similarities in vaccines’ packaging and names of vaccines that sound alike. This study adds valuable information about the general absence of serious AEs in infants vaccinated with flu vaccine; yet, providers should be vigilant to avoid these preventable errors.
Glanz JM, Clarke CL, Xu S, Daley MF, Shoup JA, Schroeder EB, Lewin BL, McClure DL, Kharbanda E, Klein NP, DeStefano F. Association between Rotavirus Vaccine and Type 1 Diabetes in Children. JAMA Pediatr. 2020 May 1;174(5):455-462. Epub 2020 Mar 9.
Type 1 diabetes mellitus (T1DM) is an autoimmune disease that tends to occur in genetically susceptible individuals and is primarily diagnosed during childhood. Previous research suggests that a live attenuated rotavirus vaccine could either increase or decrease the risk of T1DM in early childhood. Researchers conducted a study of children enrolled in 7 integrated healthcare organizations in the Vaccine Safety Datalink. There were 386,937 children enrolled born between 2006 and 2014. During their infancy, 360,169 children were exposed to the full series of rotavirus vaccination, 15,765 partially exposed and 11,003 unexposed. By the end of 2017, 464 children had developed T1DM. The incidence of T1DM was not significantly different across the vaccination groups, indicating that rotavirus vaccination is not associated with T1DM in children.
Hause AM, Hesse EM, Ng C, Marquez P, McNeil MM, Omer SB. Association Between Vaccine Exemption Policy Change in California and Adverse Event Reporting. Pediatr Infec Dis J., May; 39(5):369-373. Epub 2020 Mar 5.
California Senate Bill 277 (SB277) eliminated non-medical immunization exemptions starting February 19, 2015. Since the bill’s introduction, the rate of medical exemptions in the state has increased. There is a perception that filing a report to the Vaccine Adverse Event Reporting System (VAERS) may aid in applying for a medical exemption. Researchers wanted to describe trends of reporting to VAERS after SB277. From June 2011-July 2018, 6,703 VAERS reports were submitted from California. Parent-submitted reports increased after SB277, from 14% to 23%. The median reporting time by parents increased from 9 days post-vaccination in 2013-2014 to 31 days in 2016-2017. Overall, there was an increase in reports submitted more than 6 months post-vaccination and reports describing behavioral and developmental symptoms. These changes in reporting patterns after SB277’s implementation may indicate more parents are using VAERS to assist in applying for a medical exemption for their child.
Newcomer SR, Daley MF, Marwaney KJ, Xu S, DeStefano F, Groom HC, Jackson ML, Lewin BJ, McLean HQ, Nordin JD, Zerbo O, Glanz JM. Order of Live and Inactivated Vaccines and Risk of Non-vaccine-targeted Infections in US Children 11-23 Months of Age. Pediatr Infect Dis J., 2020 Mar:39(3);247-253.
Children in the United States receive up to 28 vaccine doses against 14 diseases before their 2nd birthday and 3 are live vaccines. Some observational studies suggest that receiving live vaccines may be associated with decreased non-vaccine targeted infection (NVTI) risk. Researchers conducted a retrospective study within the Vaccine Safety Datalink to estimate the risk of NVTIs based on most recent vaccine type received in children 11-23 months of age. Electronic health records and immunization data were reviewed from children born between 2003-2013. Among 428,608 children, 4.9% had more than 1 immunization visit with live vaccines only and 10.3% had a NVTI. Researchers observed modest associations between live vaccine receipt and a decreased risk of NVTIs, which may have been influenced by multiple factors, including healthcare-seeking behavior. In total, the results support the current sequence of live and inactivated vaccines in the U.S. vaccine schedule with respect to NVTI.
Walter EB, Klein NP, Wodi AP, Roundtree W, Todd CA, Wiesner A, Duffy J, Marquez PL, Broder K. Fever after Influenza, Diphtheria-Tetanus-Acellular Pertussis, and Pneumococcal Vaccinations. Pediatrics . 2020 Mar;145(3):e20191909.
A previous CDC study showed that children aged 6-23 months had an increased risk for febrile seizure after simultaneously receiving inactivated influenza vaccine (IIV), pneumococcal conjugate vaccine (PCV13) and diphtheria-tetanus-acellular pertussis vaccine (DTaP). Researchers wanted to see if administering the IIV at a separate visit reduced the risk of post-vaccination fever and potentially febrile seizure. In the 2017-2018 influenza season, 221 children aged 12-16 months were randomized at two CISA sites into 2 groups. Both groups had 2 visits, 2 weeks apart: group 1 (simultaneous) received the PCV13, DTaP, and quadrivalent IIV (IIV4) vaccines at visit 1; no vaccines at visit 2. Group 2 (sequential) received PCV13 and DTaP at visit 1 and IIV4 visit 2. Similar proportions of children in both groups had fever on days 1-2 after visits (simultaneous 8.1%; sequential 9.3%). Delaying IIV4 by 2 weeks in children receiving DTaP and PCV13 did not reduce fever occurrence after vaccination.
Havers FP, Moro PL, Hunter P, Hariri S, Bernstein H. Use of Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccines: Updated Recommendations of the Advisory Committee on Immunization Practices – United States, 2019. MMWR Morb Mortal Wkly Rep. 2020 Jan;69:77-83..
In 2005, the Advisory Committee on Immunization Practices recommended a single dose of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine for adolescents and adults. After the initial Tdap vaccine, booster doses of tetanus and diphtheria toxoids (Td) vaccine are recommended every 10 years or when indicated for wound management. During the October 2019 meeting, ACIP updated its recommendation to allow the use of Tdap or Td in situations where only Td was recommended. These situations include the tetanus booster recommended for adults every 10 years, tetanus prophylaxis when indicated for wound management in people who previously received Tdap, and for multiple doses in the catch-up immunization schedule for people 7 years of age and older with an unknown or incomplete vaccination history. This recommendation update allows providers to have flexibility at the point-of-care for patients.
Haber P, Moro PL, Ng C, Dores GM, Perez-Vilar S, Marquez PL, Cano M. Safety review of tetanus toxoid, reduced diphtheria toxoid, acellular pertussis vaccines (Tdap) in adults aged ≥ 65 years, Vaccine Adverse Event Reporting System (VAERS), United States, September 2010 – December 2018. Vaccine. . 2020 Feb 5;38(6):1476-1480. Epub 2019 Dec 28.
The Advisory Committee on Immunization Practices recommends vaccination in adults 65 years of age and older with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap). To date, few studies have assessed the safety of Tdap in this age group. Using the Vaccine Adverse Event Reporting System (VAERS), researchers analyzed reports of adverse events (AEs) following Tdap in adults 65 years and older. From September 2010 to December 2018, VAERS received 1,798 reports; 94% were classified as non-serious. The most common AEs were injection site redness (26%), pain (19%), and swelling (18%). Of 104 serious reports, 7 deaths were reported; none had evidence to suggest the vaccine caused the deaths. Serious non-death reports included nervous system disorders (35.1%; n=34) and infections (18.6%; n=18). Overall, the analysis did not identify any new safety concerns and is consistent with prior post-marketing observations and pre-licensure studies.
Li R, Stewart B, Rose C. A Bayesian approach to sequential analysis in post-licensure vaccine safety surveillance. Pharm Stat. 2020 May;19(3):291-302 Epub 2019 Dec 22.
Bayesian statistics is an approach for learning from evidence as it accumulates. While this analytic method is used in other areas of public health with acknowledged practical benefits, its potential application in vaccine safety monitoring analysis has not been fully realized. In this study, researchers compare the use of a traditional (frequentist) sequential method and a Bayesian method, with simulations and a real-world vaccine safety example. The performance was evaluated using 3 metrics: false positive rate, false negative rate, and average earliest detection time. The authors found that depending on the background rate of adverse events, the Bayesian sequential method could significantly improve performance in terms of the false negative rate and decrease the earliest time to producing a safety signal for further analysis. Overall, the Bayesian sequential approach was found to show promise as an alternative for vaccine safety monitoring.
Su JR, Haber P, Ng CS, Marquez PL, Dores GM, Perez-Vilar S, Cano MV . Erythema multiforme, Stevens Johnson syndrome, and toxic epidermal necrolysis reported after vaccination, 1999-2017. Vaccine . 2020 Feb 11;38(7): 1746-1752. Epub 2019 Dec 20.
While some dermatologic adverse events are common after vaccination (i.e. redness at the injection site), erythema multiforme (EM), Stevens Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and SJS/TEN are rare. Since the last review of VAERS data for these conditions, over 37 new vaccines were approved for use in the United States. Of the 466,027 reports to VAERS during 1999–2017, researchers identified and reviewed 984 reports of EM, 89 of SJS, 6 of SJS/TEN, and 7 of TEN. Most reports of EM (91%) were non-serious; 52% of SJS and all reports of SJS/TEN and TEN were serious. Most reports (58%) occurred within 7 days after vaccination. Childhood vaccines were reported most often; 48% of reports were of children younger than 4 years. Of 6 reported deaths, 5 were exposed or potentially exposed to medications known to cause these conditions, and 1 had severe dehydration. Overall, reporting of these conditions after vaccination remained rare, with no new safety concerns identified.
Yu W, Zheng C, Xie F, Chen W, Mercado C, Sy LS, Qian L, Glenn S, Tseng HF, Lee G, Duffy J, McNeil MM, Daley MF, Crane B, McLean HQ, Jackson LA, Jacobsen SJ. The use of natural language processing to identify vaccine-related anaphylaxis at five health care systems in the Vaccine Safety Datalink. Pharmacoepidemiolo Drug Saf. 2020 Feb;29(2): 182-188 Epub 2019 Dec 3.
Anaphylaxis is a rare but serious allergic reaction that can be caused by various triggers, including vaccine components. Natural language processing (NLP) uses computers to analyze large amounts of text. Vaccine Safety Datalink (VSD) researchers developed an NLP application to identify vaccine-related anaphylaxis cases from electronic medical record notes and implemented the method at 5 VSD sites. The NLP system was trained on a dataset of 311 potential anaphylaxis cases and validated on another 731 potential cases. NLP was then applied to the notes of 6.4 million vaccinated patients, and it captured 8 additional true cases confirmed by manual chart review. This study demonstrated the potential to apply NLP to clinical notes to identify anaphylaxis cases and its use to improve sensitivity and efficiency in future vaccine safety studies.
Hesse EM, Atanasoff S, Hibbs BF, Adegoke OJ, Ng C, Marquez P, Osborn M, Su JR, Moro PL, Shimabukuro T, Nair N. Shoulder Injury Related to Vaccine Administration (SIRVA): Petition Claims to the National Vaccine Injury Compensation Program, 2010-2016. Vaccine. 2020 Jan 29;38(5): 1076-1083. Epub 2019 Nov 28.
Petitioner claims for shoulder injury related to vaccine administration (SIRVA) to the National Vaccine Injury Compensation Program (VICP) increased substantially from 2010 to 2016. The Health Resources and Services Administration and the Centers for Disease Control and Prevention initiated a joint scientific review of clinical characteristics of SIRVA petitions to VICP. Researchers queried VICP’s Injury Compensation System database for alleged SIRVA and SIRVA-like injuries and conducted a descriptive analysis of claims recommended by VICP for concession as SIRVA injuries; 476 claims were identified and 400 of them involved influenza vaccine. Of the 476 claims, 227 reported a suspected administration error; 172 reported ‘injection too high’ on the arm. Injection too high on the arm could be a factor due to the risk of injecting into underlying non-muscular tissues. Healthcare providers should be aware of proper injection technique and anatomical landmarks when administering vaccines.
Hibbs BF, Ng CS, Museru O, Moro PL, Marquez P, Woo EJ, Cano MV, Shimabukuro TT. Reports of atypical shoulder pain and dysfunction following inactivated influenza vaccine, Vaccine Adverse Event Reporting System (VAERS), 2010-2017. Vaccine. 2020 Jan 29;38(5):1137-1143. Epub 2019 Nov 26.
Some case reports have suggested that if inactivated influenza vaccine (IIV) is improperly administered, shoulder dysfunction may occur. Researchers reviewed reports of adverse events (AEs) made to the Vaccine Adverse Event Reporting System (VAERS) following IIV from July 2010 to June 2017. During this time, approximately 996 million flu vaccine doses were distributed in the United States. Of the 59,230 reports submitted, 1,220 met analysis criteria of atypical shoulder pain and dysfunction starting within 48 hours following IIV and continuing for more than 1 week. The analysis suggests these reports were not common, averaging 2% of flu vaccine AEs reported each year; most were females (82.6%), median age was 52 years. While the cause of these cases is unknown, vaccines given improperly might be a factor. Proper vaccine administration education and training are preventive measures.
Donahue JG, Kieke BA, Lewis EM, Weintraub ES, Hanson KE, McClure DL, Vickers ER, Gee J, Daley MF, Destefano F, Hechter RC, Jackson LA, Klein NP, Naleway AL, Nelson JC, Belongia EA. Near Real-Time Surveillance to Assess the Safety of the 9-valent Human Papillomavirus Vaccine. Pediatrics. 2019 Dec; 144(6): e20191808. Epub 2019 Nov 18.
Gardasil 9 (human papillomavirus 9-valent vaccine, recombinant; 9vHPV) was approved in 2014 for females and males to protect against 9 types of human papillomavirus infections that can cause cancer. CDC’s Vaccine Safety Datalink (VSD) conducted near real-time post-licensure safety monitoring following 9vHPV for 11 pre-specified adverse events (AEs), including anaphylaxis, allergic reaction, appendicitis, certain neurological disorders, pancreatitis, and stroke. From October 2015 to October 2017, 838,991 9vHPV doses were administered to people aged 9-26 years at 6 VSD sites. Statistical signals were detected for 2 expected AEs: injection site reactions and syncope. Signals were also detected for appendicitis, pancreatitis, and allergic reaction; however, evaluation and medical record reviews did not confirm these to be true associations. Overall, no new safety concerns were identified. The results are consistent with pre-licensure clinical trial data and support the favorable safety profile of 9vHPV.
Shimabukuro TT, Su JR, Marquez PL, Mba-Jonas A, Arana JE, Cano MV. Safety of the 9-Valent Human Papillomavirus Vaccine. Pediatrics 2019 Dec; 144(6). pii: e20191791. Epub 2019 Nov 18.
Gardasil 9 (human papillomavirus 9-valent vaccine, recombinant; 9vHPV) was approved in 2014 for females and males to protect against 9 types of human papillomavirus infections that can cause cancer. Researchers analyzed reports of adverse events (AEs) after 9vHPV to the Vaccine Adverse Event Reporting System (VAERS) from December 2014 to December 2017. During that time, approximately 28 million 9vHPV doses were distributed in the United States. Of the 7,244 reports received, 31% were female, nearly 22% were male, and 47% of reports did not identify gender. Over 97% of reports were classified as non-serious. There were 2 deaths reported; no information in the reports or medical records suggested the deaths were related to vaccination. Overall, the analysis revealed no new or unexpected safety concerns. The 9vHPV safety profile is consistent with pre-licensure clinical trial data, and with the post-marketing safety data of Gardasil, the earlier quadrivalent HPV vaccine.
Moro PL, McNeil MM. Challenges in evaluating post-licensure vaccine safety: observations from the Center for Disease Control and Prevention. Expert Rev Vaccines. 2019 Oct; 18(10): 1091-1101 Epub 2019 Oct 19.
There is overwhelming scientific evidence that supports the safety of vaccines and their proven ability to prevent illness and death caused by infectious diseases. Yet like any medicine, no vaccine can be considered completely safe and completely effective. Prior to licensure, vaccines undergo extensive safety and efficacy evaluations. After licensure, they require follow up studies and continuous monitoring to investigate any new or unexpected adverse events (AEs). This article presents challenges in monitoring U.S. vaccines for AEs after licensure and describes CDC’s post-licensure safety surveillance infrastructure, including the Vaccine Adverse Event Reporting System, the Vaccine Safety Datalink, and the Clinical Immunization Safety Assessment project. The authors describe each system’s unique strengths and limitations, and the harmonized approach they provide in meeting vaccine safety monitoring challenges.
Groom HC, Smith N, Irving SA, Koppolu P, Vazquez-Benitez G, Kharbanda EO, Daley MF, Donahue JG, Getahun D, Jackson LA, Klein NP, McCarthy NL, Nordin JD, Panagiotakopoulos L, Naleway AL. Uptake and safety of hepatitis A vaccination during pregnancy: A Vaccine Safety Datalink study. Vaccine . 2019 Oct 16;37(44):6648-6655. Epub 2019 Sep 20.
Although uncommon, infection with hepatitis A virus during pregnancy is associated with gestational complications and pre-term labor. CDC recommends that pregnant women who are at an increased risk of contracting hepatitis A get the Hepatitis A vaccine (HepA). Current safety data, however, are limited on maternal HepA vaccination. Researchers used the Vaccine Safety Datalink to compare pregnancies with HepA exposure to other vaccine exposures, and those with no exposure, from 2004-2015. Of nearly 667,000 pregnancies, 1,140 had HepA exposure. The rate of maternal HepA vaccination was low, and rarely due to documented risk factors. The results did not show an increased risk of adverse events for HepA vaccination during pregnancy. There was an identified association of maternal HepA exposure and small-for-gestational age (SGA) infants, however, the difference in rates were small (4%), and likely due to other factors. Further research may be needed to further explore this association.
McNeil MM, Paradowska-Stankiewicz I, Miller ER, Marquez PL, Seshadri S, Collins LC Jr, Cano MV. Adverse events following adenovirus type 4 and type 7 vaccine, live, oral in the Vaccine Adverse Event Reporting System (VAERS), United States, October 2011-July 2018. Vaccine . 2019 Oct 16; 37(44): 6760-6767 Epub 2019 Sep 20.
