Causality assessment of adverse events reported to the Vaccine Adverse Event Reporting System (VAERS)

Adverse events following immunization (AEFI) reported to the national Vaccine Adverse Event Reporting System (VAERS) represent true causally related events, as well as events that are temporally, but not necessarily causally related to vaccine.     

Reactogenicity within 2 weeks after mRNA COVID-19 vaccines: Findings from the CDC v-safe surveillance system

BackgroundPost-authorization monitoring of mRNA-based COVID-19 vaccines is needed to better characterize their reactogenicity. We assessed reactions reported during the 2 weeks after receipt of BNT162b2 (Pfizer–BioNTech) and mRNA-1273 (Moderna) vaccines.MethodsWe monitored persons who enrolled in v-safe after vaccination health checker^SM, a U.S. smartphone-based vaccine monitoring system, after receiving BNT162b2 or mRNA-1273. V-safe participants received text message prompts to complete web-based surveys. We analyzed responses from persons who received BNT162b2 or mRNA-1273 from December 14, 2020 through March 14, 2021 and completed at least one survey by March 28, 2021. We measured the proportion of participants reporting local and systemic reactions solicited in surveys completed days 0 through 7 post-vaccination. For day 14 surveys, participants described new or worsening symptoms in a free-text response. We assessed the proportion of participants reporting new or worsening local and systemic reactions.ResultsOne-third of participants were aged <45 years, two-thirds were female, and approximately half received BNT162b2 vaccine. A total of 4,717,908 participants reported during the 7 days after dose 1 and 2,906,377 reported during the 7 days after dose 2. Most reported at least one injection-site reaction (68.5% after dose 1; 72.9% after dose 2) or at least one systemic reaction (50.6% after dose 1; 69.5% after dose 2). Reactogenicity was greater after dose 2 and among mRNA-1273 recipients, persons aged <45 years, and females. New or worsening local and systemic reactions were uncommon during week 2 after either dose; the most frequent were local reactions for dose 1 mRNA-1273 recipients (2.6%). These reactions were reported more often among females after dose 1 mRNA-1273 (3.6%).ConclusionsDuring post-authorization monitoring among >4 million vaccinees, local and systemic reactions were commonly reported following mRNA-based vaccines. Reactions were most common during the first week following dose 2 and among persons aged <45 years, females, and mRNA-1273 recipients.     

Safety monitoring in the Vaccine Adverse Event Reporting System (VAERS)

The Centers for Disease Control and Prevention (CDC) and the U.S. Food and Drug Administration (FDA) conduct post-licensure vaccine safety monitoring using the Vaccine Adverse Event Reporting System (VAERS), a spontaneous (or passive) reporting system. This means that after a vaccine is approved, CDC and FDA continue to monitor safety while it is distributed in the marketplace for use by collecting and analyzing spontaneous reports of adverse events that occur in persons following vaccination. Various methods and statistical techniques are used to analyze VAERS data, which CDC and FDA use to guide further safety evaluations and inform decisions around vaccine recommendations and regulatory action. VAERS data must be interpreted with caution due to the inherent limitations of passive surveillance. VAERS is primarily a safety signal detection and hypothesis generating system. Generally, VAERS data cannot be used to determine if a vaccine caused an adverse event. VAERS data interpreted alone or out of context can lead to erroneous conclusions about cause and effect as well as the risk of adverse events occurring following vaccination. CDC makes VAERS data available to the public and readily accessible online.We describe fundamental vaccine safety concepts, provide an overview of VAERS for healthcare professionals who provide vaccinations and might want to report or better understand a vaccine adverse event, and explain how CDC and FDA analyze VAERS data. We also describe strengths and limitations, and address common misconceptions about VAERS. Information in this review will be helpful for healthcare professionals counseling patients, parents, and others on vaccine safety and benefit-risk balance of vaccination.     

Data mining in the US Vaccine Adverse Event Reporting System (VAERS): early detection of intussusception and other events after rotavirus vaccination

The Vaccine Adverse Event Reporting System (VAERS) is the US passive surveillance system monitoring vaccine safety. A major limitation of VAERS is the lack of denominator data (number of doses of administered vaccine), an element necessary for calculating reporting rates. Empirical Bayesian data mining, a data analysis method, utilizes the number of events reported for each vaccine and statistically screens the database for higher than expected vaccine-event combinations signaling a potential vaccine-associated event. This is the first study of data mining in VAERS designed to test the utility of this method to detect retrospectively a known side effect of vaccination–intussusception following rotavirus (RV) vaccine. From October 1998 to December 1999, 112 cases of intussusception were reported. The data mining method was able to detect a signal for RV-intussusception in February 1999 when only four cases were reported. These results demonstrate the utility of data mining to detect significant vaccine-associated events at early date. Data mining appears to be an efficient and effective computer-based program that may enhance early detection of adverse events in passive surveillance systems.     

