COVID-19 Vaccine Safety First Year Findings in Adolescents

We analyzed data reported to v-safe and VAERS before May 23, 2022 for US adolescents ages 12 to 17 years who received a primary series BNT-162b2 vaccine dose during December 14, 2020 through May 10, 2022. We did not include v-safe and VAERS reports for adolescents ages 12 to 15 years if their recorded vaccination occurred before the EUA expansion on May 10, 2021, when the vaccine was authorized for this age group. The Centers for Disease Control and Prevention (CDC) established v-safe (https://vsafe.cdc.gov) to monitor reactogenicity and health impacts after COVID-19 vaccination. We described daily health surveys completed by v-safe participants in the week after vaccination as previously described (Supplemental Information).⁸  CDC’s v-safe call center contacts vaccine recipients or a parent or guardian when a health survey indicates a vaccine recipient received medical care after vaccination and encourages completion of a VAERS report if indicated. VAERS is a US passive surveillance system comanaged by the CDC and FDA that accepts reports of adverse events after vaccination from any source, including healthcare providers, vaccine manufacturers, and members of the public.⁹  The COVID-19 vaccine EUAs and CDC Provider Agreements for the COVID-19 Vaccination Program outline mandatory reporting elements.¹⁰  Symptoms, signs, and diagnostic findings in the VAERS reports are assigned Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (PTs) by trained staff.¹¹  More than 1 MedDRA PT may be assigned to a report; these terms include symptoms and diagnostic evaluations and do not necessarily correspond to medical diagnoses. VAERS reports are further classified as serious if hospitalization, prolongation of hospitalization, life-threatening illness, permanent disability, congenital anomaly or birth defect, or death are noted by the reporter.¹²  VAERS staff follow-up on serious reports and reports of selected adverse events to request additional information, including medical records, death certificates, and autopsy reports are obtained death, if available. We identified, reviewed, and adjudicated reports to VAERS of potential MIS-C and myocarditis after receipt of BNT-162b2 by using methods similar to those previously described (Supplemental Information).^6,13,14  Other VAERS reports were not clinically reviewed. We calculated crude reporting rates for prespecified adverse events of special interest (AESI) using doses administered through May 10, 2022 as the denominator (Supplemental Information).⁷ 

These surveillance activities were reviewed by CDC and conducted consistent with applicable federal law and CDC policy (45 C.F.R. part 46.102(l)(2), 21 C.F.R. part 56; 42 U.S.C. §241(d); 5 U.S.C. §552a; 44 U.S.C. §3501 et seq.).

In the first year of use under EUA, 15 493 807 adolescents ages 12 to 17 years received at least 1 primary-dose BNT-162b2 vaccine; 172 032 (1.1%) enrolled in v-safe, completing a total of 1 199 763 day 0 to 7 surveys. The median age of participants was 16 years, 54.6% were girls, 62.7% were white, and 73.4% were non-Hispanic or Latino ethnicity (Table 1). Surveys for adolescents ages 12 to 15 were completed by guardians; for those ages 16 to 17, over 97% were completed by the vaccinee. When queried, most registrants reported BNT-162b2 was administered alone, without other concurrent vaccinations (97.0% and 99.0% for dose 1 and 2, respectively). Influenza was the most common vaccine reported to be administered concurrently with BNT-162b2 (Table 2). Approximately one-third (35.7%) of total surveys were completed during May 2021, when the EUA was expanded to include 12 to 15-year-olds.

Participants commonly reported local injection site reactions after both doses, with most respondents reporting reactions on the day after vaccination (Table 3). During the first week, these reports of vaccine reactions decreased each subsequent day. Injection site pain was the most reported local reaction after both doses. Systemic reactions were more frequently reported after dose 2 than dose 1 (52.5% of respondents after dose 1 vs 65.8% after dose 2; P < .0001). Most systemic reactions were reported on the day after vaccination; reporting of systemic reactions decreased over time since vaccination. Fatigue, headache, and myalgia were the most common systemic reactions after each dose. Approximately 4% of respondents reported that they were unable to work or attend school in the week after receiving dose 2, compared with 1.3% who missed work or school because of symptoms after dose 1 (P < .0001). Fewer than 1% of respondents received medical care for symptoms reported in the week following vaccination, regardless of dose received.