Adenovirus vaccine (adenovirus type 4 and type 7, live, oral) was licensed by FDA in March 2011 for use in U.S. military personnel ages 17-50 years. The vaccine was first routinely given to recruits in October 2011. Researchers reviewed reports of adverse events (AEs) following the adenovirus vaccine from October 2011 to July 2018 using the Vaccine Adverse Event Reporting System (VAERS). VAERS received 100 adverse event reports; 39 were considered serious. While the reporting rate for serious AEs was higher than with other vaccines given in a comparison recruit population (39% versus 18%), no unexpected or concerning pattern of adenovirus vaccine AEs were identified. Reports showed multiple other vaccines (95%) and penicillin G (50%) were given at the same time, and these exposures may have contributed to the higher reporting rate for serious AEs observed with the adenovirus vaccine. Future studies without these exposures would be helpful in clarifying the vaccine’s safety profile.
Donahue JG, Kieke BA, King JP, Mascola MA, Shimabukuro TT, DeStefano F, Hanson KE, McClure DL, Olaiya O, Glanz JM, Hechter RC, Irving SA, Jackson LA, Klein NP, Naleway AL, Weintraub ES, Belongia EA. Inactivated influenza vaccine and spontaneous abortion in the Vaccine Safety Datalink in 2012-13, 2013-14, and 2014-15. Vaccine. 2019 Oct 16;37(44):6673-6681. Epub 2019 Sep 17.
A prior study in the Vaccine Safety Datalink (VSD) covering the two influenza seasons from 2010-2012 reported an association between inactivated influenza vaccine (IIV) and spontaneous abortion (SAB), but only among women who had also been vaccinated in the previous influenza season. In follow-up, VSD researchers conducted a larger case-control study over three more recent influenza seasons (2012-2015). Women with SAB were matched with women who had live births according to VSD site, influenza vaccination status in the previous influenza season, and other factors. The main analysis included 1,236 women. During the three influenza seasons, researchers found no association between IIV and SAB, including among women vaccinated in the previous season. These findings lend support to current recommendations for influenza vaccination at any time during pregnancy, including the first trimester.
Kochhar S, Excler JL, Bok K, Gurwith M, McNeil MM, Seligman SJ, Khuri-Bulos N, Klug B, Laderoute M, Robertson JS, Singh V, Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG). Defining the Interval for Monitoring Potential Adverse Events Following Immunization (AEFIs) After Receipt of Live Viral Vectored Vaccines. Vaccine. 2019 Sep 10;37(38): 5796-5802.
New viral vector vaccines that use live viruses to create an immune response are being developed to fight serious infectious agents like HIV and Ebola. As some live recombinant vectored vaccines may replicate, a key challenge is defining the length of time for monitoring potential adverse events following immunization (AEFI). Potential options include: 1) adapting from the current relevant regulatory guidelines; 2) convening a panel of experts to review the evidence from a systematic literature search to narrow down a list of likely potential or known AEFI and establish the optimal risk window(s); and 3) conducting “near real-time” prospective monitoring for unknown clustering’s of AEFI in validated large linked vaccine safety databases. Depending on the infrastructure, human resources, and databases available in different countries, the authors suggest appropriate options can be determined by regulatory agencies and investigators.
Christianson MS, Wodi P, Talaat K, Halsey N. Primary Ovarian Insufficiency and Human Papilloma Virus Vaccines: A Review of the Current Evidence. Am J Obstet Gynecol . 2020 Mar;222(3):239-244. Epub 2019 Aug 31.
Human papillomavirus (HPV) is the primary cause of cervical cancer, and vaccination is the primary means of preventing cancers caused by HPV infection. Despite HPV vaccine being available for over a decade, coverage rates are lower than other vaccines. Public concerns regarding the vaccine’s safety, including that it may cause primary ovarian insufficiency (POI), have been identified as an important barrier to vaccination. POI-related concerns are driven in part by isolated reports of ovarian failure following the HPV vaccine. In this Clinical Immunization Safety Assessment Project review, researchers summarize published peer-reviewed literature on HPV vaccines and POI. In summary, the current evidence is insufficient to suggest or support a causal relationship between HPV vaccination and POI. Healthcare providers can help address concerns about POI and the HPV vaccine by sharing these findings during consultations with their patients.
DeStefano F, Monk Bodenstab H, Offit PA. Principal Controversies in Vaccine Safety in the United States. Clin Infect Dis. 2019 Aug 1;69(4):726-731.
Concerns about vaccine safety can lead to decreased acceptance of vaccines and resurgence of vaccine-preventable diseases. The authors summarize the key evidence on some of the main current vaccine safety controversies in the United States, including: 1) MMR vaccine and autism; 2) thimerosal, a mercury-based vaccine preservative, and the risk of neurodevelopmental disorders; 3) vaccine-induced Guillain-Barré Syndrome (GBS); 4) vaccine-induced autoimmune diseases; 5) safety of HPV vaccine; 6) aluminum adjuvant-induced autoimmune diseases and other disorders; and 7) too many vaccines given early in life predisposing children to health and developmental problems. A possible small increased risk of GBS following influenza vaccination has been identified, but the magnitude of the increase is less than the risk of GBS following influenza infection. Otherwise, the biological and epidemiologic evidence does not support any of the reviewed vaccine safety concerns.
McNeil MM. Vaccine-Associated Anaphylaxis. Curr Treat Options Allergy. 2019 Sep; 6(3): 297-308. Epub 2019 Jul 16.
Anaphylaxis is a rare, serious hypersensitivity reaction, which can happen within minutes and is characterized by multisystem involvement. Although anaphylaxis may occur after any vaccine, the risk following flu vaccines is important to understand due to the large number of persons vaccinated annually. This review looks at two recent CDC studies that confirm its rarity. In a 25-year review of data from the Vaccine Adverse Event Reporting System, reports in children most commonly followed childhood vaccinations, and in adults most often followed influenza vaccine. In a Vaccine Safety Datalink study, the estimated incidence of anaphylaxis was 1.3 per million vaccine doses administered for all vaccines and 1.6 per million doses for IIV3 (trivalent) influenza vaccine. Despite its rarity, the rapid onset and potentially lethal nature of anaphylaxis requires that all personnel and facilities providing vaccinations have procedures in place to treat it.
Edwards K, Hanquet G, Black S, Mignot E, Jankosky C, Shimabukuro T, Miller E, Nohynek H, Neels P. Meeting Report Narcolepsy and Pandemic Influenza Vaccination: What We Know and What We Need to Know Before the Next Pandemic? A Report From the 2 nd IABS Meeting. Biologicals. 2019 Jul;60:1-7.
Scientific and public health experts and key stakeholders gathered to discuss the state of knowledge on the relationship between adjuvanted monovalent pH1N1 vaccines and narcolepsy. There was consensus that an increased risk of narcolepsy was consistently observed after Pandemrix (AS03-adjuvanted), but similar associations following Arepanrix (AS03) or Focetria (MF59) were not observed. It is not clear whether the differences are due to vaccine composition or other factors such as the timing of large-scale vaccination programs relative to pH1N1 wild-type virus circulation in different geographic regions. Limitations of retrospective observational methodologies could also be contributing to some of the differences across studies. Additional research is needed to further explain the association and possible mechanistic pathways, and to aid in planning and preparation for vaccination programs in advance of the next influenza pandemic.
Hesse EM, Hibbs BF, Cano MV. Notes from the Field: Administration of Expired Injectable Influenza Vaccines Reported to the Vaccine Adverse Event Reporting System — United States, July 2018–March 2019. MMWR Morb Mortal Wkly Rep. 2019; 68: 529–530. 2019 June 14.
During the 2018-2019 flu season, the Vaccine Adverse Event Reporting System received 125 reports (totaling 192 patients) of people receiving expired inactivated influenza vaccine (IIV). During that time, 169.1 million doses of seasonal flu vaccine were distributed. Of those who received the expired IIV, 70% were in high-risks group for influenza (under the age of 5, over the age of 50 and pregnant women). Researchers found the reported adverse events were consistent with adverse events following administration of non-expired seasonal IIV, suggesting no additional safety issues associated with receipt of expired IIV. To avoid inadvertent administration of expired IIV, CDC recommends facilities that administer vaccines follow the guidance in the Vaccine Storage and Handling Toolkit, and make plans for the safe disposal or return of any remaining IIV after the expiration date of June 30 each year.
Weinmann S, Naleway AL, Koppolu P, Baxter R, Belongia EA, Hambidge SJ, Irving SA, Jackson ML, Lewin B, Liles E, Marin M, Smith N, Weintraub E, Chun C. Incidence of Herpes Zoster Among Children: 2003-2014. Pediatrics. 2019 Jul; 144(1). Pii: e20182917. Epub 2019 Jun 10.
After the 1996 introduction of routine varicella (chickenpox) vaccination in the U.S., most studies evaluating the incidence of pediatric herpes zoster (HZ), also known as shingles, reported lower incidence over time, with varying degrees of decline. Researchers used data from 6 integrated health care organizations surveyed by the Vaccine Safety Datalink to examine HZ incidence rate in children from 2003-2014. Using electronic medical records from children aged 0 to 17 years, researchers identified HZ cases and calculated HZ incidence rates for all children and children who were vaccinated versus unvaccinated. Researchers then calculated rates for the 12-year period, examined temporal trends, and compared HZ rates by month and year of age at vaccination. This population-based study confirms the decline in pediatric HZ incidence and the significantly lower incidence among children who are vaccinated, and reinforces the benefit of routine varicella vaccination to prevent pediatric HZ.
Moro PL, Arana J, Marquez PL, Ng C, Barash F, Hibbs BF, Cano M. Is there any harm in administering extra-doses of vaccine to a person? Excess doses of vaccine reported to the Vaccine Adverse Event Reporting System (VAERS), 2007-2017. Vaccine. 2019 Jun 19; 37(28): 3730-3734. Epub 2019 May 30.
The administration of an extra dose of a vaccine may occur due to a vaccination error or when there is need to provide immunization in a person with uncertain vaccination histories (e.g., refugees). There is little data available on the safety of an extra dose of vaccine. Researchers searched for adverse events following the administration of excess doses of vaccines using the Vaccine Adverse Events Reporting System from January 2007 through the end of July 2017. Of 366,815 total reports received, over 5,000 (1.4%) reported an excess dose of vaccine was administered and less than 4,000 (76.9%) did not describe an AE. The top two vaccines reported were trivalent inactivated influenza (15.4%), and varicella (13.9%). The most common events were fever (12.8%), and injection site reaction (9.7%). Among reports where an AE was reported, researchers did not observe any unexpected conditions or clustering of AEs.
Hanson KE, McLean HQ, Belongia EA, Stokley S, McNeil MM, Gee J, VanWormer JJ. Sociodemograhic and clinical correlates of human papillomavirus vaccine attitudes and receipt among Wisconsin adolescents. Papillomavirus Res. 2019 Dec; 8: 100168; Epub 2019 May 25.
Few studies have assessed adolescent human papillomavirus (HPV) vaccine attitudes and whether they are associated with vaccination uptake. The Vaccine Safety Datalink conducted an HPV vaccine study in an integrated healthcare system to identify factors associated with adolescents’ attitude changes and their link to vaccine receipt. Adolescents who had not completed the HPV vaccine series were surveyed using a modified version of the Carolina HPV Immunization Attitudes and Beliefs Scale before and during a campaign to improve HPV vaccination rates. Adolescents’ attitudes to HPV slightly improved during the period of the campaign. However, attitude changes were not associated with receipt of HPV vaccines and adolescents identified as opposed to HPV vaccine before the campaign began were less likely to receive a HPV vaccine dose afterwards. More research is needed to learn how HPV vaccine attitudes form in parents and children, and how best to address concerns about vaccine harms.
Kochhar S, Edwards KM, Ropero Alvarez AM, Moro PL, Ortiz JR. Introduction of new vaccines for immunization in pregnancy – Programmatic, regulatory, safety and ethical considerations . Vaccine . 2019 May 31; 37(25): 3267-3277. Epub 2019 May 6.
Women are encouraged to get immunizations when they are pregnant; but in certain areas of the world, there are no programs to implement vaccine recommendations. Maternal immunization is a promising strategy to reduce infectious disease-related illness and death in pregnant women and their infants. Pre-requisites for introducing immunization during pregnancy include: (1) political commitment and adequate financial resources, (2) healthcare workers to deliver vaccines, (3) combining immunization programs with prenatal care and maternal/child health services, and (4) access to prenatal care for pregnant women in low and middle-income countries where births occur in healthcare facilities. A system to advance a vaccine program from product licensure to successful country-level implementation needs to include evidence of anticipated vaccine program impact, developing supportive policies, and translating policies into local action.
Hechter RC, Qian L, Tartof SY, Sy LS, Klein NP, Weintraub E, Mercado C, Naleway A, McLean HQ, Jacobsen SJ. Vaccine safety in HIV-infected adults within the Vaccine Safety Datalink Project . Vaccine. 2019 May 31; 37(25): 3296-3302. Epub 2019 May 4.
Despite the increased risk of vaccine-preventable infectious diseases in adults with HIV, vaccine coverage among this risk group remains low; safety concerns around side effects or impact on HIV disease may be a factor. Using data from 5 U.S. integrated healthcare sites in the Vaccine Safety Datalink, researchers evaluated the safety of recommended vaccinations among HIV-infected adults. They evaluated 20,417 HIV-infected adults from 2002-2013 and found an elevated risk of cellulitis and infection, particularly among patients with high viral load and those who received bacterial vaccines. These findings were consistent with prior reports in the literature. The analysis did not find an increased risk of other adverse events of interest. Patients with HIV with very high viral load might have elevated risk for stroke and cerebrovascular diseases; future research should examine further. Overall, this study reassures that vaccines currently recommended for HIV-infected adults are safe.
Cook AJ, Wellman RD, Marsh T, Shoaibi A, Tiwari R, Nguyen M, Boudreau D, Weintraub ES, Jackson L, Nelson JS. Applying sequential surveillance methods that use regression adjustment or weighting to control confounding in a multisite, rare-event, distributed setting: Part 2 in-depth example of a reanalysis of the measles-mumps-rubella-varicella combination vaccine and seizure risk. J Clin Epidemiol. 2019 Sep; 113: 114-122. Epub 2019 May 2.
Safety surveillance of newly marketed vaccines is a public health priority. National systems have linked vast amounts of electronic health record (EHR) data across multiple health care organizations and insurers. This allows monitoring of large patient groups for potential safety concerns. Group sequential methods (methods of evaluating data as it is entered) involve routine estimation and testing of vaccine-outcome associations over time. This method can lead to earlier identification of excess risk compared with one-time analysis. Researchers assessed the use of two different sequential methods for safety monitoring: analysis-based confounder adjustment (influential variables) and weighting (the number items or events). Both methods were applied to the FDA’s Sentinel network, that already positively paired the outcome to the vaccine. The estimates from both methods were similar and comparable to prior studies of different designs and are viable alternatives for safety monitoring.
DeStefano F, Shimabukuro TT. The MMR Vaccine and Autism. Annu Rev Virol. 2019 Sep; 6. Epub 2019 Apr 15.
The most damaging vaccine safety controversy of recent years began as an exploration of the possible role of measles and measles vaccines in causing of inflammatory bowel disease (IBD). That work eventually evolved into a report published in 1998, but subsequently retracted by the journal, that suggested Measles-mumps-rubella (MMR) vaccine causes autism. Although numerous scientific studies have since refuted a connection between MMR vaccine and autism, some parents are still hesitant to accept MMR vaccination of their children because they are uncertain about the safety of the vaccine. In this review, the authors summarize the genesis of the controversy and review the scientific evidence against a causal association. Also discussed is the effect of the controversy on MMR vaccine acceptance and the resurgence of measles outbreaks, as well as what can be done to bolster vaccine confidence, including the central role of scientists and healthcare providers.
Zheng C, Yu W, Xie F, Chen W, Mercado C, Sy LS, Qian L, Glenn S, Lee G, Tseng HF, Duffy J, Jackson LA, Daley MF, Crane B, McLean HQ, Jacobsen SJ. The use of natural language processing to identify Tdap-related local reactions at five health care systems in the Vaccine Safety Datalink , International Journal of Medical Informatics , 2019 Jul; 127(1386-5056): 27-34. Epub 2019 Apr 13.
The Vaccine Safety Datalink (VSD) plays a critical role in monitoring adverse events after vaccinations by using the electronic health records. Most studies performed in the VSD rely on diagnosis codes and manual chart review for outcome identification and confirmation. A natural language processing (NLP) system was developed, then deployed and executed at multiple institutions. The system achieved reasonable accuracy in identifying a specific vaccine-related adverse event. This study demonstrates the feasibility of using NLP to reduce the potential burden of conducting manual chart review in future vaccine safety studies. “False negatives” of diagnosis codes are not commonly investigated in vaccine safety studies. NLP can identify cases missed by diagnosis codes. NLP has many potential applications in future vaccine safety studies based on the considerations of the pros and cons of NLP and the specific requirements of the study.
Myers TR, McCarthy NL, Panagiotakopoulos L, Omer SB. Estimation of the Incidence of Guillain-Barré Syndrome During Pregnancy in the United States . Open Forum Infectious Diseases . 2019 Mar; 6(3): ofz071.
Guillain-Barré syndrome (GBS) is an adverse event of interest after vaccination, yet little is known about how frequently this rare neurologic disorder occurs during pregnancy. GBS may be an outcome of particular interest during Zika vaccine trials, because it has been associated with Zika virus infection. In this Vaccine Safety Datalink study, researchers identified potential GBS cases from January 1, 2004 through July 31, 2015 during pregnancy and the 42 days following birth. Of the 1.2 million pregnancies that met inclusion criteria, 35 potential cases of GBS were identified and 2 cases were confirmed as incident GBS during pregnancy. The resulting estimated incidence rate for GBS during pregnancy was 2.8 GBS cases per million person-years. These findings will help inform future safety assessments of Zika and other vaccines in pregnant populations.
Klein NP, Goddard K, Lewis E, Ross P, Gee J, DeStefano F, Baxter R. Long term risk of developing type 1 diabetes after HPV vaccination in males and females. Vaccine . 2019 Mar 28; 37(14):1938-1944. Epub 2019 Mar 1.