Adverse events after anthrax vaccination reported to the Vaccine Adverse Event Reporting System (VAERS), 1990-2007

During the period March 1, 1998 to January 14, 2007, approximately 6 million doses of Anthrax vaccine adsorbed (AVA) vaccine were administered. As of January 16, 2007, 4753 reports of adverse events following receipt of AVA vaccination had been submitted to the Vaccine Adverse Event Reporting System (VAERS). Taken together, reports to VAERS did not definitively link any serious unexpected risk to this vaccine, and review of death and serious reports did not show a distinctive pattern indicative of a causal relationship to AVA vaccination. Continued monitoring of VAERS and analysis of potential associations between AVA vaccination and rare, serious events is warranted.     

Adverse events following quadrivalent meningococcal CRM-conjugate vaccine (Menveo®) reported to the Vaccine Adverse Event Reporting system (VAERS), 2010–2015

BackgroundLimited data are available describing the post-licensure safety of meningococcal vaccines, including Menveo®. We reviewed reports of adverse events (AEs) to the Vaccine Adverse Event Reporting System (VAERS) to assess safety in all age groups.MethodsVAERS is a national spontaneous vaccine safety surveillance system co-administered by the Centers for Disease Control and Prevention and the US Food and Drug Administration. We searched the VAERS database for US reports of adverse events in persons who received Menveo from 1 January 2010 through 31 December 2015. We clinically reviewed reports and available medical records for serious AEs, selected pre-specified outcomes, and vaccination during pregnancy. We used empirical Bayesian data mining to identify AEs that were disproportionately reported after receipt of Menveo.ResultsDuring the study period, VAERS received 2614 US reports after receipt of Menveo. Of these, 67 were classified as serious, including 1 report of death. Adolescents (aged 11–18 years) accounted for 74% of reports. Most of the reported AEs were non-serious and described AEs consistent with data from pre-licensure studies. Anaphylaxis and syncope were the two most common events in the serious reports. We did not identify any new safety concerns after review of AEs that exceeded the data mining threshold, although we did observe disproportionate reporting for terms that were not associated with an adverse event (e.g., “incorrect drug dosage form administered”, “wrong technique in drug usage process”). Although reports were limited, we did not find any evidence for concern regarding the use of Menveo during pregnancy.ConclusionsIn our review of VAERS reports, findings of AEs were consistent with the data from pre-licensure studies. Vaccine providers should continue to emphasize and adhere to proper administration of the vaccine.     

Thrombocytopenia after vaccination: case reports to the US Vaccine Adverse Event Reporting System, 1990-2008

We reviewed thrombocytopenia (TP) reports to the US Vaccine Adverse Event Reporting System (VAERS). We examined TP patterns for differences in single versus multiple immunization reports, presence of a live viral vaccine, seriousness, age, and interval to symptom onset. We found 1510 reports of possible TP and after exclusions evaluated 1440 for possible causes. Most (1078; 75%) met the regulatory definition of a serious adverse event. TP was reported after inactivated and live viral vaccines. Platelet counts <10 × 10⁹/L were reported. Identified vaccines could be prioritized for hypothesis-testing studies.     

Elective termination of pregnancy after vaccination reported to the Vaccine Adverse Event Reporting System (VAERS): 1990-2006

