Background

Findings

Interpretation

Funding

In December, 2020, two mRNA COVID-19 vaccines (BNT162b2 [Pfizer-BioNTech]; and mRNA-1273 [Moderna]) were granted emergency use authorisation (EUA) by the US Food and Drug Administration (FDA) as two-dose series and recommended for use by the Advisory Committee on Immunization Practices (ACIP). ^1, 2

In clinical trials, both mRNA COVID-19 vaccines showed acceptable safety profiles;^3, 4

the most frequently reported local and systemic symptoms were injection-site pain, fatigue, and headache. Reactogenicity was more frequently reported after dose two than after dose one and among participants younger than 65 years than among older participants.^{3, 4, 5}

Post-authorisation safety monitoring can characterise the safety profiles of mRNA-based COVID-19 vaccines in large and heterogeneous populations. ⁶

Phased administration of COVID-19 vaccines in the USA began with health-care workers and long-term care-facility residents and was expanded to the general population during spring 2021; however, implementation plans varied by state.⁷

The major sources of initial US safety data were the Vaccine Adverse Event Reporting System (VAERS), a spontaneous, passive reporting system;⁸

and v-safe,⁹

a new active monitoring system. VAERS was established in 1990 as the US early warning system to rapidly detect adverse events that might occur following vaccinations. V-safe was established in 2020 specifically for monitoring COVID-19 vaccine safety in the USA and collects information on reactogenicity and effects on health following COVID-19 vaccination.

Previous reports from these systems have been issued

We aimed to review VAERS and v-safe data during the first 6 months of the US vaccination programme, when more than 298 million doses of mRNA COVID-19 vaccines were administered, to better characterise the safety profile of mRNA vaccines.

During the study period, VAERS received and processed 340 522 reports: 164 669 following BNT162b2 and 175 816 following mRNA-1273 vaccination (table 1). Of these reports, 313 499 (92·1%) were classified as non-serious; 22 527 (6·6%) were serious, not resulting in death; and 4496 (1·3%) were deaths (table 1). 246 085 (72·3%) reports were among female participants and 154 171 (45·3%) reports were among those aged 18–49 years; median age was 50 years (IQR 36–64; table 1). 169 877 (49·9%) of those reporting race or ethnicity identified as non-Hispanic White, and for 75 334 (22·1%) race and ethnicity were unknown (table 1). The most common MedDRA preferred terms assigned to non-serious reports were headache (64 064 [20·4%] of 313 499), fatigue (52 048 [16·6%]), pyrexia (51 023 [16·3%]), chills (49 234 [15·7%]), and pain (47 745 [15·2%]; table 1). The most common MedDRA preferred terms assigned to serious reports were dyspnoea (4175 [15·4%] of 27 023), death (3802 [14·1%]), pyrexia (2986 [11·0%]), fatigue (2608 [9·7%]), and headache (2567 [9·5%]; table 1).

The reporting rate to VAERS was 1049·2 non-serious reports per million vaccine doses, and 90·4 serious reports per million doses (table 2). Among the prespecified adverse events of special interest, reporting rates ranged from 0·1 narcolepsy reports per million doses administered to 31·3 reports of COVID-19 disease per million doses administered (table 2). 4496 reports of death were made to VAERS following receipt of an mRNA COVID-19 vaccine (table 3). After review by clinical staff, 25 reports were excluded because of miscoding of death or duplicate reporting. Of the 4471 reports of deaths analysed, 2086 (46·7%) were reported following BNT162b2 and 2385 (53·3%) following mRNA-1273. 1906 (42·6%) deaths were in female vaccine recipients and 2485 (55·6%) were in male recipients; the median age of participants who died was 76 years (IQR 66–86; table 3). 3647 (81·6%) deaths were reported among individuals aged 60 years or older (table 3). 821 (18·4%) deaths were identified as being in long-term care-facility residents. Time to death following vaccination was available for 4118 (92·1%) reports; median time was 10·0 days (IQR 3–25). The greatest number of death reports occurred on day 1 (470 [11·4%] of 4118) and day 2 (312 [7·6%] 4118) following vaccination (appendix p 10).

