Vaccine Safety

METHODS OF MONITORING IMMUNIZATION SAFETY

Because vaccines are given to healthy children and adults, a higher standard of safety is expected of immunizations compared with other medical interventions. Tolerance of adverse reactions to pharmaceutical products (e.g., vaccines, contraceptives) given to healthy people—especially infants and toddlers—is substantially lower than to therapeutic agents (e.g., antibiotics, insulin) used to treat illness. This translates into a need to investigate the possible causes of much rarer adverse events after vaccinations than may be acceptable for other pharmaceutical products. Safety monitoring is performed both before and after vaccine licensure, with slightly different goals based on the methodological strengths and weaknesses of each step.

PASSIVE REPORTING SYSTEMS, INCLUDING THE VACCINE ADVERSE EVENT REPORTING SYSTEM

Informal or formal passive surveillance or spontaneous reporting systems (SRSs) have been the cornerstone of most postlicensure safety monitoring systems because of their relative ease and low cost of operations. The national reporting of adverse events following immunizations can be done through the same reporting channels as those used for other adverse drug reactions (e.g., as in the United Kingdom ) or with reporting forms or surveillance systems different from the drug safety monitoring systems (e.g., as in the United States ). Vaccine manufacturers also maintain spontaneous reporting systems (SRSs) for their products and they forward reports to appropriate national regulatory authorities. ^,

Several countries, including the United States, have mechanisms for passive surveillance of immunization safety. In 1987, Canada developed the Vaccine Associated Adverse Event Reporting System. ^, Serious vaccine-associated adverse event reports are reviewed by the Advisory Committee on Causality Assessment consisting of a panel of experts. The Netherlands also convenes an annual panel to categorize reports, which are then published. The United Kingdom and most members of the former Commonwealth use the yellow card system, whereby a reporting form is attached to officially issued prescription pads. ^, Data on adverse drug events (including vaccines) from several countries are compiled by the World Health Organization (WHO) Collaborating Center for International Drug Monitoring in Uppsala, Sweden. The World Health Organization has promoted the development and implementation of SRSs for vaccine adverse events in its member countries. Currently, more than 100 countries have at least minimal capacity for reporting adverse events following immunization (AEFI). With so many different passive surveillance systems that collect information on various medical events following vaccination, standardized definitions of vaccine-related adverse events can improve comparability of findings. Implementation of similar standards across national boundaries has been advanced by the International Conference on Harmonization and the Brighton Collaboration.

In the United States, the National Childhood Vaccine Injury Act of 1986 mandated that healthcare providers report certain adverse events after immunizations. The Vaccine Adverse Events Reporting System (VAERS) was implemented jointly by the Centers for Disease Control and Prevention (CDC) and the US Food and Drug Administration (FDA) in 1990 to provide a unified national focus for a collection of all reports of clinically significant adverse events, including, but not limited to, those mandated for reporting. The VAERS form collects narrative descriptions of adverse events. Patients and their parents—not just healthcare professionals—are permitted to report to VAERS, and there is no restriction on the interval between vaccination and symptoms that can be reported. Report forms, assistance in completing the form, and answers to other questions about VAERS are available on the VAERS website ( vaers.hhs.gov ). Web-based reporting is the primary means for submitting reports to VAERS, but reports can also be submitted on paper forms or by telephone or FAX. Submitted reports are entered into a database. Reporters of selected serious events are contacted by trained clinical staff to obtain additional details, including medical records. Reporters are sent letters 1 year after report receipt to obtain additional information, including the patient’s recovery status. VAERS data (without personal identifiers) are also available to the public (at vaers.hhs.gov and at wonder.cdc.gov/vaers.html ).