Despite scientific evidence, public concerns that the human papillomavirus (HPV) vaccine can cause autoimmune diseases persist. The Vaccine Safety Datalink evaluated whether HPV vaccine is associated with a long-term increased risk of type 1 diabetes at one participating site. This retrospective cohort study identified all potential type 1 diabetes cases from Kaiser Permanente Northern California members who were between 11 and 26 years old any time after June 2006 through December 2015 – over 900,000 individuals. Of the 2,613 cases of type 1 diabetes identified, 338 (123 vaccinated with HPV and 265 unvaccinated) remained in the analysis. Over the 10 years of the study period, comparing vaccinated with unvaccinated persons, researchers did not find an increased risk of type 1 diabetes associated with HPV vaccine receipt.
Haber P, Moro PL, Ng C, Dores GM, Lewis P, Cano M. Post-licensure surveillance of trivalent adjuvanted influenza vaccine (aIIV3; Fluad), Vaccine Adverse Event Reporting System (VAERS), United States, July 2016-June 2018. Vaccine . 2019 Mar 7;37(11):1516-1520. Epub 2019 Feb 7.
Trivalent adjuvanted influenza vaccine (aIIV3; Fluad®) was approved in the U.S. in 2015 for adults aged 65 years and older, and has been in use since the 2016-2017 influenza season. Using the Vaccine Adverse Event Reporting System, researchers analyzed U.S. reports for aIIV3 submitted from July 2016 to June 2018, totaling 630 reports. Of note, there were 79 reports of people under the age of 65 who received the vaccine. The most commonly reported adverse events were consistent with pre-licensure studies, and included injection site pain and redness. Researchers did not identify any new safety concerns associated with aIIV3 among individuals indicated for the vaccine (65 years of age or older). Importantly, vaccine providers should be aware of and follow the prescribing information for the vaccine and administer it only to patients in the recommended age range.
Hesse EM, Shimabukuro TT, Su JR, et al. Postlicensure Safety Surveillance of Recombinant Zoster Vaccine (Shingrix) — United States, October 2017–June 2018 . MMWR Morb Mortal Wkly Rep. 2019 Feb 1; 68(4):91–94.
This is the first report covering post-licensure safety monitoring of the recombinant zoster vaccine (RZV; Shingrix, GSK) in the Vaccine Adverse Event Reporting System (VAERS) during the initial 8 months of use in the United States. From October 2017 to June 2018, VAERS received 4,381 adverse event reports related to Shingrix; 4,251 (97%) were classified as non-serious. During that timeframe, about 3.2 million doses of Shingrix were distributed in the United States. The most common symptoms reported were fever, and injection site pain and redness. These findings are consistent with pre-licensure clinical trial data, and no unexpected patterns were detected. Clinicians should counsel patients to expect common reactions such as pain, swelling, and redness at the injection site, along with possible body aches, fever, and chills. These reactions usually resolve on their own in 2 to 3 days.
Landazabal CS, Moro PL, Lewis P, Omer SB. Safety of 9-valent human papillomavirus vaccine administration among pregnant women: Adverse event reports in the Vaccine Adverse Event Reporting System (VAERS), 2014-2017 . Vaccine . 2019 Feb 21; 37(9):1229-1234. Epub 2019 Jan 16.
9-valent human papillomavirus vaccine (9vHPV) was approved by FDA in December 2014. 9vHPV is not recommended during pregnancy but some women of childbearing age may be inadvertently exposed. This study assessed reports to Vaccine Adverse Event Reporting System (VAERS) of pregnant women vaccinated with 9vHPV in the United States between December 2014-December 2017. Disproportionate reporting of adverse events (AEs) was assessed using proportional reporting ratios. A total of 82 pregnancy reports were identified. Sixty reports (73.2%) did not describe an AE. The most frequently reported AEs were miscarriage and injection site reactions (both n=3; 3.7%). Of note, miscarriage may occur in up to one-third of pregnancies; the observed reports in this study were not unusual or unexpected. No disproportional reporting for any AE was found. Overall, no unexpected AEs were observed among these pregnancy reports.
Su JR, Moro PL, Ng CS, Lewis PW, Said MA, Cano MV. Anaphylaxis after vaccination reported to the Vaccine Adverse Event Reporting System, 1990-2016. J Allergy Clin Immunol . 2019 Apr; 143(4):1465-1473. Epub 2019 Jan 14.
Anaphylaxis is a rare, potentially life-threatening hypersensitivity reaction that can occur after vaccination. During 1990–2016, the Vaccine Adverse Event Reporting System (VAERS) received a total of 467,960 reports. Researchers identified 828 reports describing persons who were physician-diagnosed with or met the Brighton Collaboration case definition for anaphylaxis. Of reports in people aged 18 years or younger, 65% were male; childhood vaccines were most commonly reported. Of reports in people aged 19 years and older, 80% were female, and influenza vaccines were most commonly reported. Over 40% of the 828 reports described persons with no history of hypersensitivity. Of 8 reported deaths, 4 had no history of hypersensitivity. Anaphylaxis after vaccination is rare, but can occur, including among persons with no history of hypersensitivity. Providers who administer vaccines should be prepared to manage severe hypersensitivity reactions.
Tartof SY, Qian L, Liu IA, Tseng HF, Sy LS, Hechter RC, Lewin BJ, Jacobsen SJ. Safety of Influenza Vaccination Administered During Hospitalization . Mayo Clin Proc . 2019 Mar; 94(3):397-407. Epub 2019 Jan 8.
CDC recommends that hospitalized patients who are eligible to receive influenza vaccine be vaccinated before discharge; however, previous data suggest that rates of influenza immunization among hospitalized patients before discharge remain low. In a retrospective cohort study conducted at Kaiser Permanente Southern California, investigators analyzed whether influenza vaccination during hospitalization was associated with an increased risk of outpatient and emergency department visits, readmissions, fever, and clinical laboratory evaluations for infection in the 7 days following discharge. Investigators found no increased risk for these outcomes among those vaccination during hospitalization compared with those who were never vaccinated or were vaccinated at other times. These findings provide reassurance about the safety of influenza vaccination during hospitalization.
McClure DL, Jacobsen SJ, Klein NP, Naleway AL, Kharbanda EO, Glanz JM, Jackson LA, Weintraub ES, McLean HQ. Similar relative risks of seizures following measles containing vaccination in children born preterm compared to full-term without previous seizures or seizure-related disorders . Vaccine . 2019 Jan 3; 37(1):76-79. Epub 2018 Nov 23.
In the United States, measles-mumps-rubella (MMR) and measles-mumps-rubella-varicella (MMRV) vaccines are recommended to children at age 12 months and older. These vaccines are associated with a small increased risk of febrile seizures during the second week after vaccination. This Vaccine Safety Datalink study assessed the relative risk of febrile seizures after MMR/MMRV vaccination in children born preterm and children born full-term. Prior to this study, limited data were available on the safety of vaccinations given during the second year of life in preterm children. Researchers looked at 532,375 children (45,343 preterm and 487,032 full-term) who received their first dose of measles-containing vaccine at age 12 through 23 months. The data showed similar relative risk of seizure in both groups. The results support current Advisory Committee on Immunization Practices recommendations to administer the first dose of these vaccines at age 12 through 15 months for all children, including those born preterm.
McNeil MM, Duderstadt SK, Sabatier JF, Ma GG, Duffy J. Vaccination and Risk of Lone Atrial Fibrillation in the Active Component United States Military. Hum Vaccin Immunother. 2018 Nov 16;15(3): 669-676. Epub 2019 Jan 8.
In this retrospective population-based cohort study of nearly 3 million U.S. military personnel, researchers looked at whether receiving the anthrax vaccine absorbed (AVA) increased the risk of atrial fibrillation in those who did not have identifiable underlying risk factors or structural heart disease (lone atrial fibrillation). The authors used the Defense Medical Surveillance System to review military personnel on active duty from January 1, 1998 through December 31, 2006. Following over 11,000 person-years of service, the study found no elevated risk of diagnosed lone atrial fibrillation associated with AVA (adjusted risk ratio of 0.99), influenza, or smallpox vaccinations given during military service. These findings may be helpful in planning future vaccine safety research.
Moro PL, Lewis P, Cano M Adverse events following purified chick embryo cell rabies vaccine in the Vaccine Adverse Event Reporting System (VAERS) in the United States, 2006-2017 – Correspondence Travel Medicine and Infectious Disease 2019 May-Jun; 29(1477-8939): 80-81. Epub 2018 Oct 26.
Rabies is a viral disease of mammals most often transmitted through the bite of a rabid animal and is life threatening. For those exposed to the virus, the benefits of vaccination outweigh the risks. There are two cell cultures rabies vaccines available in the United States: human diploid cell vaccine (HDCV – licensed in 1980) and purified chick embryo cell vaccine (PCECV – licensed in 1997). A safety study on PCECV has not been done since 2005. Researchers re-assessed the safety of the vaccine in the Vaccine Adverse Event Reporting System (VAERS) from January 2006 through June 2017. Excluding non-U.S. reports and duplicate records, VAERS received 604 reports involving PCECV during the 10 year time frame. Of those, 42 were coded as serious reports. No deaths were reported. Data mining analysis did not reveal disproportional reporting for any adverse event. Adverse events reported were consistent with previous post-licensure study and no new or unexpected adverse events were observed.
Weibel D, Sturkenboom M, Black S, de Ridder M, Dodd C, Bonhoeffer J, Vanrolleghem A, van der Maas N, Lammers GJ, Overeem S, Cauch-Dudek K, Juhasz D, Campitelli M, Datta AN, Kallwei U, Huan WT, Hsu CY, Chen HC, Giner-Soriano M, Morros R, Gaig C, Tió E, Perez-Vilar S, Diez-Domingo J, Puertas FJ, Svenson LW, Mahmud SM, Carleton B, Naus M, Arnheim-Dahlström L, Pedersen L, DeStefano F, Shimabukuro TT. Narcolepsy and Adjuvanted Pandemic Influenza A (H1N1) 2009 Vaccines – Multi-county Assessment. Vaccine. 2018 Oct 1;26(41):6202-6211.
In 2010, a safety signal was detected for narcolepsy in several European countries following vaccination with Pandemrix, a monovalent pandemic H1N1 (pH1N1) vaccine containing AS03 adjuvant. The reports followed large-scale pH1N1 vaccination campaigns during 2009-10. To investigate further, a study team including CDC scientists analyzed vaccine safety data on adjuvanted pH1N1 vaccines (Arenaprix-AS03, Focetria-MF59, and Pandemrix-AS03) from 10 global study sites. Researchers did not detect any new associations between the vaccines and narcolepsy.
Suragh TA, Lamprianou A, MacDonald NE, Loharikar AR, Balakrishnan MR, Benes O, Hyde TB, McNeil MM. Cluster Anxiety-Related Adverse Events Following Immunization (AEFI): An Assessment of Reports Detected in Social Media and Those Identified Using an Online Search Engine. Vaccine. 2018 Sep25;26(40):5949-5954.
Adverse events following immunization (AEFI) that arise from anxiety can occur in clusters and may result in unnecessary medical treatments and disrupted vaccination programs. News of these incidents can spread rapidly via the internet and social media. In this study, researchers used Google and Facebook to identify reports of cluster anxiety-related AEFIs not found in traditional peer-reviewed literature and found 39 reports referring to 18 unique cluster events. The most common vaccine mentioned was human papillomavirus (HPV) vaccine (48.7%). The majority of reports (97.4%) involved children; all occurred in a school setting or as part of vaccination campaigns. Five vaccination programs were reportedly halted despite investigations finding no link between the adverse events and the vaccines. These results demonstrate the potential for using information from the web to supplement traditional sources for identifying cluster anxiety-related AEFIs.
Suragh TA, Lewis P, Arana J, Mba-Jonas A, Li R, Stewart B, Shimabukuro TT, Cano M. Safety of bivalent human papillomavirus vaccine in the US vaccine adverse event reporting system (VAERS), 2009-2017. Br J Clin Pharmacol . 2018 Dec; 84(12):2928-2932. Epub 2018 Sep 21.
In 2009, bivalent human papillomavirus vaccine (2vHPV, Cervarix) was licensed for use in the United States. Due to low use in the marketplace, the manufacturer stopped supplying 2vHPV in the United States in 2016 and withdrew it from the U.S. market completely in late 2017. The vaccine is currently licensed and used in at least 134 other countries worldwide. In this review, reports submitted to the Vaccine Adverse Event Reporting Systems (VAERS) following 2vHPV vaccination during 2009-2017 were analyzed. During this period, over 720,000 2vHPV doses were distributed in the U.S.; VAERS received 241 adverse event reports. Researchers did not identify any new or unexpected safety concerns in their review.
Fortner KB, Swamy GK, Broder KR, Jimenez-Truque N, Zhu Y, Moro PL, Liang J, Walter EB, Heine RP, Moody MA, Yoder S, Edwards KM. Reactogenicity and immunogenicity of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) in pregnant and nonpregnant women . Vaccine. 2018 Oct 8; 36(42):6354-6360. Epub 2018 Sep 13.
CDC recommends that pregnant women receive Tdap vaccine to protect young infants from pertussis (whooping cough). The CISA Project study enrolled 374 pregnant and 225 nonpregnant women to evaluate safety and immune responses after Tdap; 53% of the pregnant women had received Tdap in the past. Pregnancy and infant health outcomes were also assessed and will be described in a future report. Injection-site and systemic reactions (e.g., fever) were assessed for 7 days after Tdap. Blood was collected from the women before and after Tdap to evaluate immune responses. Researchers found that Tdap was well-tolerated in pregnant and nonpregnant women. Pregnant women were more likely to report moderate or severe injection-site pain (18%) compared with nonpregnant women (11%) but this did not lead to medical visits. Prior Tdap receipt did not increase occurrence of moderate or severe reactions in pregnant women. Immune responses to all Tdap vaccine antigens were robust in both groups.
Groom HC, Irving SA, Koppolu P, Smith N, Vazquez-Benitez G, Kharbanda EO, Daley MF, Donahue JG, Getahun D, Jackson LA, Tse Kawai A, Klein NP, McCarthy NL, Nordin JD, Sukumaran L, Naleway AL. Uptake and safety of Hepatitis B vaccination during pregnancy: A Vaccine Safety Datalink study . Vaccine . 2018 Oct 1; 36(41):6111-6116. Epub 2018 Sep 5.
Hepatitis B virus (HBV) infection acquired during pregnancy can pose a risk to the infant at birth that can lead to significant and lifelong morbidity. Hepatitis B vaccine (HepB) is recommended for anyone at increased risk for contracting HBV infection, including pregnant women. Prior to this study, limited data were available on the safety of HepB administration during pregnancy. In this Vaccine Safety Datalink retrospective cohort study, researchers assessed potential association between maternal HepB vaccinations and pre-specified maternal and infant safety outcomes, looking at pregnancies resulting in live births from 2004-2015. Women were continuously enrolled from 6 months pre-pregnancy to 6 weeks postpartum. Most women who received maternal HepB did not have high-risk indications for vaccination. The study found there was no increased risk for the examined adverse events in women who received maternal HepB or in their offspring.
Grohskopf LA, Sokolow LZ, Broder KR, Walter EB, Fry AM, Jernigan DB. Prevention and Control of Seasonal Influenza with Vaccines: Recommendation of the Advisory Committee on Immunization Practices – United States, 2018-2019 Influenza Season. MMWR Recomm Rep. 2018 Aug 24;67(No. RR-3):1-20.
Routine annual influenza vaccination is recommended for all persons 6 months of age and older who do not have contraindications. A licensed, recommended, and age-appropriate vaccine should be used. Inactivated influenza vaccines (IIVs), recombinant influenza vaccine (RIV), and live attenuated influenza vaccine (LAIV) are expected to be available for the 2018–19 season. For adults 65 years and older, any age-appropriate IIV formulation or RIV4 are acceptable options. Given unknown but theoretical concerns of increased reactogenicity when administering two new adjuvant-containing vaccines, selection of a nonadjuvanted influenza vaccine may be considered in situations where influenza vaccine and another vaccine containing a new adjuvant are to be administered concomitantly; vaccination should not be delayed if a specific product is not available. Vaccines with newer adjuvants, like other vaccines, should be administered at separate sites from other vaccines that are given concomitantly.
Naleway AL, Mittendorf KF, Irving SA, Henninger ML, Crane B, Smith N, Daley MF, Gee J. Primary Ovarian Insufficiency and Adolescent Vaccination . Pediatrics. 2018 Sep; 14(3). Epub 2018 Aug 21.
Published case series have suggested a potential association between human papillomavirus (HPV) vaccination and primary ovarian insufficiency (POI). But, no population-based epidemiological studies have been reported. To the authors’ knowledge, this new Vaccine Safety Datalink study – a population-based, retrospective cohort study of nearly 200,000 women – is a first, and overcomes some of the limitations of earlier post-licensure monitoring that relied on passive reporting. Researchers found there was no elevated risk of POI following HPV, Tdap, IIV, and MenACWY vaccination in women of reproductive age. These findings should lessen concern about potential impact on fertility from adolescent vaccination.
Haber P, Amin M, Ng C, Weintraub E, McNeil MM. Reports of lower respiratory tract infection following dose 1 of RotaTeq and Rotarix vaccines to the Vaccine Adverse Event Reporting System (VAERS), 2008-2016 . Hum Vaccin Immunother. 2018 Jul 11:1-5. Epub 2018 Jul 26.
A recent GlaxoSmithKline post-marketing study found a possible association between the administration of the first dose of the rotavirus vaccine Rotarix and lower respiratory tract infections (LRTI) in infants 0-6 days after vaccination. Using Vaccine Adverse Event Reporting System data, this study examined reports of LRTIs in infants 6-15 weeks old who received one of two rotavirus vaccines, Rotarix or RotaTeq, in addition to either the 7-valent (PCV7) or 13-valent (PCV13) pneumococcal conjugate vaccine. Reports of LRTIs occurring in the 0-29 day window following the first dose of the rotavirus vaccination were analyzed between January 2008 and December 2016. Researchers found LRTI rates were not different in those infants from rates of LRTIs in infants receiving other recommended childhood vaccines.