During the study period, 7 914 583 mRNA COVID-19 vaccine recipients enrolled in v-safe after dose one or dose two and completed at least one post-vaccination health survey during days 0–7 (table 4). The median age of v-safe participants was 50 years (IQR 36–63), 4 975 209 (62·9%) were female, 2 860 738 (36·1%) were male, and 4 701 715 (59·4%) identified as non-Hispanic White (table 4). 6 775 515 participants completed at least one survey during days 0–7 after dose one (table 5). Of these participants, 4 644 989 (68·6%) reported a local injection-site reaction and 3 573 429 (52·7%) reported a systemic reaction (table 5). Of the 5 674 420 participants who completed surveys after dose two, 4 068 447 (71·7%) reported an injection-site reaction and 4 018 920 (70·8%) a systemic reaction (table 5). Local injection-site reactions were reported more frequently after mRNA-1273 than after BNT162b2 (table 5). A similar pattern was found for systemic reactions after mRNA-1273 versus BNT162b2 (table 5). The most frequently reported events after dose one of either mRNA vaccine included injection-site pain, fatigue, and headache, which were also more frequent after dose two than after dose one (table 5). Differences in proportions of reactogenicity by dose number were similar after stratifying by age (<65 vs ≥65 years) and sex (appendix p 6). More reactogenicity was reported among participants younger than 65 years than older participants and by female participants than male participants (appendix p 6).

Local and systemic reactions stratified by manufacturer, dose, days after vaccination, and severity are shown in the figure. Most reported symptoms were mild (figure). Participants reported moderate and severe reactogenicity most commonly on day 1 after dose two of either mRNA vaccine (figure). The proportion of participants who reported symptoms was greatest on day 1 and then decreased subsequently (figure). The highest proportions of participants reporting severe symptoms occurred on day 1 following dose two of mRNA-1273 (appendix p 8). On all other days, proportions of participants reporting severe symptoms did not exceed 3·0% for any individual symptom (appendix pp 7–8).

In this analysis of VAERS and v-safe data from the first 6 months of COVID-19 vaccination rollout in the USA, when over 298 million doses of mRNA vaccines were administered, we found that reactogenicity was similar to what was reported from clinical trials and from early post-authorisation monitoring.

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In both VAERS and v-safe, local injection-site and systemic reactions were commonly reported. V-safe participants more frequently reported transient reactions following mRNA-1273 than following BNT162b2, and more frequently following dose two of either vaccine compared with after dose one. Female participants and individuals younger than 65 years reported adverse events and reactions more frequently than male participants and those aged 65 years and older, respectively. Reporting rates for death were higher in older age groups, as expected on the basis of general age-specific mortality in the general adult population.

Safety monitoring of COVID-19 vaccines has been the most comprehensive in US history and has used established systems, including the Vaccine Safety Datalink (VSD),

VAERS, and a new system, v-safe, developed specifically for monitoring COVID-19 vaccine safety. During the study period, all COVID-19 vaccines were administered under EUAs, which require vaccine providers to report all serious adverse events (including deaths) that occur after vaccination to VAERS, regardless of whether they were plausibly associated with vaccination. Heightened public awareness of the COVID-19 vaccination programme, outreach and education to health-care providers and hospitals about COVID-19 EUA reporting requirements for adverse events, and adherence to EUA reporting requirements by providers and health systems, probably all contributed to the high volume of VAERS reports received.

Data from US safety monitoring systems for all COVID-19 vaccines authorised or approved by the FDA have been reviewed regularly by the ACIP COVID-19 Vaccines Safety Technical Work Group

and at public ACIP meetings.

Similar to reports following receipt of other vaccines routinely administered to adults, most VAERS reports following mRNA COVID-19 vaccination were non-serious.

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Serious adverse events detected in VAERS and VSD

surveillance prompted specific safety evaluations for anaphylaxis,

thrombosis with thrombocytopenia syndrome,

myocarditis,

and Guillain-Barré syndrome.

After reports of anaphylaxis following mRNA vaccination with both vaccines, clinical guidance and management recommendations were updated.

Also during this time period, a safety signal for myocarditis was identified and investigated further in VAERS and other US safety systems.

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Thrombosis with thrombocytopenia syndrome

and Guillain-Barré syndrome

have been associated with Janssen’s Ad26.COV2.S adenoviral vector COVID-19 vaccine but not with mRNA vaccines. ACIP has conducted several benefit–risk assessments for each of the authorised or approved US COVID-19 vaccines;

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these assessments have resulted in several modifications to clinical guidance and a preferential recommendation for mRNA vaccines.

Reactogenicity findings following mRNA COVID-19 vaccination from VAERS and v-safe data are similar to those from a large study in the UK.

The observed patterns might be explained in part by host characteristics known to influence reactogenicity, including age, sex, and the presence of underlying medical conditions.

Female recipients have more vigorous antibody responses

to certain vaccines and also tend to report more severe local and systemic reactions to influenza vaccine, compared with male recipients.

Female recipients might also be more likely than male recipients to respond to surveys.

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Younger people might be more comfortable with smartphone-based surveys and more likely to respond to surveys generally.