Because VAERS is the only surveillance system covering the entire US population with data available on a relatively timely basis, it is the frontline system for detecting possible new, unusual, or extremely rare adverse events. For example, in 1999 passive reports to VAERS of intussusception among children vaccinated with RotaShield were the first postlicensure signal of a problem, leading to epidemiologic studies that verified the association. ^, Similarly, initial reports to VAERS of a previously unrecognized serious yellow fever vaccine-associated neurotropic disease and viscerotropic disease ^, have since been confirmed elsewhere. Individual VAERS reports are reviewed by medical personnel at FDA and CDC. In addition, automated screening for signals is conducted. using methods such as empirical Bayesian data mining to identify vaccine-event adverse event combinations that are reported more frequently following a specific vaccine than following all other vaccines combined.

Despite the aforementioned uses, SRSs for drug and vaccine safety have a number of major methodological weaknesses. Underreporting, biased reporting, and incomplete reporting are inherent to all such passive systems, and potential safety concerns might be missed. Some increases in adverse events detected by VAERS might not be true increases, but instead might be the result of increases in reporting efficiency, vaccine coverage, or media attention. ^,

Perhaps the most important methodological weakness of VAERS, however, is that it does not contain the information necessary for formal epidemiologic analyses. Such analyses require calculation of the rate of the adverse event after vaccination and a comparison rate among unvaccinated persons. The VAERS database provides data only for the number of persons who may have experienced an adverse event following immunization and, even then, only in a biased and underreported manner. VAERS lacks data on the denominator of total number of people vaccinated and the corresponding data on the number of cases and denominator population of unvaccinated people. Sometimes reporting rates can be calculated by using VAERS case reports for the numerator and, if available, doses of vaccines administered (or, if unavailable, data on vaccine doses distributed or vaccine coverage survey data) for the denominator. These rates can then be compared with the background rate of the same adverse event in the absence of vaccination, if available. Because of under-reporting, however, VAERS reporting rates will usually be lower than the actual rates of adverse events following immunization.

A higher proportion of serious events, such as seizures, that follow vaccinations are likely to be reported to VAERS than milder events, such as rash, or delayed events requiring laboratory assessment, such as thrombocytopenic purpura after measles-mumps-rubella (MMR) vaccination. ^, Formal evaluation has been limited by the quality of diagnostic information on VAERS reports, especially when determining whether a serious event reported to VAERS has been diagnosed accurately. ^, The problems with reporting efficiency and potentially biased reporting and the inherent lack of an adequate control group limit the certainty with which conclusions can be drawn from SRSs. Public availability of VAERS data can raise concerns about vaccines that are unfounded. Recognition of these limitations in large part has helped stimulate the creation of more population-based methods of assessing vaccine safety.

MONITORING SAFETY IN A MASS IMMUNIZATION CAMPAIGN: COVID-19 VACCINES

In mass-immunization campaigns during which many people are vaccinated in a short time period, sometimes with newly developed vaccines, it is critical to have a vaccine safety monitoring system in place that can detect potential safety problems early so that investigations can be initiated and corrective actions, when necessary, can be taken as soon as possible. Mass-immunization campaigns are often conducted in developing countries, which poses a particular challenge of ensuring injection safety. In any setting in which large numbers of immunizations are being administered, more adverse events will coincidentally occur following immunization. Thus it is important to have background rates available of expected outcomes of interest for safety monitoring to allow rapid evaluation of whether reported adverse events are occurring at a rate following immunization that is higher than would be expected by chance alone.

On December 31, 2019, the emergence of a severe coronavirus infection not previously seen in humans was reported in Wuhan, China. Coronavirus disease 2019 (COVID-19) is caused by the new virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In response to a rapidly increasing number of reported cases outside of China, on March 11, 2020, the World Health Organization declared the novel coronavirus outbreak a global pandemic, and the United States declared a national emergency in March 2020 to respond to the emerging COVID-19 pandemic.

Rapid development of vaccines was a critical strategy to control the pandemic. Worldwide, more than 130 vaccine candidates entered various stages of development, including whole virus, viral vector, nucleic acid, and protein-based vaccines. Vaccines were developed and tested at unprecedented speed and some (e.g., messenger RNA vaccines) were based on platforms that had not previously been used to produce human vaccines. Given that hundreds of millions of people were to be vaccinated with these novel vaccines, comprehensive postlicensure safety monitoring was critical. Achieving high levels of vaccination against COVID-19 disease with highly effective vaccines was essential to controlling the COVID-19 pandemic and saving lives. Hesitancy to be vaccinated, however, often related to uncertainties about the safety of the vaccines, arose as an impediment to achieving high vaccination level goals. The existence of a system to closely monitor vaccine safety and quickly identify potential vaccine safety problems is critical to fostering public confidence in the safety of vaccines and promote vaccine acceptance.