Respondents rated the severity of their local and systemic reactions following each vaccine dose based on how the reactions impacted their ability to complete activities of daily living (Table 4). Although the total proportion of respondents reporting local injection site pain was similar after each dose (∼61% after dose 1 or dose 2), the proportion of participants who reported their pain as moderate or severe was higher after dose 2 compared with dose 1 (28.5% vs 21.2%; P < .0001). Similarly, systemic reactions such as fatigue (47.3% vs 30.7%; P < .0001), headache (46.1% vs 27.5%; P < .0001), myalgia (35.0% vs 23.2%; P < .0001), and fever (22.2% vs 7.5%; P < .0001) were more commonly reported generally and more commonly reported as more severe after dose 2 compared with dose 1.

During December 14, 2020 through May 10, 2022, 32 268 525 primary series BNT-162b2 vaccine doses were administered to adolescents ages 12 to 17 years. In that period, VAERS received and processed 20 240 reports of adverse events among adolescents; the median age was 15 years and over half (51.9%) of the reports were for adolescent girls (Table 5). The month with the most reports filed was June 2021 (3690). Most reports indicated BNT-162b2 was administered alone (20 038; 99%); seasonal inactivated influenza vaccine was the most frequently simultaneously administered vaccine (74; 36.6% of reported coadministered vaccines), followed by other routine adolescent vaccinations, including quadrivalent meningococcal, 9-valent HPV, and Tdap (Table 6).

Most VAERS reports were classified as nonserious (18 514; 91.5%) (Table 7). Dizziness (3063; 15.1%) was the most commonly reported adverse event. Systemic reactions known to be associated with the vaccine (headache [2104; 10.4%], pyrexia (fever) [1967; 9.7%], nausea [1912; 9.5%], fatigue [1580; 7.8%], and pain [1163; 5.8%]) were also frequently reported. There were 6089 (30.1%) reports of vaccination errors, including product storage errors (1885; 9.3%), underdoses (934; 4.6%), and product administered to a patient of an inappropriate age (865; 4.3%). Among reports listing a vaccination error, 321 of 6089 (5.3%) also reported an adverse health event; 27 (8.4%) were classified as serious. VAERS received 56 reports of anaphylaxis occurring on the day of or day after vaccination; 63 anaphylaxis cases were reported in the week after vaccination (Table 8). These cases were not reviewed or adjudicated; however, if all 63 reports met the Brighton Collaboration case definition,¹⁵  the reporting rate would be 1.95 cases per million vaccine doses administered. There were 501 reports of seizures occurring in the first week following vaccination among adolescents aged 12 to 17 years. Sixty-nine of these reports were classified as serious, and pre-existing seizures were noted in 31 of 69 (44.9%).

From December 14, 2020, through May 10, 2022, 84 potential cases of MIS-C were reported to VAERS among 12 to 17-years-olds within 90 days after receipt of a BNT-162b2 dose (Fig 1) (Supplemental Information). Forty (47.6%) met the 2020 CDC MIS-C case definition; of these, 34 (85.0%) had evidence of past or recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, 4 (10.0%) did not have evidence of past or recent SARS-CoV-2 infection, and infection status could not be determined for 2 (5.0%). Thirty-nine of the 40 were discharged from the hospital; 1 case with evidence of past or recent SARS-CoV-2 infection was transferred to a rehabilitation facility.

During the surveillance period, 681 VAERS reports met the search for myocarditis; in 642 we obtained sufficient information from healthcare provider interviews or medical record reviews to apply the CDC case definition. Seventy-two were misclassified or did not meet the case definition for myocarditis; 570 cases were confirmed (17.7 cases per million second doses administered). Most cases (514 of 570; 90.2%) occurred in boys. When stratified by age, sex, and vaccine dose received, adolescent boys ages 16 to 17 years after dose 2 had the highest reporting rate (84.0 cases per million second doses administered) (Table 9). At the time of reporting, 77.0% indicated that they had fully recovered from symptoms of myocarditis. CDC has requested additional follow-up information for cases who reported any continuing symptoms.