Kharbanda EO, Vazquez-Benitez G, Lipkind HS, Sheth SS, Zhu J, Naleway AL, Klein NP, Hechter R, Daley MF, Donahue JG, Jackson ML, Kawai AT, Sukumaran L, Nordin JD. Risk of Spontaneous Abortion After Inadvertent Human Papillomavirus Vaccination in Pregnancy . Obstet. Gynecol. 2018 Jul; 132(1): 35-44.
Quadrivalent human papillomavirus vaccine (4vHPV) is not recommended during pregnancy but may be given inadvertently when pregnancy status is not known. While data on HPV vaccine exposures during or around the time of pregnancy have not raised concerns, additional safety studies are needed. Using the Vaccine Safety Datalink, researchers conducted a retrospective observational cohort study that evaluated the risk of spontaneous abortion following 4vHPV before and during pregnancy. Between January 2008 and November 2014, 2,800 pregnancies were identified with 4vHPV exposure. The authors found the risk of spontaneous abortion did not increase among women who received 4vHPV before or during pregnancy. These findings are consistent with pre-licensures clinical trials and post-licensure safety studies.
Su JR, Ng C, Lewis PW, Cano MV. Adverse events after vaccination among HIV-positive persons, 1990-2016. PLoS One . 2018 Jun 19; 13(6) e0199229.
Vaccines are especially critical for people with chronic health conditions such as HIV infection, and are recommended by Advisory Committee on Immunization Practices and CDC based on a person’s immune status. Through this study, researchers looked at U.S. reports to Vaccine Adverse Event Reporting System during 1990-2016 to investigate if people living with HIV experienced unexpected adverse events (AEs) or unusual patterns of AEs after vaccination. The analysis found no unexpected or unusual patterns of AEs. These results support the safety of recommended vaccines in people with HIV. Of note, 2 people with HIV with severely compromised immune systems died from widespread infection after receiving live virus vaccines. Healthcare providers should be aware of a patient’s immune status prior to administration of live virus vaccines. Following ACIP best practices can help prevent rare, but life-threatening, AEs.
Walker WL, Hills SL, Miller ER, Fischer M, Rabe IB. Adverse events following vaccination with an inactivated, Vero cell culture-derived Japanese encephalitis vaccine in the United States, 2012-2016 . Vaccine . 2018 Jul 5; 36(29):4369-4374. Epub 2018 Jun 8.
Inactivated Vero cell culture-derived vaccine (JE-VC; IXIARO) was licensed by Food and Drug Administration in 2009 and has a generally favorable safety profile. In this review of adverse events (AEs) following JE-VC reported to Vaccine Adverse Event Reporting System during May 1, 2012 through April 30, 2016, researchers found reporting rates of AEs were similar to those of the previous analysis (2009-2012). Although reporting rates of AEs in children could not be calculated, there were low numbers of reported events in this age group. Safety surveillance for this relatively new vaccine continues to be important to monitor AE reporting rates and identify possible rare serious events.
Moro PL, Perez-Vilar S, Lewis P, Bryant-Genevier M, Kamiya H, Cano M. Safety Surveillance of Diphtheria and Tetanus Toxoids and Acellular Pertussis (DTaP) Vaccines . Pediatrics . 2018 Jul; 142(1). Epub 2018 Jun 4.
Diphtheria, tetanus toxoids and acellular pertussis (DTaP) vaccines were first licensed by the Food and Drug Administration in 1991. To assess the post-licensure safety of DTaP vaccines, researchers reviewed reports of adverse events following vaccination submitted to the Vaccine Adverse Event Reporting System (VAERS). From January 1991 to December 2016, 50,157 reports were submitted to VAERS following DTaP vaccination. The most frequently reported adverse events were injection site redness (25.3%), fever (19.8%), and injection site swelling (15.0%). This assessment did not identify any new or unexpected safety issues and supports the favorable safety profile from pre-clinical trials. Reports of non-serious vaccination errors, such as incorrect vaccine administered or wrong site, call for better education of providers on the specific indications for each of the DTaP vaccines.
Jackson ML, Yu O, Nelson JC, Nordin JD, Tartof SY, Klein NP, Donahue JG, Irving SA, Glanz JM, McNeil MM, Jackson LA. Safety of repeated doses of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine in adults and adolescents . Pharmacoepidemiol. Drug Saf. 2018 Aug; 27(8): 921-925. Epub 2018 Jun 3.
Because protective pertussis immunity may wane within 5 years of Tdap (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis) vaccine receipt, maintaining protection may require repeated vaccination. A possible strategy would be to recommend Tdap in place of decennial Td (tetanus toxoid, reduced diphtheria) doses. This VSD study evaluated the safety of repeated doses of tetanus-containing vaccine at intervals <10 years between doses among a population of 68,915 non-pregnant adults and adolescents. Compared to 7,521 subjects who received a subsequent dose of Td vaccine, 61,394 subjects who received a subsequent dose of Tdap did not have significantly elevated risk of medical visits for seizure, cranial nerve disorders, limb swelling, pain in limb, cellulitis, paralytic syndromes, or encephalopathy/encephalitis/meningitis. These results suggest that repeated Tdap vaccination has acceptable safety relative to Tdap vaccination followed by subsequent Td vaccination.
Tseng HF, Sy LS, Qian L, Liu IA, Mercado C, Lewin B, Tartof SY, Nelson J, Jackson LA, Daley MF, Weintraub E, Klein NP, Belongia E, Liles EG, Jacobsen SJ. Pneumococcal Conjugate Vaccine Safety in Elderly Adults . Open. Forum Infect. Dis. 2018 May 2; 5(6): ofy100. Epub 2018 Jun.
The 13-valent pneumococcal conjugate vaccine (PCV13) and the 23-valent pneumococcal polysaccharide vaccine (PPSV23) are both licensed vaccines recommended for use in adults 65 years of age and older to protect against pneumococcal disease. PPSV23 protects against 23 types of the approximately 90 types of pneumococcal bacteria and was first licensed in 1983; the newer PCV13 vaccine protects against 13 types of pneumococcal bacteria and was licensed in 2010. In this large cohort study using data from 6 Vaccine Safety Datalink sites, researchers compared the risk in adults 65 years of age and older for serious adverse events (AEs) following vaccination with either PCV13 or PPSV23. The analysis did not find an increased risk of adverse events following PCV13 administration compared to PPSV23, and should provide reassurance regarding use of PCV13.
Shimabukuro TT, Miller ER, Strikas RA, Hibbs BF, Dooling K, Goud R, Cano MV Notes from the Field: Vaccine Administration Errors Involving Recombinant Zoster Vaccine — United States, 2017–2018. MMWR Morb Mortal Wkly Rep. 2018 May 25; 67: 585–586.
During the first four months of RZV (Shingrix®) monitoring (October 20, 2017-February 20, 2018), Vaccine Adverse Event Reporting System received a total of 155 reports, of which 13 (8%) documented an administration error, some with more than one type of error. Vaccine providers may be confusing administration procedures and storage requirements between the older ZVL (Zostavax®) vaccine and the newly licensed RZV. Prior experience indicates that reports of administration errors are highest shortly after licensure and recommendation, likely due to lack of familiarity with a new vaccine. To prevent RZV administration errors, vaccine providers should be aware of prescribing information, storage requirements, preparation guidelines, and Advisory Committee on Immunization Practices recommendations for herpes zoster vaccines.
Miller ER, Lewis P, Shimabukuro TT, Su J, Moro P, Woo EJ, Jankosky C, Cano M. Post-licensure safety surveillance of zoster vaccine live (Zostavax®) in the United States, Vaccine Adverse Event Reporting System (VAERS), 2006-2015 . Hum Vaccin Immunother. 2018 Mar 26; 14(8): 1963-1969 Epub 2018 May 18.
Herpes zoster (HZ), or shingles, is caused by reactivation of varicella-zoster virus—the same virus that causes chickenpox. Live-attenuated HZ vaccine (zoster vaccine live, ZVL, Zostavax) was licensed by the Food and Drug Administration in 2006 to prevent shingles and is recommended by CDC for people 60 years and older. Researchers reviewed reports of adverse events following ZVL to the Vaccine Adverse Event Reporting System (VAERS) from May 1, 2006 through January 31, 2015. During this time, close to 22 million ZVL doses were distributed. VAERS received 23,092 reports; 96% were classified as non-serious. The most common adverse events reported included injection site pain (27%), HZ (17%), injection site swelling (17%) and rash (14%). This review did not detect new or unexpected safety signals.
Carter RJ, Idriss A, Widdowson MA, Samai M, Schrag SJ, Legardy-Williams JK, Estivariz CF, Callis A, Carr W, Webber W, Fischer ME, Hadler S, Sahr, Thompson M, Gerby SM, Edem-Hotah J, M’baindu Momoh R, McDonald W, Gee JM, Flagbata Kallon A, Spencer-Walters D, Bresee JS, Cohn A, Hersey S, Gibson L, Schuchat A, Seward JF. Implementing a Multisite Clinical Trial in the Midst of an Ebola Outbreak: Lessons Learned from the Sierra Leone Trial to Introduce a Vaccine Against Ebola. J Infect Dis. 2018 Jen 15;217(suppl_1):S16-S23. Epub 2018 May 18.
Ebola is a highly contagious disease with a high mortality rate, with no licensed vaccine available as of 2018. Vaccine development includes rigorous testing and 3 phases of clinical trials. The Sierra Leone Trial to Introduce a Vaccine Against Ebola (STRIVE) was the second clinical trial phase to study the investigational Ebola virus vaccine rVSV∆-ZEBOV-GP. It was conducted during an unprecedented Ebola epidemic. Even before the outbreak, Sierra Leone had limited infrastructure and staff to conduct the trials. The STRIVE team addressed these challenges by allocating time to renovate the sites; providing ongoing support to maintain the water, electricity, and internet services; and training nearly 350 local staff members without hindering the Ebola response efforts. By strengthening the infrastructure and increasing the number of properly trained staff, Sierra Leone is now better equipped to conduct future clinical trials and in a better position to manage Ebola cases and clusters.
Xu S, Clarke CL, Newcomer SR, Daley MF, Glanz JM. Analyzing self-controlled case series data when case confirmation rates are estimated from an internal validation sample . Biom. J. 2018 Jul; 60(4): 748-760. Epub 2018 May 16.
Vaccine safety studies are often observational studies using electronic health records (EHR), however, these studies face some challenges, including outside influences (confounding) and outcome misclassification. To handle the confounding effect, researchers use self-controlled case series (SCCS) study design and review of EHRs to validate cases. SCCS design is limited to those individuals who experienced the event during or outside of certain times. While SCCS can adjust for some factors, it cannot adjust for others. This review considered 4 approaches for analyzing SCCS data: observed cases, confirmed cases only, known confirmation rate, and multiple imputation. Researchers found through simulation that when misclassification of adverse events is present, multiple imputation analysis should be considered. When only a sample of presumptive cases can be validated, this approach can address the influence of false-positive cases in EHR data.
Zerbo O, Modaressi S, Goddard K, Lewis E, Fireman BH, Daley MF, Irving SA, Jackson LA, Donahue JG, Qian L, Getahun D, DeStefano F, McNeil MM, Klein NP. Vaccination Patterns in Children After Autism Spectrum Disorder Diagnosis and in Their Younger Siblings . JAMA Pediatr. 2018 May 1; 172(5): 469-475.
Recently, several outbreaks of vaccine-preventable diseases generated concerns about the impact of increasing rates of undervaccination. This study investigates whether rates of vaccination in children with autism spectrum disorder (ASD) and their younger siblings differ from rates of vaccination in the general pediatric population. Results show that both children with ASD and their younger siblings are significantly less likely to be fully vaccinated than children in families without a child with ASD. Although the reasons for undervaccination are not fully explored in this study, results suggest that parental refusal of vaccination may play an important role.
Liang JL, Tiwari T, Moro P, Messonnier NE, Reingold A, Sawyer M, Clark TA. Prevention of Pertussis, Tetanus, and Diphtheria with Vaccines in the United States: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2018 Apr 27 ;67(No. RR-2):1–44.
This report compiles and summarizes recommendations from CDC’s Advisory Committee on Immunization Practices on the prevention and control of tetanus, diphtheria, and pertussis in the U.S. This report is a comprehensive summary of previously published recommendations replacing previously published reports and policy notes and does not contain any new recommendations. Infants and young children are recommended to receive a 5-dose series of diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccines, with a booster dose of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine. Adults who never received Tdap are recommended to receive a booster dose. Women are recommended to receive a dose of Tdap during each pregnancy, regardless of previous receipt. Adolescents and adults are recommended to receive a booster tetanus and diphtheria toxoids (Td) vaccine every 10 years to assure ongoing protection against tetanus and diphtheria.
Donahue, J. Response to three Letters to the Editor regarding: Donahue JG, et al. Association of spontaneous abortion with receipt of inactivated influenza vaccine containing H1N1pdm09 in 2010-11 and 2011-12 . Vaccine . 2018 Apr 19; 36(17): 2231-2232.
Summaries are not made for a response to a letter to the editor.
Daley MF, Shoup JA, Newcomer SR, Jackson ML, Groom HC, Jacobsen SJ, McLean HQ, Klein NP, Weintraub ES, McNeil MM, Glanz JM. Assessing Potential Confounding and Misclassification Bias When Studying the Safety of the Childhood Immunization Schedule . Acad. Pediatr. 2018 Sept – Oct; 18(7): 754-762. Epub 2018 Mar 28.
Some parents are concerned the childhood immunization schedule could increase risk for allergic disorders, including asthma. This, along with the overall safety of the schedule, has parents delaying their children’s vaccinations. Researchers wanted to examine if there was a risk of vaccination status misclassification (between parent and health record) and if risk factors of asthma and other allergies varied by status. This survey was conducted among parents of children 19-35 months old at 8 Vaccine Safety Datalink sites. Among a sample of 2,043 parents, 1,209 (59.2%) responded. The observed agreement between parents and health record for no vaccines was 94% and 87.3 % for receiving all vaccines, no delay. Results showed that misclassification of vaccination status was uncommon, and parents’ reports of asthma risk factors generally did not vary by vaccination status. The data from this study will assist future observational studies with measurement and controlling disease risk.
Glanz JM, Newcomer SR, Daley MF, DeStefano F, Groom HC, Jackson ML, Lewin BJ, McCarthy NL, McClure DL, Narwaney KJ, Nordin JD, Zerbo O. Association Between Estimated Cumulative Vaccine Antigen Exposure Through the First 23 Months of Life and Non-Vaccine-Targeted Infections From 24 Through 47 Months of Age . JAMA . 2018 Mar 6; 319(9): 906-913.
Up to 15% of parents delay their children’s immunizations because of concerns that early childhood vaccines may overwhelm the immune system and cause children to be more susceptible to other infections. While a Danish study did not find evidence that multiple vaccine antigen exposure was associated with the risk for non-vaccine-targeted infectious diseases, this type of study has not been completed in the United States. In this case control study, data was collected from 6 Vaccine Safety Datalink sites to compare children with non-vaccine targeted infections to children without such infections. There were 944 children ages 24 through 47 months enrolled (193 cases, and 751 controls) and the results were not different between the two groups in their estimated cumulative vaccine antigen exposure during the first 23 months of life. In summary, exposure to multiple vaccines did not increase a child’s risk of non-vaccine targeted infections.
Irving SA, Groom HC, Stokley S, McNeil MM, Gee J, Smith N, Naleway AL. Human Papillomavirus Vaccine Coverage and Prevalence of Missed Opportunities for Vaccination in an Integrated Healthcare System . Acad. Pediatr. 2018 Mar; 18(2S): S85-S92.
Human papillomavirus (HPV) vaccination has been recommended in the United States for female and male adolescents since 2006 and 2011, respectively. However, vaccination rates for HPV compared to other childhood vaccines are lower. Researchers designed an assessment and provider-feedback intervention to increase HPV vaccine rate and identify missed opportunities for vaccination. The assessment and intervention occurred at 9 Oregon-based Kaiser Permanente Northwest outpatient clinics between April 2015 and June 2016. An average 29,021 adolescents ages 11-17 were included. Researchers collected baseline data four years prior to the intervention and found that vaccination rates were increasing; after intervention, there were no significant increases. Researchers did identify that missed opportunities decreased during the intervention for females 13-17 years old. Increasing HPV rates in large health systems is challenging, but other interventions are worth examining.
Kuntz J, Crane B, Weinmann S, Naleway AL. Myocarditis and pericarditis are rare following live viral vaccinations in adults . Vaccine. 2018 Mar 14; 36(12): 1524-1527. Epub 2018 Feb 15.
Cardiac complications including myocarditis, pericarditis, and arrhythmias following smallpox vaccination have been rarely reported in the United States. However, after 67 cases of myocarditis or pericarditis were reported after a vaccination campaign of military personnel, there was a need to assess these outcomes among adults after live-viral vaccinations. In this study using data from 4 Vaccine Safety Datalink sites from 1996-2007, researchers identified over 400,000 adults who received at least 1 live viral vaccine. Of those, there was only 1 probable case of pericarditis and no cases of myocarditis in 42 days following vaccination. Self-controlled risk interval analysis found there is no increased risk of myopericarditis in the 42 days following vaccination. The study findings suggest that the occurrence of myopericarditis following live viral vaccination is rare, not higher than the background rate, and much lower than rates following smallpox vaccination.
Markowitz LE, Gee J, Chesson H, Stokley S. Ten Years of Human Papillomavirus Vaccination in the United States. Acad Pediatr . 2018 Mar; 18(2S):S3-S10.