The US has a robust, multipronged vaccine safety monitoring system that has been built up over years. The main components of the system have included VAERS, as the frontline national early warning system to detect possible vaccine safety problems, and large healthcare databases, such as VSD and Medicare (Sandhu 2017), that allow timely monitoring and rigorous epidemiologic evaluation of adverse events following immunization. The established vaccine safety surveillance system is best suited for monitoring vaccines that are administered routinely in traditional medical care settings. COVID-19 vaccinations were initially administered in a public health emergency situation often outside traditional medical care facilities, including at mass vaccination sites, pharmacies, and long-term care facilities (LTCF). As a result, enhancements were made to VAERS, and a new system, the v-safe after vaccination health checker , was developed. V-safe is a voluntary smartphone-based COVID-19 vaccine safety surveillance system that enables prospective follow-up of health status and adverse events in vaccinated individuals. V-safe is able to capture real-time information on AEFI and health impact events and provide initial assessments of AEFI patterns and rates, especially of common adverse events (e.g., local and systemic reactions). It also assesses the health impact of AEFI, such as the ability to work or attend school, perform normal daily activities, and whether care from a doctor or other healthcare professional was received. Additionally, v-safe includes questions to identify women who received a COVID-19 vaccination while pregnant or who became pregnant shortly after a COVID-19 vaccination. Women self-identifying as pregnant are then contacted, and if they meet inclusion criteria, are offered enrollment in a pregnancy registry. Monitoring of COVID-19 vaccine safety was further enhanced by including the large medical care database systems of the Veteran’s Administration and FDA’s system of private health insurance claims databases. International collaborations and the contributions of academic researchers and clinical investigators also played an important role in global safety monitoring of the different COVID-19 vaccines, as well as in developing clinical guidance for identified adverse reactions. Regulatory authorities and policy bodies, including CDC’s Advisory Committee on Immunization Practices, the FDA’s Vaccines and Related Biological Products Advisory Committee, and the European Medicines Agency, regularly and closely reviewed the evolving safety data to make any necessary policy or regulatory actions.

In the initial phase of COVID-19 vaccinations, VAERS and v-safe provided timely early data that indicated that the safety profiles of the two first authorized mRNA COVID-19 vaccines were consistent with the safety data generated in the large preauthorization trials. Deaths following vaccination were reported but causes of death were consistent with background all-cause mortality and did not suggest a concerning pattern. Preliminary VAERS and v-safe data found no indications of safety problems with vaccination during pregnancy. ^,

Within a few months of initiation of vaccinations, hundreds of millions of doses of COVID-19 vaccines were administered and a few rare, but potentially serious, adverse events were identified. Rare cases of anaphylaxis, which can occur following any vaccine, were observed ^, and prompted recommendations about management and observation following vaccination.