We reviewed all available information for the 36 deaths reported to VAERS after vaccination; medical records, death certificates, or autopsy reports were available for 34. Causes of death included complications of malignancy or neoplasm (5); cardiomyopathy associated with genetic, ischemic, or non-COVID-19 infections (5); intracranial bleeding from a ruptured aneurysm or thrombus (without documented thrombocytopenia) (4); pulmonary emboli (4: 1 with chronic lung disease, 1 with bilateral air emboli, 2 with concomitant oral contraceptive use); COVID-19 disease (3); muscular dystrophy (2); myocarditis with an identified infectious agent (2: 1 parvovirus-B19 and 1 SARS-CoV-2); suicide (2); acute hyperglycemic crisis (1); epilepsy (1); metabolic syndrome (1); neuromuscular disorder (1); respiratory illness in a tracheotomy-dependent patient (1); and Clostridium sepsis (1). There was insufficient information to determine a presumptive cause of death for 4 reports. One-third (12 of 36) of the decedents had documentation of complex medical histories, with multiple diagnoses predating COVID-19 vaccination. We observed no apparent pattern or clustering of causes of death. We found no evidence to suggest that vaccination contributed to any reported death.

Using data from 2 complementary surveillance systems, v-safe and VAERS, we review safety surveillance during the first year of BNT-162b2 vaccination among US adolescents ages 12 to 17 years. In that year, over 32 million doses were administered for primary series vaccination and over 15 million adolescents were fully vaccinated.⁷  Overall, our findings are consistent with earlier reports of adverse events reported by vaccinated US residents in this age group.^4,6,13 

The expansion of the BNT-162b2 EUA to include people ages 12 to 15 years coincided with greater US vaccine availability; the greatest number of vaccinations in this age group occurred during May 2021.⁷  Safety data corresponded with vaccination administration, as v-safe received the most survey responses during May 2021 and VAERS received the most reports during June.

As expected from clinical trial³  and early safety data,⁴  adolescents experienced both local and systemic reactions following vaccination, with more substantial reactions after dose 2 than dose 1. Most adolescents reported reactions to v-safe on the day following vaccination; reporting steadily decreased during the first week after vaccination, which is consistent with previous reports to v-safe for all age groups.¹⁶  Inability to attend work or school in the week following dose 2 (4.1%) was lower than reports among adults (12.3%)¹⁶  or children ages 5 to 11 years (10.9%)⁸  and lower than previously described.⁴  These differences may be related to changes in policies regarding school attendance, the widespread return to in-person school for the 2021 to 2022 school year, or the effects of circulating virus variants. Reports of receipt of healthcare after vaccination have been low among all age groups.^4,8,16 

VAERS accepts all reports of adverse events occurring after vaccination, regardless of biological or clinical plausibility that a reported outcome could be associated with vaccination. Therefore, VAERS reports alone are not used to establish a causal association with vaccination.¹²  VAERS received reports of 37 deaths after BNT-162b2 vaccination; among 34 reports that included medical or autopsy data, we found no evidence to suggest an association between vaccination and death. During the surveillance period, which included periods of SARS-CoV-2 Δ and ο circulation, we identified 40 reports of MIS-C (1.2 cases per million vaccine doses administered). This rate is similar to the rate reported previously among persons ages 12 to 20 years who received at least 1 BNT-162b2 vaccination through August 31, 2021 (1.0 cases per million people who received at least 1 dose).¹³  For reports of MIS-C occurring after vaccination, most cases (34 of 38 with complete information) had evidence of prior SARS-CoV-2 infection. Some MIS-C cases in this report were described in the previous report¹³  and are included here to present a fuller assessment of MIS-C in this age group during the analytic period. The potential contribution of vaccination, if any, to these illnesses is unknown.¹³  Available data do not suggest an association between BNT-162b2 vaccination and death, and demonstrate that vaccination is the most effective way to prevent MIS-C.¹⁷ 

Myocarditis is a rare adverse event known to be associated with messenger RNA (mRNA) COVID-19 vaccination; risk is greater among male vaccinees and after dose 2.^4,6,18–24  Vaccination at present is the most effective approach for preventing cardiac complications related to SARS-CoV-2 infection itself, as the risk of cardiac disease after infection may be 2- to 6-fold higher than after vaccination.²⁵  The myocarditis reporting rate was lower for boys ages 12 to 15 years (48.3 cases per million second doses administered) than boys ages 16 to 17 years (84.0 cases per million second doses). These observations are consistent with previous findings that the peak risk group is boys ages 16 to 17 years, although our myocarditis reporting rates are lower than those in early reports.⁶  The Vaccine Safety Datalink, a network of 9 US healthcare organizations conducting vaccine safety monitoring, reported a myocarditis incidence rate of 137 cases per million doses administered to boys ages 16 to 17.²⁶  Similar to earlier reports, we found that most myocarditis cases reported to VAERS experienced resolution of symptoms by the time the report was submitted.⁶  A population-based cohort study found the reporting rate of myocarditis after COVID-19 mRNA vaccination was significantly higher among those who received dose 2 within 30 days of dose 1 compared with those whose doses were separated by 56 days or greater.²⁷  Extending the interval between dose 1 and dose 2 to 8 weeks may reduce the risk of myocarditis in groups at highest risk.^25,27 