Since human papillomavirus (HPV) vaccine was first introduced for females in the United States in 2006, vaccination policy has evolved as additional HPV vaccines were licensed and new data became available. The United States was the first country to adopt a gender-neutral routine HPV immunization policy in 2011. Researchers summarized reviews of the first 10 years of the HPV vaccination program, including the evolution in vaccine policy, the vaccination program and coverage, and post-licensure vaccine safety studies. Reviews show coverage is increasing, although it remains lower than for other vaccines recommended for adolescents. There are various reasons for low coverage, and efforts are ongoing to increase vaccine uptake. The safety profile of HPV vaccine has been well established from 10 years of post-licensure monitoring. Despite low coverage, the early effects of the HPV vaccination program have exceeded expectations.
Arana JE, Harrington T, Cano M, Lewis P, Mba-Jonas A, Rongxia L, Stewart B, Markowitz LE, Shimabukuro TT. Post-licensure safety monitoring of quadrivalent human papillomavirus vaccine in the Vaccine Adverse Event Reporting System (VAERS), 2009-2015 . Vaccine . 2018 Mar 20; 36(13):1781-1788. Epub 2018 Feb 21.
This study reviewed adverse events reported to Vaccine Adverse Event Reporting Systems following Gardasil® (4vHPV) vaccination between January 2009 and December 2015. A previous review did not include males because they were not recommended for vaccination at the time; this study includes both males and females. The analysis found 94.2% of the 19,760 reported adverse events were non-serious, and included headache, nausea, and fatigue. More than 60 million 4vHPV doses were distributed in the United States at the time, making the crude adverse event reporting rate 327 reports per million 4vHPV doses distributed. No unexpected or new safety concerns or reporting patterns were found.
Sukumaran L, McCarthy NL, Kharbanda EO, Vazquez-Benitez G, Lipkind HS, Jackson L, Klein NP, Naleway AL, McClure DL, Hechter RC, Kawai AT, Glanz JM, Weintraub ES. Infant Hospitalizations and Mortality After Maternal Vaccination . Pediatrics. 2018 Mar; 14(3). Epub 2018 Feb 20.
Influenza and Tdap vaccines are recommended for pregnant women. However, there are limited data on long-term outcomes of infants born to mothers vaccinated during pregnancy. This case-control study found that influenza and Tdap vaccines in pregnancy are not associated with an increased risk of hospitalization or death in infants during the first six months of life. These findings contribute to the knowledge of the long-term safety of vaccination during pregnancy.
Li R, Weintraub E, McNeil MM, Kulldorff M, Lewis EM, Nelson J, Xu S, Qian L, Klein NP, DeStefano F. Meningococcal conjugate vaccine safety surveillance in the Vaccine Safety Datalink using a tree-temporal scan data mining method . Pharmacoepidemiol. Drug Saf. 2018 Apr; 27(4): 391-397. Epub 2018 Feb 15.
Traditional pharmacovigilance techniques used in vaccine safety are generally geared to detecting adverse events (AEs) based on pre‐defined sets of conditions or diagnoses. Using a newly developed tree‐temporal scan statistic data mining method, researchers performed a pilot study to evaluate the safety profile of the meningococcal conjugate vaccine Menactra®. The authors detected known AEs following the vaccine; no new safety concerns were raised. The study demonstrates that the tree‐temporal scan statistic data mining method can be successfully applied to screen broadly for a wide range of vaccine‐AE associations within a large health care data network.
Zhou H, Thompson WW, Belongia EA, Fowlkes A, Baxter R, Jacobsen SJ, Jackson ML, Glanz JM, Naleway AL, Ford DC, Weintraub E, Shay DK. Estimated rates of influenza-associated outpatient visits during 2001-2010 in six US integrated health care delivery organizations . Influenza. Other Respir. Viruses. 2018 Jan; 12(1): 122-131. Epub 2018 Feb 15.
Influenza (flu) related illnesses are responsible for many morbidity cases during each flu season, but these illnesses are difficult to count: symptoms are non-specific, diagnostic codes for flu-related symptoms are broad, and lab testing is not routine. This makes population-based estimates of flu-related outpatient visits during flu epidemics or pandemics uncommon. In this study using data from 6 Vaccine Safety Datalink sites from 2001-2010, researchers estimated flu-related outpatient visits. Researchers modeled the rates of outpatient visits with diagnostic codes of pneumonia or acute respiratory visits. Of the nearly 7.7 million people enrolled, children had higher estimated flu-related outpatient rates than adults during pre-pandemic and pandemic seasons. Rates estimated with pneumonia visits plus flu-coded visits were similar to previous studies using confirmed flu cases. These numbers are crucial for measuring the potential benefits of flu prevention and treatment.
McNeil MM, DeStefano F. Vaccine-associated hypersensitivity . J. Allergy Clin. Immunol. 2018 Feb; 141(2): 463-472.
Vaccines are considered one of the most effective public health interventions – resulting in major reductions of vaccine preventable diseases and death. Vaccine-associated hypersensitivity reactions are not infrequent; however, serious acute-onset anaphylaxis reactions are extremely rare. Risk of anaphylaxis after all vaccines is estimated to be 1.31 per million vaccine doses administered. This review focuses on serious hypersensitivity reactions following flu vaccines, given the large number of people vaccinated yearly and the formulation changes the vaccines go through each year to match circulating flu viruses. Recent advances in vaccine technology, along with new vaccines and the universal flu vaccination recommendation (people 6 months of age and older), make continued safety monitoring for hypersensitivity reactions following flu vaccination particularly important.
McNeil MM, Hibbs BF, Miller ER, Cano MV. Notes from the Field: Errors in Administration of an Excess Dosage of Yellow Fever Vaccine – United States, 2017. MMWR Morb Mortal Wkly Rep. 2018 Jan 26; 67:109-110.
Following a March 2017 report to Vaccine Adverse Event Reporting System (VAERS) of four persons receiving incorrect dosages of yellow fever vaccine, CDC conducted a VAERS search and literature review for similar reported administration errors. Reports were few (15 in VAERS; 67 in literature) and most did not involve an adverse event. However, the error was costly in terms of medical follow-up and vaccine wastage. More distinctive single/multi-dose packaging and in-service training might prevent future errors.
Hibbs BF, Miller E, Shi J, Smith K, Lewis P, Shimabukuro TT. Safety of Vaccines That Have Been Kept Outside of Recommended Temperatures: Reports to the Vaccine Adverse Event Reporting System (VAERS), 2008-2012. Vaccine. 2018 Jan 25;36(4):553-558.
This review does not indicate any substantial direct health risk from administration of vaccines kept outside of recommended temperatures. However, there are potential costs and risks, including vaccine wastage, possible decreased protection, and patient inconvenience related to revaccination. Maintaining high vigilance, proper staff training, regular equipment maintenance, and having adequate auxiliary power are important components of comprehensive vaccine cold chain management.
Haber P, Moro PL, Ng C, Lewis PW, Hibbs B, Schillie SF, Nelson NP, Li R, Stewart B, Cano MV. Safety of Currently Licensed Hepatitis B Surface Antigen Vaccines in the United States, Vaccine Adverse Event Reporting System (VAERS), 2005-2015. Vaccine . 2018 Jan 25;26(4):559-564.
This study is based on a national vaccine safety data and reassures the public on the safety of Hepatitis B vaccine(s). Although it reveals increased reports of vaccine storage errors, and incorrect dose or wrong vaccine given to infants or adults, no adverse events are noted. The findings highlight the need for education and training of health providers on prevention of vaccine administration errors.
Schillie S, Vellozzi C, Reingold A, Harris A, Haber P, Ward JW, Nelson NP. Prevention of Hepatitis B Virus Infection in the United States: Recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep . 2018 Jan 12; 67(No. RR-1):1-31.
Hepatitis B is a serious disease that affects the liver. The virus is highly infectious and can be transmitted in the absence of visible blood. As part of the recommended immunization schedule for infants and children, Hepatitis B vaccine should be given to children in three doses between birth and 18 months of age. In January 2018, the Advisory Committee on Immunization Practices (ACIP) published new recommendations for the vaccine. These include: 1) administration of the universal hepatitis B vaccination within 24 hours of birth of medically stable infants, 2) testing pregnant women for Hepatitis B, 3) post-vaccination serologic testing for infants whose mother has an unknown hepatitis B status, and 4) the removal of lenient language for delaying the birth dose until after hospital discharge. Vaccine safety information was updated to include data from the pre- and post-licensure studies and report information from the Vaccine Adverse Events Report System from 2005 to 2015.
Newcomer SR, Kulldorff M, Xu S, Daley MF, Fireman B, Lewis E, Glanz JM. Bias from outcome misclassification in immunization schedule safety research . Pharmacoepidemiol. Drug Saf . 2018 Feb; 27(2): 221-228. Epub 2018 Jan 2.
The Institute of Medicine in 2013 recommended conducting observational studies of the childhood immunization schedule safety. However, these studies present a methodical challenge because of bias from misclassification of outcomes in electronic health record data. Using simulations, researchers evaluated the percent of valid diagnoses (positive predictive values, PPVs) as indicators of bias of an exposure-outcome association, and quantitative bias analyses methods used for bias correction. Overall outcome PPVs did not reflect the distribution of false positives by exposure and are poor indicators of bias in individual studies. Quantitative bias analysis was effective in correcting outcome misclassification bias and should be considered in immunization schedule research.
Moro PL, Zheteyeva WY, Barash F, Lewis P, Cano M. Assessing the Safety of Hepatitis B Vaccination During Pregnancy in the Vaccine Adverse Event Reporting System (VAERS), 1990-2016. Vaccine . 2018 Jan 2;26(1):50-54.
Few studies have been done on the safety of hepatitis B vaccine in pregnant women. This review describes adverse events after Hepatitis B vaccination of pregnant women reported to the Vaccine Adverse Event Reporting System (VAERS). During the period from January 1, 1990 to June 30, 2016, VAERS received 192 reports involving pregnant women following Hepatitis B vaccination. No new or unexpected safety concerns were found.
Tamez RL, Tan WV, O’Malley JT, Broder KR, Garzon MC, LaRussa P, Lauren CT. Influenza B Virus Infection and Stevens-Johnson Syndrome. Pediatr Dermatol. 2018 Jan;35(1);e45-e48.
Stevens-Johnson Syndrome (SJS) is a rare, serious disorder that affects the skin and the areas that creates and releases mucus. It starts as flu-like symptoms, and leads to a rash and blisters. Patients who develop SJS require hospitalization to manage the symptoms and identify the cause. This case reviewed SJS in a 2-year-old boy with influenza B infection. He was up to date on his immunizations, including the influenza vaccine 3 months prior to coming to coming to the hospital. He was treated with antiviral oseltamivir and IV treatment’, and his symptoms cleared up. With his diagnosis of influenza type B and SJS, there were still concerns of re-exposure to influenza B antigen during next season’s vaccination. The boy received the quadrivalent inactivated influenza vaccine the following season, was monitored and tolerated the vaccine well without reports of adverse reactions. Medical evaluation concluded that the patient’s influenza B infection was the most likely cause of SJS.
Tamez RL, Tan WV, O’Malley JT, Broder KR, Garzon MC, LaRussa P, Lauren CT. Influenza B virus infection and Stevens-Johnson syndrome. Pediatr Dermatol. 2018 Jan; 35(1):e45-e48. Epub 2017 Dec 28.
Storms AD, Chen J, Jackson LA, Nordin JD, Naleway AL, Glanz JM, Jacobsen SJ, Weintraub ES, Klein NP, Gargiullo PM, Fry AM . Rates and risk factors associated with hospitalization for pneumonia with ICU admission among adults . BMC. Pulm. Med. 2017 Dec 16; 17(1): 208.
Hibbs BF, Miller E, Shi J, Smith K, Lewis P, Shimabukuro TT. Safety of vaccines that have been kept outside of recommended temperatures: Reports to the Vaccine Adverse Event Reporting System (VAERS), 2008-2012 . Vaccine . 2018 Jan 25; 36(4):553-558. Epub 2017 Dec 14.
Haber P, Moro PL, Ng C, Lewis PW, Hibbs B, Schillie SF, Nelson NP, Li R, Stewart B, Cano MV. Safety of currently licensed hepatitis B surface antigen vaccines in the United States, Vaccine Adverse Event Reporting System (VAERS), 2005-2015 . Vaccine . 2018 Jan 25; 36(4):559-564. Epub 2017 Dec 11.
Groom HC, Irving SA, Caldwell J, Larsen R, Beaudrault S, Luther LM, Naleway AL. Implementing a Multipartner HPV Vaccination Assessment and Feedback Intervention in an Integrated Health System . J. Public Health Manag. Pract. 2017 Nov/Dec; 23(6): 589-592.
Loharikar A, Suragh TA, MacDonald NE, Balakrishnan MR, Benes O, Lamprianou S, Hyde TB, McNeil MM. Anxiety-related adverse events following immunization (AEFI): A systematic review of published clusters of illness . Vaccine . 2018 Jan 4; 36(2):299-305. Epub 2017 Nov 29.
Moro PL, Zheteyeva Y, Barash F, Lewis P, Cano M. Assessing the safety of hepatitis B vaccination during pregnancy in the Vaccine Adverse Event Reporting System (VAERS), 1990-2016 . Vaccine . 2018 Jan 2; 36(1):50-54. Epub 2017 Nov 27.
Daley MF, Clarke CL, Glanz JM, Xu S, Hambidge SJ, Donahue JG, Nordin JD, Klein NP, Jacobsen SJ, Naleway AL, Jackson ML, Lee G, Duffy J, Weintraub E. The safety of live attenuated influenza vaccine in children and adolescents 2 through 17 years of age: A Vaccine Safety Datalink study . Pharmacoepidemiol Drug Saf . 2018 Jan; 27(1): 59-68. Epub 2017 Nov 17.
Myers TR, McNeil MM, Current safety issues with quadrivalent meningococcal conjugate vaccines. Hum Vaccin Immunother , 2018 May 4; 14(5): 1175-1178; Epub 2017 Nov 8.
Kemper AR, Barnett ED, Walter EB, Hornik C, Pierre-Joseph N, Broder KR, Silverstein M, Harrington T. Drinking Water to Prevent Postvaccination Presyncope in Adolescents: A Randomized Trial. Pediatrics 2017 Nov; 140(5).
Arana J, Mba-Jonas A, Jankosky C, Lewis P, Moro PL, Shimabukuro TT, Cano M. Reports of Postural Orthostatic Tachycardia Syndrome After Human Papillomavirus Vaccination in the Vaccine Adverse Event Reporting System . J Adolesc Health . 2017 Nov; 61 (5): 577-582.
Stockwell MS, Marchant CD, Wodi AP, Barnett ED, Broder KR, Jakob K, Lewis P, Kattan M, Rezendes AM, Barrett A, Sharma D, Fernandez N, LaRussa P. A multi-site feasibility study to assess fever and wheezing in children after influenza vaccines using text messaging. Vaccine. 2017 Dec 15; 35(50):6941-6948. Epub 2017 Oct 28.
Izurieta HS, Moro PL, Chen RT. Hospital-based collaboration for epidemiological investigation of vaccine safety: A potential solution for low and middle-income countries? Vaccine . 2018 Jan 8; 36(3):345-346. Epub 2017 Oct 21.
McCarthy NL, Sukumaran L, Newcomer S, Glanz J, Daley MF, McClure D, Klein NP, Irving S, Jackson ML, Lewin B, Weintraub E. Patterns of childhood immunization and all-cause mortality . Vaccine. 2017 Dec 4; 35(48 Pt B): 6643-6648. Epub 2017 Oct 20.
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Effectiveness and safety of SARS-CoV-2 vaccine in real-world studies: a systematic review and meta-analysis
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Infectious Diseases of Poverty volume 10 , Article number: 132 ( 2021 ) Cite this article
To date, coronavirus disease 2019 (COVID-19) becomes increasingly fierce due to the emergence of variants. Rapid herd immunity through vaccination is needed to block the mutation and prevent the emergence of variants that can completely escape the immune surveillance. We aimed to systematically evaluate the effectiveness and safety of COVID-19 vaccines in the real world and to establish a reliable evidence-based basis for the actual protective effect of the COVID-19 vaccines, especially in the ensuing waves of infections dominated by variants.
We searched PubMed, Embase and Web of Science from inception to July 22, 2021. Observational studies that examined the effectiveness and safety of SARS-CoV-2 vaccines among people vaccinated were included. Random-effects or fixed-effects models were used to estimate the pooled vaccine effectiveness (VE) and incidence rate of adverse events after vaccination, and their 95% confidence intervals ( CI ).
A total of 58 studies (32 studies for vaccine effectiveness and 26 studies for vaccine safety) were included. A single dose of vaccines was 41% (95% CI : 28–54%) effective at preventing SARS-CoV-2 infections, 52% (31–73%) for symptomatic COVID-19, 66% (50–81%) for hospitalization, 45% (42–49%) for Intensive Care Unit (ICU) admissions, and 53% (15–91%) for COVID-19-related death; and two doses were 85% (81–89%) effective at preventing SARS-CoV-2 infections, 97% (97–98%) for symptomatic COVID-19, 93% (89–96%) for hospitalization, 96% (93–98%) for ICU admissions, and 95% (92–98%) effective for COVID-19-related death, respectively. The pooled VE was 85% (80–91%) for the prevention of Alpha variant of SARS-CoV-2 infections, 75% (71–79%) for the Beta variant, 54% (35–74%) for the Gamma variant, and 74% (62–85%) for the Delta variant. The overall pooled incidence rate was 1.5% (1.4–1.6%) for adverse events, 0.4 (0.2–0.5) per 10 000 for severe adverse events, and 0.1 (0.1–0.2) per 10 000 for death after vaccination.
SARS-CoV-2 vaccines have reassuring safety and could effectively reduce the death, severe cases, symptomatic cases, and infections resulting from SARS-CoV-2 across the world. In the context of global pandemic and the continuous emergence of SARS-CoV-2 variants, accelerating vaccination and improving vaccination coverage is still the most important and urgent matter, and it is also the final means to end the pandemic.