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Using v-safe data, we were able to assess the effects of mRNA vaccination on daily-life activities among vaccine recipients for the first time for a vaccine administered in the USA. These effects were most frequently reported on day 1 after vaccination. Reports about the measures of health impacts used in v-safe, although self-assessed and subjective, correlate with reports about reactogenicity: more health impacts were reported by female than by male recipients, by participants younger than 65 years compared with older participants, after dose two compared with dose one, and by those who received mRNA-1273 versus BNT162b2. Reports of seeking medical care after mRNA vaccine were rare; v-safe surveys did not ask which symptoms prompted the participant to seek medical care. Reactogenicity and its associated health impacts, even if transient, might deter some from seeking vaccination. Surveys found that nearly half of unvaccinated adults younger than 50 years expressed concern about missing work because of vaccine side-effects and that employees who were given paid leave were more likely to get vaccinated than were those without paid leave;

employer policies that accommodate such leave might increase vaccination coverage.

In our review and analysis of death reports to VAERS following mRNA vaccination, we found no unusual patterns in cause of death among the death reports received. Under the COVID-19 vaccine EUA regulations, health-care providers are required to report deaths and life-threatening adverse health events after COVID-19 vaccinations to VAERS regardless of their potential association with vaccination. These requirements make comparing the number of reported deaths to VAERS for COVID-19 vaccines with reported deaths following other adult vaccines

difficult because no other adult vaccines have been so widely administered under FDA EUAs. Initially, US COVID-19 vaccination was prioritised for individuals aged 65 years and older and those in long-term care facilities.

These populations have the highest baseline mortality risk, complicating comparisons with mortality reporting for other adult vaccines. Similar to general mortality in the adult population,

reporting rates for deaths in this analysis increased with increasing age. The concentrated reporting of deaths on the first few days after vaccination follows patterns similar to those observed for other adult vaccinations.

This pattern might represent reporting bias because the likelihood to report a serious adverse event might increase when it occurs in close temporal proximity to vaccination.

There are limitations in any review of preliminary data concerning reports of death following vaccination. A comparison with national mortality data

suggests that certain causes of death, such as accidents, suicides, or cancer, are less likely to be reported to VAERS. Underreporting to VAERS, in general, is expected.

The predominance of heart disease as a cause of death reported to VAERS warrants continued monitoring and assessment but might be driven by non-specific causes, such as cardiac arrest, that might be chosen as a terminal event if no immediate explanation for death was available. Death certificate or autopsy reports were available for only a small proportion of deaths reported to VAERS when our analyses were conducted. Finally, VAERS is designed as an early warning system to detect potential safety signals,

and VAERS data alone generally cannot establish causal relationships between vaccination and adverse events. Another surveillance system, the VSD, showed no increased risk of non-COVID-19 mortality in vaccinated people.

This study has several strengths, including the large population under surveillance and the comprehensive capture of national data from two complementary surveillance systems. Because the US Government purchased all COVID-19 doses and collected administration data, we were able to calculate VAERS reporting rates using the number of mRNA vaccine doses administered as denominators.

By contrast, VAERS analyses for non-COVID-19 vaccines rely on doses distributed, not administered. Because the number of doses distributed is greater than that of doses administered, these past VAERS analyses are likely to underestimate reporting rates of vaccine-related adverse events. Information from v-safe about how reactogenicity during the week after mRNA vaccination affects daily activities and work is novel and provides new insights.

An important limitation of this report is one shared by all VAERS analyses: we used data from a passive reporting system subject to underreporting and variable or incomplete reporting.

Although VAERS death reports were individually reviewed by CDC physicians and follow-up is ongoing to obtain additional and missing records, other reports of serious adverse events were not individually reviewed. Additionally, VAERS reports require interpretation to identify whether reports meet clinical case definitions.

A limitation of v-safe is the need for smartphone access. Because a subset of all vaccine recipients participated in v-safe, the results are unlikely to be generalisable to the entire vaccinated US population. Other differences might exist among participants who received mRNA-1273 or BNT162b2 vaccines that were unaccounted for; therefore, v-safe cannot be used to draw conclusions that one mRNA vaccine type is more reactogenic than the other. Additionally, participants in v-safe might be lost to follow-up because continuous enrolment is not required. Finally, this report only included v-safe responses received during the first week after vaccination.

During the first 6 months of the US COVID-19 vaccination programme, more than 50% of the eligible population received at least one vaccine dose.¹⁹ VAERS and v-safe data from this period show a post-authorisation safety profile for mRNA COVID-19 vaccines that is generally consistent with pre-authorisation trials

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and early post-authorisation surveillance reports.

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Serious adverse events, including myocarditis, have been identified following mRNA vaccinations; however, these events are rare. Vaccines are the most effective tool to prevent serious COVID-19 disease outcomes

and the benefits of immunisation in preventing serious morbidity and mortality strongly favour vaccination.

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VAERS and v-safe, two complementary surveillance systems, will continue to provide data needed to inform policy makers, immunisation providers, other health-care professionals, and the public about the safety of COVID-19 vaccination.

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