Probably the most concerning adverse reaction that was identified following COVID-19 vaccination is thrombosis with thrombocytopenia syndrome (TTS). Rare cases of thrombotic events with thrombocytopenia were first reported by investigators in Europe following receipt of the AstraZeneca COVID-19 vaccine. ^, The AstraZeneca vaccine was not used in the United States, but it had similarities to the J&J vaccine that was used in the United States. Both vaccines contain replication-incompetent adenoviral vectors (human [Ad26.COV2.S] for J&J and chimpanzee [ChAdOx1] for AstraZeneca) that encode the spike glycoprotein of SARS-CoV-2, the virus that causes COVID-19. Enhanced monitoring was rapidly initiated in VAERS for possible reports of TTS and six patients (after 6.85 million J&J vaccine doses were administered) were identified in the latter part of March and early April of 2021. The median symptoms onset was 9 days (range = 6–13 days) after vaccination and presenting symptoms were notable for headache, back pain, and focal neurological symptoms. The median days from vaccination to hospital admission was 15 days (range = 10–17 days). Unusual for patients presenting with thrombotic events, all six patients showed evidence of thrombocytopenia (<150,000 platelets per microliter of blood). Four patients developed intraparenchymal brain hemorrhage and one subsequently died. The CDC’s Clinical Immunization Safety Assessment (CISA) project, which includes experts in infectious disease and hematology, reviewed these and additional cases. The pathogenesis of these rare and unusual adverse events is not completely understood but they may be associated with platelet-activating antibodies against platelet factor 4 (PF4). Anti-PF4, also known as heparin-PF4 antibody, can induce thrombotic thrombocytopenia in a small percentage of persons exposed to heparin. However, none of the cases reported from Europe had recent heparin exposure. As with heparin-induced thrombocytopenia, the administration of the anticoagulant heparin should be avoided in patients with potential vaccine-associated TTS, unless heparin-induced thrombocytopenia (HIT) testing is negative. Nonheparin anticoagulants and high-dose intravenous immune globulin should be considered in treatment of patients who present with immune-mediated thrombotic events with thrombocytopenia after J&J or AstraZeneca COVID-19 vaccination. Consultation with hematology specialists is strongly recommended. No increased risk of TTS has been identified following the two mRNA-based COVID-19 vaccines.

Not long after the identification of TTS following the two viral vector vaccines, myocarditis emerged as a safety concern associated with the two mRNA vaccines. The first alerts of a possible increased risk of myocarditis in the United States came from case reports from astute clinicians. ^, The reported cases predominantly occurred in young males after the second dose. A review of reports to VAERS subsequently also found increased reports of myocarditis (including myopericarditis) following vaccination with mRNA COVID-19 vaccines. As of early June 2021, approximately 296 million doses of mRNA COVID-19 vaccines had been administered in the United States, and VAERS had received 1226 reports of myocarditis after mRNA vaccination. The median age of reported cases was 26 years (range = 12–94 years), with a median symptom onset interval of 3 days after vaccination (range = 0–179). Among reports with known vaccine dose numbers, 76% occurred after receipt of dose 2 of mRNA vaccine. Cases were reported after both Pfizer-BioNTech and Moderna vaccines. Using myocarditis cases reported to VAERS with onset within 7 days after dose 2 of an mRNA vaccine, crude reporting rates were estimated to be 40.6 cases per million-second doses of mRNA COVID-19 vaccines administered to males aged 12–29 years and 2.4 per million-second doses administered to males aged ≥30 years; reporting rates among females in these age groups were 4.2 and 1.0 per million-second doses, respectively. Among the cases reported to VAERS, preliminary treatment and outcomes data indicated that the acute clinical courses of case patients were generally mild; many patients experienced resolution of symptoms with conservative treatment, such as nonsteroidal anti-inflammatory drugs. Follow-up studies, however, had not yet been completed to evaluate longer-term outcomes of myocarditis occurring after COVID-19 vaccination. For patients with myocarditis, the American Heart Association and American College of Cardiology recommend exercise restriction until the heart recovers. Surveillance data from sources outside of the United States also suggested an increased risk of myocarditis following mRNA vaccination; the epidemiologic patterns and clinical characteristics appeared consistent across multiple countries. ^,