Since its outbreak, coronavirus disease 2019 (COVID-19) has spread rapidly, with a sharp rise in the accumulative number of infections worldwide. As of August 8, 2021, COVID-19 has already killed more than 4.2 million people and more than 203 million people were infected [ 1 ]. Given its alarming-spreading speed and the high cost of completely relying on non-pharmaceutical measures, we urgently need safe and effective vaccines to cover susceptible populations and restore people’s lives into the original [ 2 ].
According to global statistics, as of August 2, 2021, there are 326 candidate vaccines, 103 of which are in clinical trials, and 19 vaccines have been put into normal use, including 8 inactivated vaccines and 5 protein subunit vaccines, 2 RNA vaccines, as well as 4 non-replicating viral vector vaccines [ 3 ]. Our World in Data simultaneously reported that 27.3% of the world population has received at least one dose of a COVID-19 vaccine, and 13.8% is fully vaccinated [ 4 ].
To date, COVID-19 become increasingly fierce due to the emergence of variants [ 5 , 6 , 7 ]. Rapid herd immunity through vaccination is needed to block the mutation and prevent the emergence of variants that can completely escape the immune surveillance [ 6 , 8 ]. Several reviews systematically evaluated the effectiveness and/or safety of the three mainstream vaccines on the market (inactivated virus vaccines, RNA vaccines and viral vector vaccines) based on random clinical trials (RCT) yet [ 9 , 10 , 11 , 12 , 13 ].
In general, RNA vaccines are the most effective, followed by viral vector vaccines and inactivated virus vaccines [ 10 , 11 , 12 , 13 ]. The current safety of COVID-19 vaccines is acceptable for mass vaccination, but long-term monitoring of vaccine safety is needed, especially in older people with underlying conditions [ 9 , 10 , 11 , 12 , 13 ]. Inactivated vaccines had the lowest incidence of adverse events and the safety comparisons between mRNA vaccines and viral vectors were controversial [ 9 , 10 ].
RCTs usually conduct under a very demanding research circumstance, and tend to be highly consistent and limited in terms of population characteristics and experimental conditions. Actually, real-world studies differ significantly from RCTs in terms of study conditions and mass vaccination in real world requires taking into account factors, which are far more complex, such as widely heterogeneous populations, vaccine supply, willingness, medical accessibility, etc. Therefore, the real safety and effectiveness of vaccines turn out to be a major concern of international community. The results of a mass vaccination of CoronaVac in Chile demonstrated a protective effectiveness of 65.9% against the onset of COVID-19 after complete vaccination procedures [ 14 ], while the outcomes of phase 3 trials in Brazil and Turkey were 50.7% and 91.3%, reported on Sinovac’s website [ 14 ]. As for the Delta variant, the British claimed 88% protection after two doses of BNT162b2, compared with 67% for AZD1222 [ 15 ]. What is surprising is that the protection of BNT162b2 against infection in Israel is only 39% [ 16 ]. Several studies reported the effectiveness and safety of the COVID-19 vaccine in the real world recently, but the results remain controversial [ 17 , 18 , 19 , 20 ]. A comprehensive meta-analysis based upon the real-world studies is still in an urgent demand, especially for evaluating the effect of vaccines on variation strains. In the present study, we aimed to systematically evaluate the effectiveness and safety of the COVID-19 vaccine in the real world and to establish a reliable evidence-based basis for the actual protective effect of the COVID-19 vaccines, especially in the ensuing waves of infections dominated by variants.
Search strategy and selection criteria
Our methods were described in detail in our published protocol [PROSPERO (Prospective register of systematic reviews) registration, CRD42021267110]. We searched eligible studies published by 22 July 2021, from three databases including PubMed, Embase and Web of Science by the following search terms: (effectiveness OR safety) AND (COVID-19 OR coronavirus OR SARS-CoV-2) AND (vaccine OR vaccination). We used EndNoteX9.0 (Thomson ResearchSoft, Stanford, USA) to manage records, screen and exclude duplicates. This study was strictly performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).
We included observational studies that examined the effectiveness and safety of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines among people vaccinated with SARS-CoV-2 vaccines. The following studies were excluded: (1) irrelevant to the subject of the meta-analysis, such as studies that did not use SARS-CoV-2 vaccination as the exposure; (2) insufficient data to calculate the rate for the prevention of COVID-19, the prevention of hospitalization, the prevention of admission to the ICU, the prevention of COVID-19-related death, or adverse events after vaccination; (3) duplicate studies or overlapping participants; (4) RCT studies, reviews, editorials, conference papers, case reports or animal experiments; and (5) studies that did not clarify the identification of COVID-19.
Studies were identified by two investigators (LQ and QCY) independently following the criteria above, while discrepancies reconciled by a third investigator (LJ).
Data extraction and quality assessment
The primary outcome was the effectiveness of SARS-CoV-2 vaccines. The following data were extracted independently by two investigators (LQ and QCY) from the selected studies: (1) basic information of the studies, including first author, publication year and study design; (2) characteristics of the study population, including sample sizes, age groups, setting or locations; (3) kinds of the SARS-CoV-2 vaccines; (4) outcomes for the effectiveness of SARS-CoV-2 vaccines: the number of laboratory-confirmed COVID-19, hospitalization for COVID-19, admission to the ICU for COVID-19, and COVID-19-related death; and (5) outcomes for the safety of SARS-CoV-2 vaccines: the number of adverse events after vaccination.
We evaluated the risk of bias using the Newcastle–Ottawa quality assessment scale for cohort studies and case–control studies [ 21 ]. and assess the methodological quality using the checklist recommended by Agency for Healthcare Research and Quality (AHRQ) [ 22 ]. Cohort studies and case–control studies were classified as having low (≥ 7 stars), moderate (5–6 stars), and high risk of bias (≤ 4 stars) with an overall quality score of 9 stars. For cross-sectional studies, we assigned each item of the AHRQ checklist a score of 1 (answered “yes”) or 0 (answered “no” or “unclear”), and summarized scores across items to generate an overall quality score that ranged from 0 to 11. Low, moderate, and high risk of bias were identified as having a score of 8–11, 4–7 and 0–3, respectively.
Two investigators (LQ and QCY) independently assessed study quality, with disagreements resolved by a third investigator (LJ).
Data synthesis and statistical analysis
We performed a meta-analysis to pool data from included studies and assess the effectiveness and safety of SARS-CoV-2 vaccines by clinical outcomes (rates of the prevention of COVID-19, the prevention of hospitalization, the prevention of admission to the ICU, the prevention of COVID-19-related death, and adverse events after vaccination). Random-effects or fixed-effects models were used to pool the rates and adjusted estimates across studies separately, based on the heterogeneity between estimates ( I 2 ). Fixed-effects models were used if I 2 ≤ 50%, which represented low to moderate heterogeneity and random-effects models were used if I 2 > 50%, representing substantial heterogeneity.
We conducted subgroup analyses to investigate the possible sources of heterogeneity by using vaccine kinds, vaccination status, sample size, and study population as grouping variables. We used the Q test to conduct subgroup comparisons and variables were considered significant between subgroups if the subgroup difference P value was less than 0.05. Publication bias was assessed by funnel plot and Egger’s regression test. We analyzed data using Stata version 16.0 (StataCorp, Texas, USA).
A total of 4844 records were searched from the three databases. 2484 duplicates were excluded. After reading titles and abstracts, we excluded 2264 reviews, RCT studies, duplicates and other studies meeting our exclude criteria. Among the 96 studies under full-text review, 41 studies were excluded (Fig. 1 ). Ultimately, with three grey literatures included, this final meta-analysis comprised 58 eligible studies, including 32 studies [ 14 , 15 , 17 , 18 , 19 , 20 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ] for vaccine effectiveness and 26 studies [ 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 ] for vaccine safety. Characteristics of included studies are showed in Additional file 1 : Table S1, Additional file 2 : Table S2. The risk of bias of all studies we included was moderate or low.
Flowchart of the study selection
Vaccine effectiveness for different clinical outcomes of COVID-19
We separately reported the vaccine effectiveness (VE) by the first and second dose of vaccines, and conducted subgroup analysis by the days after the first or second dose (< 7 days, ≥ 7 days, ≥ 14 days, and ≥ 21 days; studies with no specific days were classified as 1 dose, 2 dose or ≥ 1 dose).
For the first dose of SARS-CoV-2 vaccines, the pooled VE was 41% (95% CI : 28–54%) for the prevention of SARS-CoV-2 infection, 52% (95% CI : 31–73%) for the prevention of symptomatic COVID-19, 66% (95% CI : 50–81%) for the prevention of hospital admissions, 45% (95% CI : 42–49%) for the prevention of ICU admissions, and 53% (95% CI : 15–91%) for the prevention of COVID-19-related death (Table 1 ). The subgroup, ≥ 21 days after the first dose, was found to have the highest VE in each clinical outcome of COVID-19, regardless of ≥ 1 dose group (Table 1 ).
For the second dose of SARS-CoV-2 vaccines, the pooled VE was 85% (95% CI : 81–89%) for the prevention of SARS-CoV-2 infection, 97% (95% CI : 97–98%) for the prevention of symptomatic COVID-19, 93% (95% CI: 89–96%) for the prevention of hospital admissions, 96% (95% CI : 93–98%) for the prevention of ICU admissions, and 95% (95% CI : 92–98%) for the prevention of COVID-19-related death (Table 1 ). VE was 94% (95% CI : 78–98%) in ≥ 21 days after the second dose for the prevention of SARS-CoV-2 infection, higher than other subgroups, regardless of 2 dose group (Table 1 ). For the prevention of symptomatic COVID-19, VE was also relatively higher in 21 days after the second dose (99%, 95% CI : 94–100%). Subgroups showed no statistically significant differences in the prevention of hospital admissions, ICU admissions and COVID-19-related death (subgroup difference P values were 0.991, 0.414, and 0.851, respectively).
Vaccine effectiveness for different variants of SARS-CoV-2 in fully vaccinated people
In the fully vaccinated groups (over 14 days after the second dose), the pooled VE was 85% (95% CI: 80–91%) for the prevention of Alpha variant of SARS-CoV-2 infection, 54% (95% CI : 35–74%) for the Gamma variant, and 74% (95% CI : 62–85%) for the Delta variant. There was only one study [ 23 ] focused on the Beta variant, which showed the VE was 75% (95% CI : 71–79%) for the prevention of the Beta variant of SARS-CoV-2 infection. BNT162b2 vaccine had the highest VE in each variant group; 92% (95% CI : 90–94%) for the Alpha variant, 62% (95% CI : 2–88%) for the Gamma variant, and 84% (95% CI : 75–92%) for the Delta variant (Fig. 2 ).
Forest plots for the vaccine effectiveness of SARS-CoV-2 vaccines in fully vaccinated populations. A Vaccine effectiveness against SARS-CoV-2 variants; B Vaccine effectiveness against SARS-CoV-2 with variants not mentioned. SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, COVID-19 coronavirus disease 2019, CI confidence interval
For studies which had not mentioned the variant of SARS-CoV-2, the pooled VE was 86% (95% CI: 76–97%) for the prevention of SARS-CoV-2 infection in fully vaccinated people. mRNA-1273 vaccine had the highest pooled VE (97%, 95% CI: 93–100%, Fig. 2 ).
Safety of SARS-CoV-2 vaccines
As Table 2 showed, the incidence rate of adverse events varied widely among different studies. We conducted subgroup analysis by study population (general population, patients and healthcare workers), vaccine type (BNT162b2, mRNA-1273, CoronaVac, and et al.), and population size (< 1000, 1000–10 000, 10 000–100 000, and > 100 000). The overall pooled incidence rate was 1.5% (95% CI : 1.4–1.6%) for adverse events, 0.4 (95% CI : 0.2–0.5) per 10 000 for severe adverse events, and 0.1 (95% CI : 0.1–0.2) per 10 000 for death after vaccination. Incidence rate of adverse events was higher in healthcare workers (53.2%, 95% CI : 28.4–77.9%), AZD1222 vaccine group (79.6%, 95% CI : 60.8–98.3%), and < 1000 population size group (57.6%, 95% CI : 47.9–67.4%). Incidence rate of sever adverse events was higher in healthcare workers (127.2, 95% CI : 62.7–191.8, per 10 000), Gam-COVID-Vac vaccine group (175.7, 95% CI : 77.2–274.2, per 10 000), and 1000–10 000 population size group (336.6, 95% CI : 41.4–631.8, per 10 000). Incidence rate of death after vaccination was higher in patients (7.6, 95% CI : 0.0–32.2, per 10 000), BNT162b2 vaccine group (29.8, 95% CI : 0.0–71.2, per 10 000), and < 1000 population size group (29.8, 95% CI : 0.0–71.2, per 10 000). Subgroups of general population, vaccine type not mentioned, and > 100 000 population size had the lowest incidence rate of adverse events, severe adverse events, and death after vaccination.
Sensitivity analysis and publication bias
In the sensitivity analyses, VE for SARS-CoV-2 infections, symptomatic COVID-19 and COVID-19-related death got relatively lower when omitting over a single dose group of Maria et al.’s work [ 33 ]; when omitting ≥ 14 days after the first dose group and ≥ 14 days after the second dose group of Alejandro et al.’s work [ 14 ], VE for SARS-CoV-2 infections, hospitalization, ICU admission and COVID-19-related death got relatively higher; and VE for all clinical status of COVID-19 became lower when omitting ≥ 14 days after the second dose group of Eric et al.’s work [ 34 ]. Incidence rate of adverse events and severe adverse events got relatively higher when omitting China CDC’s data [ 74 ]. P values of Egger’s regression test for all the meta-analysis were more than 0.05, indicating that there might not be publication bias.
To our knowledge, this is a comprehensive systematic review and meta-analysis assessing the effectiveness and safety of SARS-CoV-2 vaccines based on real-world studies, reporting pooled VE for different variants of SARS-CoV-2 and incidence rate of adverse events. This meta-analysis comprised a total of 58 studies, including 32 studies for vaccine effectiveness and 26 studies for vaccine safety. We found that a single dose of SARS-CoV-2 vaccines was about 40–60% effective at preventing any clinical status of COVID-19 and that two doses were 85% or more effective. Although vaccines were not as effective against variants of SARS-CoV-2 as original virus, the vaccine effectiveness was still over 50% for fully vaccinated people. Normal adverse events were common, while the incidence of severe adverse events or even death was very low, providing reassurance to health care providers and to vaccine recipients and promote confidence in the safety of COVID-19 vaccines. Our findings strengthen and augment evidence from previous review [ 75 ], which confirmed the effectiveness of the BNT162b2 mRNA vaccine, and additionally reported the safety of SARS-CoV-2 vaccines, giving insight on the future of SARS-CoV-2 vaccine schedules.
Although most vaccines for the prevention of COVID-19 are two-dose vaccines, we found that the pooled VE of a single dose of SARS-CoV-2 vaccines was about 50%. Recent study showed that the T cell and antibody responses induced by a single dose of the BNT162b2 vaccine were comparable to those naturally infected with SARE-CoV-2 within weeks or months after infection [ 76 ]. Our findings could help to develop vaccination strategies under certain circumstances such as countries having a shortage of vaccines. In some countries, in order to administer the first dose to a larger population, the second dose was delayed for up to 12 weeks [ 77 ]. Some countries such as Canada had even decided to delay the second dose for 16 weeks [ 78 ]. However, due to a suboptimum immune response in those receiving only a single dose of a vaccine, such an approach had a chance to give rise to the emergence of variants of SARS-CoV-2 [ 79 ]. There remains a need for large clinical trials to assess the efficacy of a single-dose administration of two-dose vaccines and the risk of increasing the emergence of variants.
Two doses of SARS-CoV-2 vaccines were highly effective at preventing hospitalization, severe cases and deaths resulting from COVID-19, while the VE of different groups of days from the second vaccine dose showed no statistically significant differences. Our findings emphasized the importance of getting fully vaccinated, for the fact that most breakthrough infections were mild or asymptomatic. A recent study showed that the occurrence of breakthrough infections with SARS-CoV-2 in fully vaccinated populations was predictable with neutralizing antibody titers during the peri-infection period [ 80 ]. We also found getting fully vaccinated was at least 50% effective at preventing SARS-CoV-2 variants infections, despite reduced effectiveness compared with original virus; and BNT162b2 vaccine was found to have the highest VE in each variant group. Studies showed that the highly mutated variants were indicative of a form of rapid, multistage evolutionary jumps, which could preferentially occur in the milieu of partial immune control [ 81 , 82 ]. Therefore, immunocompromised patients should be prioritized for anti-COVID-19 immunization to mitigate persistent SARS-CoV-2 infections, during which multimutational SARS-CoV-2 variants could arise [ 83 ].
Recently, many countries, including Israel, the United States, China and the United Kingdom, have introduced a booster of COVID-19 vaccine, namely the third dose [ 84 , 85 , 86 , 87 ]. A study of Israel showed that among people vaccinated with BNT162b2 vaccine over 60 years, the risk of COVID-19 infection and severe illness in the non-booster group was 11.3 times (95% CI: 10.4–12.3) and 19.5 times (95% CI: 12.9–29.5) than the booster group, respectively [ 84 ]. Some studies have found that the third dose of Moderna, Pfizer-BioNTech, Oxford-AstraZeneca and Sinovac produced a spike in infection-blocking neutralizing antibodies when given a few months after the second dose [ 85 , 87 , 88 ]. In addition, the common adverse events associated with the third dose did not differ significantly from the symptoms of the first two doses, ranging from mild to moderate [ 85 ]. The overall incidence rate of local and systemic adverse events was 69% (57/97) and 20% (19/97) after receiving the third dose of BNT162b2 vaccine, respectively [ 88 ]. Results of a phase 3 clinical trial involving 306 people aged 18–55 years showed that adverse events after receiving a third dose of BNT162b2 vaccine (5–8 months after completion of two doses) were similar to those reported after receiving a second dose [ 85 ]. Based on V-safe, local reactions were more frequently after dose 3 (5323/6283; 84.7%) than dose 2 (5249/6283; 83.5%) among people who received 3 doses of Moderna. Systemic reactions were reported less frequently after dose 3 (4963/6283; 79.0%) than dose 2 (5105/6283; 81.3%) [ 86 ]. On August 4, WHO called for a halt to booster shots until at least the end of September to achieve an even distribution of the vaccine [ 89 ]. At this stage, the most important thing we should be thinking about is how to reach a global cover of people at risk with the first or second dose, rather than focusing on the third dose.