Generally, live-virus vaccines are contraindicated for pregnant women because of the theoretical risk of transmission of the vaccine virus to the fetus. Advisory groups recommend avoiding pregnancy in the immediate period after administration of such contraindicated vaccines (CVs) and stress benefit-to-risk evaluation for live or inactivated vaccines regarding pregnancy. Given the limited available data and theoretical risks associated particularly with live-virus vaccines, inadvertent immunization with CVs may lead to elective termination of pregnancy (ETP), despite advisory group statements that "vaccination is not ordinarily an indication to terminate the pregnancy." The Vaccine Adverse Event Reporting System (VAERS), a national passive surveillance system managed by the Food and Drug Administration (FDA) and Centers for Disease Control and Prevention (CDC), accepts reports of adverse events after vaccination. The objectives of this review were to describe reports of ETP in VAERS and characterize the circumstances of inadvertent administration of vaccines to pregnant women among ETP reports. We reviewed VAERS reports of ETP submitted from 1990 to 2006. Reports of ETP for reasons other than vaccination during or shortly before pregnancy, such as fetal abnormalities or deaths, were excluded. Of 80 ETP reports, 62 (78%) originated from the US; 79 (99%) were reported by manufacturers. Median age of vaccinees was 26 years (range: 13-43 years; 67 reports). Seventy-three vaccinees (91%) received a single vaccine; 65 (81%) received at least one live-virus vaccine. In 48 (60%) ETP reports, vaccinees were unaware of pregnancy at time of immunization. In 15 (19%) reports, vaccinees became pregnant within 3 months of vaccination; in 13 (16%) reports, vaccinees might have been pregnant before vaccination; in 4 (5%) reports, information was missing. All 80 reports of ETP involved vaccines for which possible effects on fetal development are unknown. However, no cases of vaccine-associated congenital rubella or varicella syndromes have been reported in the medical literature. Also, these syndromes have not been reported to varicella or rubella vaccine pregnancy registries. VAERS has the limitations of passive surveillance systems. Under-reporting of ETP in VAERS could be substantial. More attention may be needed to assess the likelihood of pregnancy when administering vaccines to women with child-bearing potential, and to inform women who learn they are pregnant shortly after being immunized of current information on risks. Quantifying the frequency of ETP related to CVs and the risk (if any) to the fetus of such vaccines can help to inform policy, practice, and individual decision making. Good quality information may be obtained from controlled observational studies.     

Safety of vaccines that have been kept outside of recommended temperatures: Reports to the Vaccine Adverse Event Reporting System (VAERS), 2008–2012

BackgroundVaccines should be stored and handled according to manufacturer specifications. Inadequate cold chain management can affect potency; but, limited data exist on adverse events (AE) following administration of vaccines kept outside of recommended temperatures.ObjectiveTo describe reports to the Vaccine Adverse Event Reporting System (VAERS) involving vaccines inappropriately stored outside of recommended temperatures and/or exposed to temperatures outside of manufacturer specifications for inappropriate amounts of time.MethodsWe searched the VAERS database (analytic period 2008–2012) for reports describing vaccines kept outside of recommended temperatures. We analyzed reports by vaccine type, length outside of recommended temperature and type of temperature excursion, AE following receipt of potentially compromised vaccine, and reasons for cold chain breakdown.ResultsWe identified 476 reports of vaccines kept outside of recommended temperatures; 77% described cluster incidents involving multiple patients. The most commonly reported vaccines were quadrivalent human papillomavirus (n = 146, 30%), 23-valent pneumococcal polysaccharide (n = 51, 11%), and measles, mumps, and rubella (n = 45, 9%). Length of time vaccines were kept outside of recommended temperatures ranged from 15 mins to 6 months (median 51 h). Most (n = 458, 96%) reports involved patients who were administered potentially compromised vaccines; AE were reported in 32 (7%), with local reactions (n = 21) most frequent. Two reports described multiple patients contracting diseases they were vaccinated against, indicating possible influenza vaccine failure. Lack of vigilance, inadequate training, and equipment failure were reasons cited for cold chain management breakdowns.ConclusionsOur 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 and parent 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.     

Severe combined immunodeficiency (SCID) and rotavirus vaccination: Reports to the Vaccine Adverse Events Reporting System (VAERS)

Background

Rotavirus vaccines are the only live vaccines recommended for infants in the US. Postmarketing reports have described severe gastroenteritis with vaccine viral shedding in infants who received rotavirus vaccine and were later diagnosed with SCID. The US Food and Drug Administration recently approved labeling changes for RotaTeq and Rotarix contraindicating administration to individuals with a history of SCID. We queried VAERS to characterize reports of SCID after rotavirus vaccination.

Methods

VAERS inclusion criteria included current US-licensed rotavirus vaccines, report dates from February 3, 2006 to January 15, 2010, and queries for the MedDRA preferred term “combined immunodeficiency” as well as any text containing the terms, “SCID” or “combined immunodeficiency.”

Results

We identified nine reports of SCID and rotavirus vaccination in infants between 3 and 9 months of age. All but one case presented with diarrhea among other symptoms. All infants were hospitalized and had workups leading to the SCID diagnosis. Stool rotavirus testing was positive in all cases and the virus was identified as the vaccine strain in six cases. Prolonged viral shedding was documented in five cases. No deaths were reported.