Simultaneous vaccination with BNT-162b2 and other vaccines among adolescents ages 12 to 17 years was not common; only 1% to 3% of participants in VAERS or v-safe reported that they received a concurrent vaccination. This finding was not unexpected, as the adolescent vaccine schedule includes fewer routine vaccinations than the schedule for younger children. CDC clinical guidance states that COVID-19 vaccines may be administered without regard to timing of other vaccines, including simultaneous administration of COVID-19 vaccine and other vaccines.²⁸ 

The findings in this report are subject to several limitations. Data from these 2 surveillance systems may not be representative of the BNT-162b2 vaccinated US population. V-safe is a voluntary program and participants may be more likely to report an adverse event than the general vaccinated population. Some v-safe participants completed surveys for only 1 primary vaccine dose; participants who did not report a second dose may not have received it or may have been lost to follow-up. VAERS data are subject to reporting biases, including underreporting of nonserious events.⁹  Because VAERS is a passive, numerator-only surveillance system, rates of adverse events generally cannot be calculated directly. However, using COVID-19 doses administered in the US population, reporting rates for adverse events can be estimated, and reporting ratios for adverse events can be used to evaluate disproportional reporting of adverse events for specific vaccines. A vaccinated person could report adverse reactions to both v-safe and VAERS. V-safe collects information on common, expected, and specific reactions. VAERS collects additional data and is designed to serve as a signal detection system for new or rare serious adverse events. For both surveillance systems, disparities in access to smartphone and computer technology may impact reporting. Data collection, including review of myocarditis, MIS-C, and death reports, is ongoing in each system.

The Advisory Committee on Immunization Practices and the American Academy of Pediatrics currently recommend that adolescents ages 12 to 17 years receive a 2-dose primary series of an mRNA COVID-19 vaccine and a bivalent booster >2 months after completed primary series or previously received monovalent booster.^29–31  After 1 year of EUA administration, ∼60% of adolescents have received a primary COVID-19 vaccine series.⁷  Our safety findings, collected during the administration of ∼32 million primary series doses of BNT-162b2 vaccine to adolescents ages 12 to 17 years, are consistent with previously reported data. Local and systemic reactions are relatively common; they are usually mild and resolve quickly. Postvaccination myocarditis is a rare complication most commonly reported in boys following dose 2 of an mRNA-based vaccine. We found no new serious safety concerns in the US adolescent population vaccinated with BNT-162b2. Our findings provide additional evidence to support the US COVID-19 vaccination program in adolescents to prevent COVID-19 and its serious complications.

We thank members of the MIS-C Review Group: Lara Akinbami, E. Gloria Anyalechi, Angela Campbell, C. Buddy Creech (Vanderbilt University Medical Center), Kathryn Edwards (Vanderbilt University Medical Center), Satoshi Kamidani (Children’s Healthcare of Atlanta and Emory University School of Medicine), David W. McCormick, Datta Munshi, Oidda Museru, Elizabeth Schlaudecker (University of Cincinnati College of Medicine, Cincinnati Children’s Hospital Medical Center), Mary Staat (University of Cincinnati College of Medicine, Cincinnati Children’s Hospital Medical Center), Allan Taylor, and Anna Yousaf; and acknowledge Karen Broder for her leadership and support.

BNT-162b2

Pfizer-BioNTech mRNA COVID-19 vaccine

CDC

Centers for Disease Control and Prevention

COVID-19

coronavirus disease 2019

EUA

Emergency Use Authorization

FDA

Food and Drug Administration

MedDRA

Medical Dictionary for Regulatory Activities

MIS-C

multisystem inflammatory syndrome in children

mRNA

messenger ribonucleic acid

PT

preferred terms

SARS-CoV-2

severe acute respiratory syndrome coronavirus 2

VAERS

Vaccine Adverse Events Reporting System