Based on real world studies, our results preliminarily showed that complete inoculation of COVID-19 vaccines was still effective against infection of variants, although the VE was generally diminished compared with the original virus. Particularly, the pooled VE was 54% (95% CI : 35–74%) for the Gamma variant, and 74% (95% CI : 62–85%) for the Delta variant. Since the wide spread of COVID-19, a number of variants have drawn extensive attention of international community, including Alpha variant (B.1.1.7), first identified in the United Kingdom; Beta variant (B.1.351) in South Africa; Gamma variant (P.1), initially appeared in Brazil; and the most infectious one to date, Delta variant (B.1.617.2) [ 90 ]. Israel recently reported a breakthrough infection of SARS-CoV-2, dominated by variant B.1.1.7 in a small number of fully vaccinated health care workers, raising concerns about the effectiveness of the original vaccine against those variants [ 80 ]. According to an observational cohort study in Qatar, VE of the BNT162b2 vaccine against the Alpha (B.1.1.7) and Beta (B.1.351) variants was 87% (95% CI : 81.8–90.7%) and 75.0% (95% CI : 70.5–7.9%), respectively [ 23 ]. Based on the National Immunization Management System of England, results from a recent real-world study of all the general population showed that the AZD1222 and BNT162b2 vaccines protected against symptomatic SARS-CoV-2 infection of Alpha variant with 74.5% (95% CI : 68.4–79.4%) and 93.7% (95% CI : 91.6–95.3%) [ 15 ]. In contrast, the VE against the Delta variant was 67.0% (95% CI : 61.3–71.8%) for two doses of AZD1222 vaccine and 88% (95% CI : 85.3–90.1%) for BNT162b2 vaccine [ 15 ].
In terms of adverse events after vaccination, the pooled incidence rate was very low, only 1.5% (95% CI : 1.4–1.6%). However, the prevalence of adverse events reported in large population (population size > 100 000) was much lower than that in small to medium population size. On the one hand, the vaccination population in the small to medium scale studies we included were mostly composed by health care workers, patients with specific diseases or the elderly. And these people are more concerned about their health and more sensitive to changes of themselves. But it remains to be proved whether patients or the elderly are more likely to have adverse events than the general. Mainstream vaccines currently on the market have maintained robust safety in specific populations such as cancer patients, organ transplant recipients, patients with rheumatic and musculoskeletal diseases, pregnant women and the elderly [ 54 , 91 , 92 , 93 , 94 ]. A prospective study by Tal Goshen-lag suggests that the safety of BNT162b2 vaccine in cancer patients is consistent with those previous reports [ 91 ]. In addition, the incidence rate of adverse events reported in the heart–lung transplant population is even lower than that in general population [ 95 ]. On the other hand, large scale studies at the national level are mostly based on national electronic health records or adverse event reporting systems, and it is likely that most mild or moderate symptoms are actually not reported.
Compared with the usual local adverse events (such as pain at the injection site, redness at the injection site, etc.) and normal systemic reactions (such as fatigue, myalgia, etc.), serious and life-threatening adverse events were rare due to our results. A meta-analysis based on RCTs only showed three cases of anaphylactic shock among 58 889 COVID-19 vaccine recipients and one in the placebo group [ 11 ]. The exact mechanisms underlying most of the adverse events are still unclear, accordingly we cannot establish a causal relation between severe adverse events and vaccination directly based on observational studies. In general, varying degrees of adverse events occur after different types of COVID-19 vaccination. Nevertheless, the benefits far outweigh the risks.
Our results showed the effectiveness and safety of different types of vaccines varied greatly. Regardless of SARS-CoV-2 variants, vaccine effectiveness varied from 66% (CoronaVac [ 14 ]) to 97% (mRNA-1273 [ 18 , 20 , 45 , 46 ]). The incidence rate of adverse events varied widely among different types of vaccines, which, however, could be explained by the sample size and population group of participants. BNT162b2, AZD1222, mRNA-1273 and CoronaVac were all found to have high vaccine efficacy and acceptable adverse-event profile in recent published studies [ 96 , 97 , 98 , 99 ]. A meta-analysis, focusing on the potential vaccine candidate which have reached to the phase 3 of clinical development, also found that although many of the vaccines caused more adverse events than the controls, most were mild, transient and manageable [ 100 ]. However, severe adverse events did occur, and there remains the need to implement a unified global surveillance system to monitor the adverse events of COVID-19 vaccines around the world [ 101 ]. A recent study employed a knowledge-based or rational strategy to perform a prioritization matrix of approved COVID-19 vaccines, and led to a scale with JANSSEN (Ad26.COV2.S) in the first place, and AZD1222, BNT162b2, and Sputnik V in second place, followed by BBIBP-CorV, CoronaVac and mRNA-1273 in third place [ 101 ]. Moreover, when deciding the priority of vaccines, the socioeconomic characteristics of each country should also be considered.
Our meta-analysis still has several limitations. First, we may include limited basic data on specific populations, as vaccination is slowly being promoted in populations under the age of 18 or over 60. Second, due to the limitation of the original real-world study, we did not conduct subgroup analysis based on more population characteristics, such as age. When analyzing the efficacy and safety of COVID-19 vaccine, we may have neglected the discussion on the heterogeneity from these sources. Third, most of the original studies only collected adverse events within 7 days after vaccination, which may limit the duration of follow-up for safety analysis.
Based on the real-world studies, SARS-CoV-2 vaccines have reassuring safety and could effectively reduce the death, severe cases, symptomatic cases, and infections resulting from SARS-CoV-2 across the world. In the context of global pandemic and the continuous emergence of SARS-CoV-2 variants, accelerating vaccination and improving vaccination coverage is still the most important and urgent matter, and it is also the final means to end the pandemic.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and its additional information files.
Coronavirus disease 2019
Severe Acute Respiratory Syndrome Coronavirus 2
Intensive care unit
Random clinical trials
Preferred reporting items for systematic reviews and meta-analyses
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This study was funded by the National Natural Science Foundation of China (72122001; 71934002) and the National Science and Technology Key Projects on Prevention and Treatment of Major infectious disease of China (2020ZX10001002). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the paper. No payment was received by any of the co-authors for the preparation of this article.
Qiao Liu and Chenyuan Qin are joint first authors
Authors and Affiliations
Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, 100191, China
Qiao Liu, Chenyuan Qin, Min Liu & Jue Liu
Institute for Global Health and Development, Peking University, Beijing, 100871, China
Chenyuan Qin & Jue Liu
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LQ and QCY contributed equally as first authors. LJ and LM contributed equally as correspondence authors. LJ and LM conceived and designed the study; LQ, QCY and LJ carried out the literature searches, extracted the data, and assessed the study quality; LQ and QCY performed the statistical analysis and wrote the manuscript; LJ, LM, LQ and QCY revised the manuscript. All authors read and approved the final manuscript.
Correspondence to Min Liu or Jue Liu .
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Additional file 1: table s1..
Characteristic of studies included for vaccine effectiveness.
Additional file 2: Table S2.
Characteristic of studies included for vaccine safety.
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Liu, Q., Qin, C., Liu, M. et al. Effectiveness and safety of SARS-CoV-2 vaccine in real-world studies: a systematic review and meta-analysis. Infect Dis Poverty 10 , 132 (2021). https://doi.org/10.1186/s40249-021-00915-3
Received : 07 September 2021
Accepted : 01 November 2021
Published : 14 November 2021
DOI : https://doi.org/10.1186/s40249-021-00915-3
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Safety & effectiveness of COVID-19 vaccines: A narrative review
1 Department of Public Health, Post-graduate School of Occupational Medicine, Catholic University of the Sacred Heart, Rome, Italy
Jaime A. Teixeira da Silva
2 Independent Researcher, Kagawa-Ken, Japan
3 Department of Economics, Thompson Rivers University, Kamloops, British Columbia, Canada
4 Division of Surgery, ICAR-Indian Veterinary Research Institute, Bareilly, Uttar Pradesh, India
There are currently eight vaccines against SARS-CoV-2 that have received Emergency Use Authorization by the WHO that can offer some protection to the world’s population during the COVID-19 pandemic. Though research is being published all over the world, public health officials, policymakers and governments are collecting evidence-based information to establish the public health policies. Unfortunately, continued international travel, violations of lockdowns and social distancing, the lack of mask use, the emergence of mutant strains of the virus and lower adherence by a sector of the global population that remains sceptical of the protection offered by vaccines, or about any risks associated with vaccines, hamper these efforts. Here we examine the literature on the efficacy, effectiveness and safety of COVID-19 vaccines, with an emphasis on select categories of individuals and against new SARS-CoV-2 strains. The literature shows that these eight vaccines are highly effective in protecting the population from severe disease and death, but there are some issues concerning safety and adverse effects. Further, booster shots and variant-specific vaccines would also be required.
The World Health Organization (WHO) list of Emergency Use Authorization (EUA)-qualified COVID-19 vaccines (as on 20 December, 2021) contains eight vaccines, namely the three adenoviral-vectored vaccines ChAdOx1 nCoV-19 (University of Oxford/AstraZeneca), Ad26.CoV2.S (Janssen), Covishield, CrAdOxI, nCoV-19 (Serum Institute of India), two whole-inactivated coronavirus, which are the Covilo/BBIBP-CorV (SinoPharm/Beijing Institute of Biological Products), CoronaVac (Sinovac) and Covaxin, BBV152 (Bharat Biotech), and the messenger RNA (mRNA) vaccines mRNA-1273 (Moderna) and BNT162b2 (Pfizer-BioNTech) 1 . mRNA vaccines work by injecting mRNA that encodes the SARS-CoV-2 spike protein directly into the host and have several advantages over conventional vaccine types, including improved safety, low potential for mutations, lower risk of antigen degradation in vivo and the potential for rapid mass production at a lower cost 2 , although there are still challenges remaining regarding their pharmacological stability 3 .
Another mRNA vaccine, CureVac, was developed in the European Union (EU) by CureVac N.V. and the Coalition for Epidemic Preparedness Innovations, with the hope of being cheaper and lasting longer than other mRNA vaccines, but results on June 16, 2021 from a 40,000-person phase III two-dose trial found it 47 per cent effective at preventing the disease, which was lower than the ≥50 per cent requirement for approval by the WHO 4 . Other vaccines produced by Janssen, AstraZeneca, Sputnik-V and CanSino, use human and primate adenovirus vectors 5 . The vaccines manufactured by Novavax and GSK/Sanofi companies consist of purified pre-fusion stabilized SARS-CoV-2 spike protein, which is given in combination with an adjuvant to boost the immune response 6 . On June 1, 2021, the WHO validated the use of the Chinese Sinovac - CoronaVac COVID-19 vaccine for emergency use, although with interim policy recommendations 7 . CoronaVac is an inactivated vaccine with easy storage requirements 8 . It was only 51 per cent effective at preventing COVID-19 in late-stage trials 9 . The vaccine’s safety, immunogenicity and efficacy need to be tested across the three phases of clinical trials, although ‘protection against severe disease and death is difficult to assess only in phase 3 clinical trials’ 10 .
Vaccination against COVID-19 started in India on January 16, 2021 11 . The Indian government and States launched an extensive vaccination campaign against COVID-19, targeting 300 million beneficiaries of priority groups such as healthcare and frontline workers and individuals older than 50 12 . India’s drug regulator (Central Drugs and Standards Committee - CDSCO) approved restricted emergency use of Covishield and Covaxin in India. Covishield (AstraZeneca vaccine ChAdOx1/AZD1222), approved for EUA by the WHO, is a two-dose version of the Oxford/AstraZeneca vaccine manufactured by the Serum Institute of India 13 , while Covaxin (BBV152 vaccine) is an inactivated-virus vaccine 11 , 14 . Phase I (safety and immunogenicity) and phase II trial (immune response and safety) data of Covaxin are published 15 . A phase 3 study confirmed the clinical efficacy of BBV152 against symptomatic COVID-19 disease and safety monitoring and assessment did not raise concerns about the vaccine 16 .
In April 2021, the Indian Government approved Sputnik V as a third vaccine 12 . Sputnik V (Gam-COVID-Vac), which is a dual vector-based vaccine that combines type 26 and rAd5 recombinant adenovirus (rAd), exhibited 91.6 per cent efficacy against COVID-19 17 . Sinopharm’s BBIBP-CorV (Covilo) showed 79 per cent efficacy against symptomatic SARS-CoV-2 infection and hospitalization in a large multi-country phase III trial after administering two doses 21 days apart, but efficacy could not be determined in people aged 60+ and with comorbidities, and there was an underrepresentation of women 18 .
In October 2021, India crossed the one billion vaccine doses milestone and by January 16, 2022, 70 per cent adult population was fully vaccinated 19 .
Efficacy/effectiveness of current COVID-19 vaccines
A systematic review on the efficacy of vaccines covering studies from January 1 to May 14, 2021 identified 30 studies, showed 80-90 per cent vaccine efficacy against symptomatic and asymptomatic infections in fully vaccinated people in nearly all studies 20 . In clinical trials, three vaccines had higher (>90%) efficacy against COVID-19 infection [Pfizer-BioNTech (~95%), Moderna (~94%) and Sputnik V (~92%)] than the vaccines by Oxford-AstraZeneca (~70%) and Janssen (54-72%), against moderate and severe forms of COVID-19 infection 10 . The mRNA vaccines showed high efficacy against infection and a very high level of protection against severe disease, hospitalization and death while the risk of severe forms of COVID-19 infection and deaths was reduced by Moderna, Sputnik V, Janssen and Oxford-AstraZeneca vaccines. In contrast, this information was not available in the published trials for the Pfizer-BioNTech vaccine 20 , 21 . Compared to the Pfizer vaccine, the Moderna vaccine can be kept at higher temperatures, making it easier to transport and store 22 . Other vaccines produced by other companies, and with positive efficacy results, received EUA status in some countries 23 . The longitudinal assessment of vaccine participants is a necessary critical assessment because it provides information on whether vaccination can achieve long-lasting immunity 24 .
Although most evidence suggests that ‘immune responses elicited by SARS-CoV-2 infection are present and might protect against’ reinfection, but the experience with seasonal coronaviruses and the present experience with SARS-CoV-2 suggest that immunity to natural infection might wane over time, as reinfection cases occur 25 . For this reason, an extra booster dose can continue to offer protection 26 .
Regarding the interchangeability of COVID-19 vaccines, the WHO recommends using the same COVID-19 vaccine for both doses of a two-dose schedule 27 , but there is scientific evidence of the effectiveness of heterologous vaccination with AstraZeneca or Covishield as the first dose and an mRNA vaccine as the second dose 28 , 29 , 30 .
Safety and adverse effects of current COVID-19 vaccines
As shown in Table I , current vaccines have demonstrated considerable efficacy in diminishing mild, moderate and severe cases with a low risk of adverse events 21 . For some of these vaccines [such as Convidicea (AD5-nCoV), Janssen (Ad26.COV2.S), Sinopharm (BBIBP-CorV), Covaxin (BBV152) and Sinovac (CoronaVac)], there is the information available on their immunogenicity and safety from phase I and II vaccine recipients, but evidence of their effectiveness is not clear 21 . Due to urgency, health regulatory agencies such as the EMA in the EU and the Food and Drug Administration (FDA) in the US evaluated only short-term adverse effects before their authorization. Records of adverse events in trial results on the BNT162b2 mRNA COVID-19 vaccine (Pfizer-BioNTech vaccine) continued up to six months from the second dose 39 . Mild-to-moderate local responses such as discomfort, redness or inflammation at the injection site were the most commonly reported adverse effects in the clinical trials, while systemic events included fatigue, headache, body aches and fever 39 . There were four serious issues among BNT162b2 participants in a clinical trial: shoulder injury from vaccine administration, right axillary lymphadenopathy, paroxysmal ventricular arrhythmia and right leg paresthesia 39 . Another adverse reaction in the Pfizer-BioNTech trial was lymphadenopathy with 64 vaccine recipients (0.3%) versus only six in the placebo group (<0.1%) 39 . The clinical trial on the mRNA-1273 COVID-19 vaccine, manufactured by ModernaTX Inc., reported no serious adverse events, while moderate or mild adverse events included headache, fatigue, myalgia, chills and injection-site discomfort, but these were dose-dependent and more common after the second immunization 40 .
Type, regime, efficacy, safety, protection against variants and storage of COVID-19 vaccines listed by the World Health Organization: Findings from clinical trials and preliminary studies
Information gathered above from various sources can be also validated from: https://www.mckinsey.com /industries/pharmaceuticals-and-medical-products/our-insights/on-pins-and-needles-will-COVID-19-vaccines-save-the-world and https://www.statista.com /chart/23510/estimated-effectiveness-of-COVID-19-vaccine-candidates /. Cost per dose obtained from: https://www.statista.com /chart/23658/reported-cost-per-dose-of-COVID-19-vaccines/ and https://observer.com /2020/08/COVID19-vaccine- price-comparison-moderna-pfizer-novavax-johnson-astrazeneca /. All vaccines report mild-to-moderate local reactions ( e.g. , pain, redness, or swelling at the injection) and a few systemic events ( e.g ., fatigue, headache, body aches, and fever), For information on protection against variants see: https://www.businessinsider.in /science/news/one-chart-shows-how-well-covid-19-vaccines-work-against-the-3-most-worrisome-coronavirus-variants/articleshow/81472174.cms , WHO. Background document on the Bharat Biotech BBV152 Covaxin vaccine against COVID-19. Released on November 3, 2021. Available from: https://extranet.who.int /iris/restricted/bitstream/handle/10665/347044/WHO-2019-nCoV-vaccines-SAGE-recommendation-BBV152-background-2021.1-eng.pdf?sequence=1&isAllowed=y ; For the cost of Covaxin: https://www.dnaindia.com /india/report-bharat-biotech-announces-price-of-Covaxin-rs-600-for-states-rs-1200-for-private-hospitals-2887737.