Conclusion

The aforementioned labeling changes were warranted given the risk posed by live rotavirus vaccine to individuals with SCID, as illustrated by these VAERS cases. Although congenital, SCID was not diagnosed in these infants until after rotavirus vaccination. Earlier identification of SCID (e.g., from expanded newborn screening or heightened clinical vigilance) could prevent inadvertent live rotavirus vaccine administration and also potentially result in earlier life-saving stem cell transplants.     

Thrombocytopenia after Ad.26.COV2.S COVID-19 vaccine: Reports to the vaccine adverse event reporting system

BackgroundOn February 27, 2021, the Food and Drug Administration (FDA) issued an Emergency Use Authorization for Ad.26.COV2.S COVID-19 vaccine. As part of post-authorization safety surveillance, the FDA has identified a potential safety concern for thrombocytopenia following receipt of Ad.26.COV2.S COVID-19 vaccine.MethodsReports of thrombocytopenia were identified in a passive reporting system (Vaccine Adverse Event Reporting System; VAERS) February-December 2021. Demographics, clinical characteristics, laboratory values, and relevant medical history were reviewed. The reporting rate was analyzed, including calculation of the observed-to-expected ratio based on vaccine administration data and the background rate of thrombocytopenia in the general (unvaccinated) population.ResultsAs of December 31, 2021, 100 reports of thrombocytopenia were identified in VAERS following vaccination with Ad.26.COV2.S. The median platelet count was 33,000 per µL (interquartile range 8,000–86,000). Fifteen reports (15%) documented a platelet count of 5,000 per µL or lower. The median time to onset of thrombocytopenia was 9 days (interquartile range 3–18.5), with most cases (69; 69%) beginning within 14 days after vaccination. A large majority of cases (84; 84%) were serious, including six deaths. With approximately 16,292,911 doses of Ad.26.COV2.S administered to adults in the US, the crude reporting rate was 0.61 cases of thrombocytopenia per 100,000 doses administered. The overall estimated observed-to-expected rate ratio was 2.43 (95% CI 1.97, 2.95).ConclusionsThese findings suggest an increased risk of thrombocytopenia following receipt of Ad.26.COV2.S.     

SIRVA (Shoulder Injury Related to Vaccine Administration) following mRNA COVID-19 Vaccination: Case discussion and literature review

Shoulder injury related to vaccine administration (SIRVA) is an increasingly recognised complication after vaccination and presents with significant shoulder pain and stiffness. SIRVA is thought to occur as a result of improper administration of vaccine into the subdeltoid bursa or shoulder joint. This results in an inflammatory cascade that damages the structures in the shoulder region. The incidence of SIRVA is relatively higher for influenza vaccination due its widespread administration. We present a reported case of SIRVA following a mRNA COVID-19 vaccination and review the current literature. As we embark on a worldwide scale of COVID-19 vaccination, it is of utmost important that we use proper vaccination techniques and screen patients at risk of SIRVA. This would improve the efficacy of the vaccine and improve the outcomes of the vaccination programme.     

Post-licensure safety monitoring of quadrivalent human papillomavirus vaccine in the Vaccine Adverse Event Reporting System (VAERS), 2009–2015

BackgroundThe Food and Drug Administration (FDA) approved quadrivalent human papillomavirus vaccine (4vHPV) for use in females and males aged 9–26 years, since 2006 and 2009 respectively. We characterized reports to the Vaccine Adverse Event Reporting System (VAERS), a US spontaneous reporting system, in females and males who received 4vHPV vaccination.MethodsWe searched VAERS for US reports of adverse events (AEs) following 4vHPV from January 2009 through December 2015. Signs and symptoms were coded using Medical Dictionary for Regulatory Activities (MedDRA). We calculated reporting rates and conducted empirical Bayesian data mining to identify disproportional reports. Clinicians reviewed available information, including medical records, and reports of selected pre-specified conditions.FindingsVAERS received 19,760 reports following 4vHPV; 60.2% in females, 17.2% in males, and in 22.6% sex was missing. Overall, 94.2% of reports were non-serious; dizziness, syncope and injection site reactions were commonly reported in both males and females. Headache, fatigue and nausea were commonly reported serious AEs. More than 60 million 4vHPV doses were distributed during the study period. Crude AE reporting rates were 327 reports per million 4vHPV doses distributed for all reports, and 19 per million for serious reports. Among 29 verified reports of death, there was no pattern of clustering of deaths by diagnosis, co-morbidities, age, or interval from vaccination to death.InterpretationNo new or unexpected safety concerns or reporting patterns of 4vHPV with clinically important AEs were detected. Safety profile of 4vHPV is consistent with data from pre-licensure trials and postmarketing safety data.     