As of this writing, evidence was emerging of a possible increased risk of Guillain-Barré Syndrome (GBS) associated with the two viral vector vaccines, J&J/Janssen COVID-19 vaccine, and AZ COVID-19 vaccine. On July 13, 2021, FDA revised the vaccine recipient and vaccination provider fact sheets for the J&J/Janssen COVID-19 vaccine to include information on an apparent increased risk of Guillain-Barré Syndrome (GBS) following vaccination based on an analysis of reports to VAERS. At that time, VAERS had received 100 preliminary reports of GBS following vaccination with the Janssen vaccine after approximately 12.5 million doses were administered. The European Medicines Agency (EMA) also issued a statement that GBS would be listed as a very rare side effect of the J&J COVID-19 vaccine. In addition, EMA also recommended adding a warning about GBS following the AZ COVID-19 vaccine manufactured in Europe. This was based on spontaneous reporting to the European pharmacovigilance system of a total of 227 cases of GBS during a time when about 51.4 million doses of AZ vaccine had been given to people in the European Union and European Economic Area. The data on GBS following viral vector vaccines was based on reports to spontaneous reporting systems and was insufficient to establish a causal relationship pending availability of more definitive epidemiologic data. No signal of a possible increased risk of GBS was identified with the Moderna and Pfizer-BioNTech mRNA COVID-19 vaccines.

Millions of people in the United States, as well as worldwide, received COVID-19 vaccines under the most intense safety monitoring in US history. Overall, the postauthorization safety profiles for COVID-19 vaccines in the early months of the vaccines’ authorization in the United States were largely consistent with data from preauthorization clinical trials. A few safety signals of rare adverse events were identified, including anaphylaxis, TTS, myocarditis, and GBS. ACIP determined that, overall, the benefits of COVID-19 vaccination in preventing COVID-19 morbidity and mortality outweighed the risks for these rare serious adverse events.

WEIGHING THE EVIDENCE AND ASSESSING CAUSALITY

A central function of vaccine safety monitoring and assessment activities is to determine if specific adverse events following immunization are caused by a vaccine. This determination is important in guiding immunization policy, individual care, and potentially compensation decisions. Causality assessment may be performed at the individual or population level. Epidemiologic studies provide measures of risk on a population level, but they do not provide evidence that a particular vaccine caused an adverse event in a particular individual. It is often not possible to infer causality in individual cases of adverse events following immunization, except in certain special situations. Circumstances in which a causal association in individual cases can reasonably be inferred include: (1) local reactions at a vaccine injection site; (2) immediate hypersensitivity reactions (in absence of other exposures); (3) recurrence of the same adverse event in the same individual following repeat exposure to the same vaccine; (4) isolation of vaccine virus (from typically sterile site), as, for example, Urabe mumps vaccine and aseptic meningitis; and (5) a unique clinical syndrome, such as vaccine-associated paralytic polio.

More general causality assessments rely on weighing different pieces of evidence using criteria such as strength of association, consistency of findings, temporal relationships, potential biases, and possible biological mechanisms. In the United States, the most authoritative assessments of causality have been conducted by the Institute of Medicine (IOM) (now renamed the National Academy of Medicine), whose findings have been particularly influential in compiling the vaccine injury table of the National Vaccine Injury Compensation Program. The IOM has conducted three comprehensive reviews of adverse effects of vaccines, as well as several focused reviews of specific vaccine safety topics. As highlighted in Table 83.3 , the adverse reactions for which there is strong evidence of a causal association with recommended childhood vaccines in the United States are few and tend to occur rarely. Newer vaccines and certain other vaccines, however, were not covered in the latest IOM review in 2012. This gap was addressed by two systematic reviews of the literature commissioned by the Agency for Healthcare Research and Quality. ^, Those reviews identified a few additional adverse events where the evidence favors a causal association, including pneumococcal conjugate vaccine and febrile seizure, and hepatitis A vaccine and idiopathic thrombocytopenic purpura.

In addition to identifying causal associations, IOM reviews have also been influential in clarifying particularly controversial issues where the evidence does not favor a causal association. These include pertussis vaccines and SIDS, vaccines and autism, hepatitis B vaccine and multiple sclerosis, and vaccines and type 1 diabetes.

SELECTED TOPICS IN VACCINE SAFETY

Unfortunately, vaccine safety issues have increasingly taken on a life of their own outside of the scientific arena. In particular, for various chronic diseases and certain poorly understood conditions, immunizations—as a relatively universal exposure—have made all too convenient a hypothesized link. Case studies of some of these controversies and other topics of current interest ^, are discussed in the following sections.