Myocarditis and pericarditis were reported in individuals receiving mRNA vaccines (Pfizer-BioNTech BNT162b2 and Moderna SpikeVax), especially in young males after the second dose, so the US Centres for Disease Control and Prevention (CDC) and FDA developed educational material for vaccine recipients and providers that described the possibility of myocarditis and its symptoms to be able to recognize and manage it 41 . There are insufficient data to describe the efficacy, safety and effectiveness of the BNT162b2 in children under 16 and the SpikeVax vaccine in individuals under 18 42 . Although the balance of benefits and risks varied by age and gender, but the benefits of preventing the COVID-19 disease and associated hospitalizations, intensive care unit admissions and deaths outweighed the risks such as expected myocarditis cases after vaccination in all populations for which vaccination was recommended 41 . There are currently no alternatives to mRNA COVID-19 vaccines for youths, so on May 10, 2021, the FDA expanded the EUA of the Pfizer-BioNTech COVID-19 vaccine to include adolescents 12 through 15 yr of age 41 .
Anaphylaxis has been the only life-threatening condition reported during the vaccination campaign with the Pfizer-BioNTech vaccine, so it has to be appropriately managed and prevented 43 . Hypersensitivity-related adverse events for Pfizer-BioNTech and Moderna trial participants relative to the placebo groups were 0.12 and 0.4 per cent higher, respectively 39 , 40 . In addition, the Pfizer-BioNTech trial reported one ‘drug hypersensitivity reaction’ and one case of anaphylaxis, while Moderna reported two cases of ‘delayed hypersensitivity reactions’ 44 .
By December 23, 2020, among the 1,893,360 first doses of Pfizer-BioNTech vaccines administered in the US, only 0.2 per cent of adverse events were reported and submitted to the Vaccine Adverse Event Reporting System (VAERS) 45 . As of January 10, 2021, a reported 4,041,396 first doses of Moderna COVID-19 vaccine had been administered in the United States, and reports of 1,266 (0.03%) adverse events after receipt of Moderna COVID-19 vaccine were submitted to VAERS 46 .
Allergic reactions from the two available mRNA COVID-19 vaccines were due to polyethylene glycol (PEG) 47 , also known as macrogol, while for the AstraZeneca and Johnson and Johnson COVID-19 vaccines, the filler polysorbate 80, also known as Tween 80, has been implicated in allergic reactions 48 , 49 , 50 . Allergic reactions are rare, but the CDC recommends avoiding mRNA vaccines in individuals who had anaphylaxis in the past 42 , 51 . In addition, the CDC guidance indicates precaution for allergy due to ‘a potential cross-reactive hypersensitivity between ingredients in mRNA and adenovirus vector COVID-19 vaccines’ 52 .
The occurrence of thrombosis with thrombocytopenia syndrome was linked to adenovirus vector vaccines such as ChAdOx1 nCoV-19 (Oxford-AstraZeneca) and AD26.CoV2·S (Johnson and Johnson), raising concerns 43 . For example, a population-based cohort study in Denmark and Norway showed ‘increased rates of venous thromboembolic events, including cerebral venous thrombosis’ in recipients of ChAdOx1, more venous thromboembolic events were observed in the vaccinated cohort than expected in the general population, and the standardized morbidity ratio was significantly greater than unity 53 .
ChAdOx1 nCoV-19 vaccine induced immune thrombotic thrombocytopenia and cerebral venous sinus thrombosis with fatal intracerebral haemorrhaging 53 , 54 , 55 . Following administration of the Johnson & Johnson vaccine, a case of thrombocytopenia, elevated D-dimers and pulmonary emboli was found 56 . EMA reported other blood clots associated with thrombocytopenia, including arterial thromboses and splanchnic vein thrombosis, after administration of the AstraZeneca vaccine 57 . All patients in each series had high levels of antibodies against antigenic complexes of platelet factor 4, as seen in heparin-induced thrombocytopenia. Therefore, this condition was defined as ‘vaccine-induced immune thrombotic thrombocytopenia’, requiring high-dose immunoglobulins and certain non-heparin anticoagulants for treatment 57 , 58 . A case report of Guillain−Barre syndrome followed the administration of the first dose of the ChAdOx1 vaccine 59 , and two cases of autoimmune hepatitis were triggered by Covishield vaccination 60 .
The Coalition of Epidemic Preparedness Innovations (CEPI) questioned the use of alum and other adjuvants that might promote T-helper2 (Th2) responses 61 . Moreover, T-helper17 (Th17) inflammatory responses, which play a role in the pathogenesis of COVID-19-related pneumonia and oedema by promoting eosinophilic activation and infiltration, could also explain coronavirus-vaccine immune enhancement 62 . Therefore, an understanding of Th17 responses is critical for the successful clinical development and production of COVID-19 vaccines and plays a potential role in selecting vaccine dose, adjuvants and route 62 .
Do COVID-19 vaccines sensitize humans to antibody-dependent enhanced (ADE) breakthrough infection? ADE is a complex phenomenon that includes vaccine hypersensitivity (VAH), delayed-type hypersensitivity and/or an Arthus reaction 63 . VAH has a complex and poorly defined immunopathology post-vaccination outcome that may be associated with non-protective antibodies 64 . ADE in SARS-CoV and MERS-CoV infection showed the development of poorly or non-neutralizing antibodies after vaccination or infection enhance subsequent infections 65 . Several SARS-CoV and MERS-CoV vaccines have elicited a post-challenge VAH in laboratory animals. For example, in the 1960s, the formalin-inactivated measles vaccine in children caused VAH 8-12 months after the vaccination, leading to lung lesions, revealing damage to parenchymal tissue, pulmonary neutrophilia with abundant macrophages and lymphocytes and excess eosinophils 66 . Lessons learned from adverse effects caused by SARS-CoV and MERS-CoV vaccines may help to develop better immunotherapeutics and vaccines against SARS-CoV-2 65 .
Overvaccination in patients predisposed to autoimmune disease may enhance the possibility of developing an autoimmune response 63 . Since the mRNA vaccines against COVID-19 are the first mRNA vaccines authorized for the market, there is a possibility that these may generate strong type 1 interferon responses that could lead to inflammation and autoimmune conditions 67 .
A vaccine in the market requires safety monitoring surveillance to detect and evaluate rare adverse events not identified in prelicensure clinical trials. In the US, the CDC has three long-standing vaccine safety programmes: VAERS, the Vaccine Safety Datalink and the Clinical Immunization Safety Assessment 68 .
Efficacy of the vaccines against new viral strains
Considering that the SARS-CoV-2 virus, like other viruses, mutates 69 , 70 , why are some RNA vaccines effective against the new strains of the SARS-CoV-2 virus, while others are less, or not at all? These new variants result from mutations in the viral genomes, occurring due to the consequences of viral replication, which are advantageous to the survival of the virus. Among these variants, WHO, US CDC, and the EU’s European Centre for Disease Prevention identified some variants as being significant variants, referring to them as variants of concern (VOCs) and variants of interest (VOIs) ( Table II ). VOCs emerged as a more significant threat to public health due to their enhanced transmissibility and infectivity 71 . Global concern is the continued spread of the highly transmissible Delta variant, which has become predominant worldwide 72 , 73 and has better transmission potential (60%) than the alpha variant 74 . Currently, omicron variant is becoming the predominant strain resulting from a combination of increased transmissibility and the ability to evade natural and artificial immunization 75 . WHO monitors the global spread and epidemiology of VOCs and VOIs and coordinates laboratory investigations 76 .
Characteristics of SARS-CoV-2 variants of concern (VOC, Alpha, Beta, Gamma, Delta and omicron) and variants of interest (VOI, Lambda and Mu)
Last updated: 20 December 2021. Information obtained from WHO ( https://www.who.int /en/activities/tracking-SARS-CoV-2-variants/ ) there are a number of variants that are being monitored currently and can be found at the WHO as we as at the USA Center of Disease Control and Prevention found ( https://www.cdc.gov /coronavirus/2019-ncov/variants/variant-info.html ); CDC has no VOI listed and only two VOCs: Delta and Omicron; There is also information in the magazine about: https://www.businessinsider.com /COVID-19-vaccine-efficacy-variants-india-south-africa-brazil-uk-2021-5 ; for transmission see: https://www.aljazeera.com /news/2021/7/7/map-tracking-the-COVID-19-delta-variant . WHO, World Health Organization; CDC, Centres for Disease Control; VOI, variants of interest; VOCs, variants of concerns; N/A, not available
Several SARS-CoV-2 VOCs have emerged and were originally identified in the UK (variant B.1.1.7 or alpha), South Africa (B.1.351 or beta), Brazil (P.1 or gamma), India (B.1.617.2 or delta) and South Africa (B.1.1.529 or omicron) 77 . These VOCs are considered severe public health threats because of their association with higher transmissibility, morbidity, mortality and potential immune escape 78 by infection or vaccine-induced antibodies resulting from the accumulation of mutations in the spike protein 79 . In other words, these may alter the clinical manifestation of the disease and efficacy of available vaccines and therapeutics, as well as the ability of reverse transcription-polymerase chain reaction (RT-PCR) assays to detect the virus 80 .
Though the efficacy of the ChAdOx1 nCoV-19 vaccine against the alpha variant was similar to that reported in previous studies 81 , the vaccine conferred only minimal protection against COVID-19 infection caused by the Beta variant 82 . The NVX-CoV2373 vaccine (Novavax) also demonstrated efficacy against the Alpha and Beta variants of SARS-CoV-2 83 . The Novavax vaccine is 86 per cent efficacious against the Alpha variant and 60 per cent efficacious against the Beta variant 84 . Although the neutralization capacity of several COVID-19 vaccines (mRNA-1273, NVX-CoV2373, BNT162b2 and ChAdOx1 nCoV-19) was reduced against the Beta (B.1.351) variant 85 , but Covaxin conferred significant protection against both Beta (B.1.351) and Delta (B.1.617.2) variants 70 .
Similarly, the single-dose Janssen COVID-19 vaccine candidate demonstrated efficacy against the Beta variant 86 . The Moderna vaccine candidate (mRNA-1273) also demonstrated efficacy against the Alpha and Beta SARS-CoV-2 variants, findings that were based on in vitro neutralization studies conducted using serum collected from individuals vaccinated with the mRNA-1273 vaccine 87 . Therefore, South Africa adjourned campaigns to vaccinate its front-line health care workers (HCWs) with the Oxford-AstraZeneca vaccine after a small clinical trial suggested that it ineffectively prevented mild to moderate illness from the dominant variant in the country 88 . The results of a clinical trial confirmed that a two-dose regimen of the ChAdOx1 nCoV-19 (AstraZeneca) vaccine did not protect individuals against the mild-to-moderate B.1.351 variant 89 .
Mutations observed in the SARS-CoV-2 variants identified in the UK and South Africa had small effects on the effectiveness of the Pfizer-BioNTech vaccine 90 . A two-strain mathematical framework using Ontario (Canada) as a case study found that, given the levels of under-reporting and case levels at that time, ‘a variant strain was unlikely to dominate’ until the first quarter of 2021, and high vaccine efficacy was required across strains to make it possible to have an immune population in Ontario by the end of 2021 91 . The UK research showed that the Pfizer–BioNTech vaccine was 92 per cent effective against symptomatic cases of the alpha variant and offered 83 per cent protection against the Delta variant 92 . A study in Qatar found similar results: the Pfizer–BioNTech vaccine offered 90 per cent protection against the Alpha variant and 75 per cent protection against the Beta variant 93 . In a US-based study carried out during July 2021, 346 of the 469 COVID-19 cases (74%) among Massachusetts residents occurred in fully vaccinated people with two doses of Pfizer-BioNTech, Moderna, or a single dose of Janssen vaccine ≥14 days before exposure 94 . Genomic sequencing of testing identified the new Delta variant in 90 per cent of cases 86 . Even vaccinated people may get infected with COVID-19 due to the Delta variant, and on July 27, 2021, the US CDC released a recommendation to invite citizens to wear masks in indoor public environments where the risk of COVID-19 transmission is high 84 .
The neutralization potential of BBV152/Covaxin, the inactivated SARS-CoV-2 vaccine rolled out in India, was also effective against Beta and Delta variants, but since reduced neutralization activity may result in reduced vaccine effectiveness, further studies are needed for Covaxin against these two variants 78 . A single dose of Pfizer or AstraZeneca offered little protection against the Beta and Delta variants and a neutralizing response was generated against the Delta variant only after the administration of the second dose 74 . Despite being lower, the remaining neutralization capacity conferred by the Pfizer vaccine against Delta and other VOCs was protective 95 .
Until February 6, 2022, the WHO described eight variants of interest (VOIs), namely Epsilon (B.1.427 and B.1.429); Zeta (P.2); Eta (B.1.525); Theta (P.3); Iota (B.1.526); Kappa (B.1.617.1); Lambda (C.37)and Mu (B.1.621) 96 . However, there is still a lack of detailed knowledge about their transmissibility, infectivity, re-infectivity, immune escape and vaccine activity 61 . A preprint highlighted that the lambda variant (lineage C.37), which spread from Peru in December 2020, displayed increased infectivity and immune escape against the Coronovac vaccine 97 . Table II summarizes the profiles of the VOCs and VOIs. The most recent data on the variants reported in India are available at the Indian SARS-CoV-2 Genomic Consortia (INSACOG) website. The predominant SARS-CoV-2 variant currently circulating in India is Delta (B.1.617.2 and AY.4) 98 . Covaxin (BBV152) exhibited good protection (65.2%) against the Delta variant, and although a minor reduction in the neutralizing antibody titre was observed, the sera of vaccinated individuals still effectively neutralized the Delta, Delta AY.1 and B.1.617.3 variants 99 . In contrast, breakthrough infections were reported due to the Delta variant in individuals fully vaccinated with Covishield 100 .
Safety and efficacy of the vaccines in select categories of people
Another issue is that clinical trials are studies conducted on select categories of individuals, generally healthy people. Thus, concerns exist about safety and effectiveness in specific categories of people. For instance, there are doubts that all COVID-19 vaccines can stimulate an immune response in older individuals (≥65 yr), especially those with co-morbidities, such as hypertension, obesity and diabetes mellitus 101 . Older patients, especially those older than 65 and with co-morbidities, are more susceptible to a severe form of COVID-19 that can progress rapidly, often leading to death 102 . In general, the efficacy of vaccines in older people is not well studied. The impact of immunosenescence on vaccine safety is even more uncertain 2 . The presence of chronic diseases ( e.g ., diabetes) and fragility, including immunodepression, may be better forecasters of weak immunologic responses than age 103 .
Even though the safety and efficacy of COVID-19 vaccines in older people are critical to their health 2 , no studies have been done to examine the response of this category of individuals to all COVID-19 vaccines. Vaccines developed by the University of Oxford/AstraZeneca (ChAdOx1) and Janssen (Ad26.COV2) depend on the genetic alteration of adenoviruses that are inactivated, due to the replacement of the E1 gene with the spike gene 2 . The ChAdOx1 nCoV-19 (AZD1222) vaccine is better tolerated by older than younger people, and after the second dose, it has similar immunogenicity across all ages 104 . However, additional assessment of AZD1222 is planned 105 . A second trial on the Moderna vaccine showed binding- and neutralizing-antibody responses in older people (>55 yr), similar to previously reported vaccine recipients between 18 and 55 yr of age 40 .
Pregnant and lactating women are excluded from vaccine research because they are not recognized as a high-priority group, despite the risk of complications and poor perinatal outcomes 106 , and because of previous experience of pregnancies complicated by infection with other coronaviruses, such as SARS-CoV and MERS-CoV, making pregnant women vulnerable to severe SARS-CoV-2 disease 107 . A retrospective study based on the clinical criteria confirmed that pregnancy significantly increased the risk of severe COVID-19 108 . Based on a review of maternal and neonatal COVID-19 morbidity and mortality data, the COVID-19 vaccines should be administered to those at the highest risk of severe infection until the safety and efficacy of vaccines are thoroughly validated 109 . Therefore, in consultation with their obstetricians, pregnant women will need to consider the benefits and risks of COVID-19 vaccines. The US CDC, the American College of Obstetricians and Gynaecologists and the Society for Maternal-Foetal Medicine each issued guidance supporting vaccination in pregnant individuals 110 .
Another critical issue concerns COVID-19 vaccination in children. Children of any age are susceptible to SARS-CoV-2 infection, including severe disease manifestations. Previously healthy children are also at risk of severe COVID-19 and multisystem inflammatory syndrome in children (MIS-C) 68 . Children might differ from adults in terms of the safety, reactogenicity and immunogenicity of vaccines 68 . Paediatric clinical trials can offer direct and indirect benefits from COVID-19 vaccination 111 .
Updates on COVID-19 and vaccines
On November 26, 2021, the WHO designated B.1.1.529 (Omicron) as a new VoC, although its pathogenicity as well as its potential to evade immune response from vaccines and natural immunity is relatively unknown 112 . Since other variants could emerge in the future, coordinated global responses that address vaccines and lockdown measures against SARS-CoV-2, surveillance systems that monitor viral mutations and the effectiveness of vaccines, as well as overcoming vaccine and economic inequalities, are needed.
A third dose of the Pfizer-BioNTech vaccine is effective in protecting individuals against severe COVID-19-related outcomes, compared with receiving only two doses at least five months prior 113 . A booster of Moderna or Pfizer-BioNTech may produce antibodies against SARS-CoV-2 in organ transplant patients with an immunodepression state 114 , 115 . On August 13, 2021, the US FDA authorized a third dose of the Pfizer-BioNTech or Moderna vaccines for immunocompromised people, who are particularly at risk for severe disease 116 , and the EMA concluded that an extra dose of these COVID-19 vaccines may be given to these patients at least 28 days after their second dose 117 .
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