Anaphylaxis rates associated with COVID-19 vaccines are comparable to those of other vaccines

We retrieved data on 8940 anaphylaxis cases post-COVID-19 vaccination from the US Vaccine Adverse Event Reporting System and the European EudraVigilance from week 52/2020 through week 31/2021 and compared them with those of other vaccines. Overall, 837,830,000 COVID-19 vaccine doses were delivered in the US and Europe during the study period, for which the vaccine name was known. The mean anaphylaxis rate was estimated at 10.67 cases per 10⁶ doses of COVID-19 vaccines (range: 7.99-19.39 cases per 10⁶ doses depending on the vaccine). COVID-19 vaccines ranked fifth in reported anaphylaxis rates, behind rabies, tick-borne encephalitis, measles-mumps-rubella-varicella, and human papillomavirus vaccines (70.77, 20, 19.8, and 13.65 cases per 10⁶ vaccine doses, respectively). COVID-19 vaccines are within the range of anaphylaxis rates reported across several common vaccines in these two passive reporting systems. These data should be communicated to reassure the general population about the safety profile of COVID-19 vaccines.     

Post-licensure safety surveillance of 23-valent pneumococcal polysaccharide vaccine in the Vaccine Adverse Event Reporting System (VAERS), 1990–2013

Background23-Valent pneumococcal polysaccharide vaccine, trade name Pneumovax^®23 (PPSV23), has been used for decades in the Unites States and has an extensive clinical record. However, limited post-licensure safety assessment has been conducted.ObjectiveTo analyze reports submitted to the Vaccine Adverse Event Reporting System (VAERS) following PPSV23 from 1990 to 2013 in order to characterize its safety profile.MethodsWe searched the VAERS database for US reports following PPSV23 for persons vaccinated from 1990 to 2013. We assessed safety through: automated analysis of VAERS data, crude adverse event (AE) reporting rates based on PPSV23 doses distributed in the US market, clinical review of death reports and reports involving vaccine administered to pregnant women, and empirical Bayesian data mining to assess for disproportional reporting.ResultsDuring the study period, VAERS received 25,168 PPSV23 reports; 92% were non-serious, 67% were in females and 86% were in adults aged ≥19 years. When PPSV23 was administered alone, fever (43%), injection site erythema (28%) and injection site pain (25%) were the most commonly reported non-serious AEs in children. Injection site erythema (32%), injection site pain (27%) and injection site swelling (23%) were the most commonly reported non-serious AEs in adults. Of serious reports (2129, 8% of total), fever was most commonly reported in both children (69%) and adults (39%). There were 66 reports of death, four in children and 62 in adults. Clinical review of death reports did not reveal any concerning patterns that would suggest a causal association with PPSV23. No disproportional reporting of unexpected AEs was observed in empirical Bayesian data mining.ConclusionsWe did not identify any new or unexpected safety concerns for PPSV23. The VAERS data are consistent with safety data from pre-licensure clinical trials and other post-licensure studies.     

The Role of Media and the Internet on Vaccine Adverse Event Reporting: A Case Study of Human Papillomavirus Vaccination

PurposeThis study aimed to determine the temporal association of print media coverage and Internet search activity with adverse events reports associated with the human papillomavirus vaccine Gardasil (HPV4) and the meningitis vaccine Menactra (MNQ) among United States adolescents.MethodsWe used moderated linear regression to test the relationships between print media reports in top circulating newspapers, Internet search activity, and reports to the Vaccine Adverse Event Reporting System (VAERS) for HPV4 and MNQ during the first 2.5 years after Food and Drug Administration approval.ResultsCompared with MNQ, HPV4 had more coverage in the print media and Internet search activity, which corresponded with the frequency of VAERS reports. In February 2007, we observed a spike in print media for HPV4. Although media coverage waned, Internet search activity remained stable and predicted the rise in HPV4-associated VAERS reports.ConclusionsWe demonstrate that media coverage and Internet search activity, in particular, may promote increased adverse event reporting. Public health officials who have long recognized the importance of proactive engagement with news media must now consider strategies for meaningful participation in Internet discussions.