May 23, 2022

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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

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Summary

Background

In December, 2020, two mRNA-based COVID-19 vaccines were authorised for use in the USA. We aimed to describe US surveillance data collected through the Vaccine Adverse Event Reporting System (VAERS), a passive system, and v-safe, a new active system, during the first 6 months of the US COVID-19 vaccination programme.

Methods

In this observational study, we analysed data reported to VAERS and v-safe during Dec 14, 2020, to June 14, 2021. VAERS reports were categorised as non-serious, serious, or death. Reporting rates were calculated using numbers of COVID-19 doses administered as the denominator. We analysed v-safe survey reports from days 0–7 after vaccination for reactogenicity, severity (mild, moderate, or severe), and health impacts (ie, unable to perform normal daily activities, unable to work, or received care from a medical professional).

Findings

During the study period, 298 792 852 doses of mRNA vaccines were administered in the USA. VAERS processed 340 522 reports: 313 499 (92·1%) were non-serious, 22 527 (6·6%) were serious (non-death), and 4496 (1·3%) were deaths. Over half of 7 914 583 v-safe participants self-reported local and systemic reactogenicity, more frequently after dose two (4 068 447 [71·7%] of 5 674 420 participants for local reactogenicity and 4 018 920 [70·8%] for systemic) than after dose one (4 644 989 [68·6%] of 6 775 515 participants for local reactogenicity and 3 573 429 [52·7%] for systemic). Injection-site pain (4 488 402 [66·2%] of 6 775 515 participants after dose one and 3 890 848 [68·6%] of 5 674 420 participants after dose two), fatigue (2 295 205 [33·9%] participants after dose one and 3 158 299 participants [55·7%] after dose two), and headache (1 831 471 [27·0%] participants after dose one and 2 623 721 [46·2%] participants after dose two) were commonly reported during days 0–7 following vaccination. Reactogenicity was reported most frequently the day after vaccination; most reactions were mild. More reports of being unable to work, do normal activities, or of seeking medical care occurred after dose two (1 821 421 [32·1%]) than after dose one (808 963 [11·9%]); less than 1% of participants reported seeking medical care after vaccination (56 647 [0·8%] after dose one and 53 077 [0·9%] after dose two).

Interpretation

Safety data from more than 298 million doses of mRNA COVID-19 vaccine administered in the first 6 months of the US vaccination programme show that most reported adverse events were mild and short in duration.

Funding

US Centers for Disease Control and Prevention.

Results

From Dec 14, 2020, to June 14, 2021, 298 792 852 doses of mRNA COVID-19 vaccines were administered in the USA: 167 177 332 were BNT162b2 and 131 639 515 were mRNA-1273 (appendix p 2). A greater proportion of vaccines was administered to females (155 969 573 [53·2%]) than to males (134 373 958 [45·8%]). The median age at vaccination was 50 years (IQR 33–65) for BNT162b2 and 56 years (39–68) for mRNA-1273. 112 698 875 (38·4%) recipients were non-Hispanic White. Race and ethnicity was unknown for 102 227 532 (34·9%) of all vaccine recipients.
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).

Table 1Characteristics of reports received and processed by VAERS for mRNA COVID-19 vaccines

Data are n or n (%). Includes vaccines administered from Dec 14, 2020, to June 14, 2021. VAERS=Vaccine Adverse Event Reporting System. MedDRA=Medical Dictionary for Regulatory Activities.

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).

Table 2Frequency and rates of adverse events of special interest reported to VAERS by recipients of mRNA COVID-19 vaccines

Includes vaccines administered from Dec 14, 2020, to June 14, 2021. VAERS=Vaccine Adverse Event Reporting System.

Table 3Frequency and rates of death reported to VAERS by recipients of mRNA COVID-19 vaccines, by sex and age group

Includes reports made and vaccines administered from Dec 14, 2020, to June 14, 2021. VAERS=Vaccine Adverse Event Reporting System.

Death certificates or autopsy reports were available for clinical review for 808 (18·1%) of 4471 reports of deaths. Among these, causes of death were most commonly diseases of the heart (376 [46·5%]) and COVID-19 (102 [12·6%]; appendix pp 3–4). Among the 3663 reports of death without a death certificate or autopsy, causes of death were most commonly unknown or unclear (1984 [54·2%]), diseases of the heart (621 [17·0%]), and COVID-19 (317 [8·7%]; appendix pp 3–4). Causes of death among reports with death certificate or autopsy reports available are shown by age in appendix p 5.
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 (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).

Table 4Demographic characteristics of v-safe participants reporting receipt of an mRNA COVID-19 vaccine and completing at least one health survey 0–7 days after vaccination

Data are n (%). Includes vaccines administered from Dec 14, 2020, to June 14, 2021.

Table 5Local and systemic reactions and health impacts following mRNA COVID-19 vaccines reported during days 0–7 after vaccination to v-safe, by manufacturer and dose

Data are n (%). Includes health check-in surveys made and vaccines administered from Dec 14, 2020, to June 14, 2021.

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).

FigureLocal and systemic reactions to mRNA COVID-19 vaccines reported to v-safe, by manufacturer, dose, days after vaccination, and severity

Figure shows top reactions by reported frequency, after showing by dose number and by manufacturer. These top six reactions were determined by reported frequency after dose two of both mRNA COVID-19 vaccines in v-safe, excluding fever because it was not rated mild, moderate, or severe. Mild was defined as “noticeable symptoms but they aren’t a problem”, moderate as “symptoms that limit normal activities”, and severe as “make normal daily activities difficult or impossible”.

Reported health impacts were greater following dose two of either vaccine than dose one, and after mRNA-1273 than after BNT162b2 (table 5). After dose two of BNT162b2, 598 584 (20·5%) of 2 920 526 participants were unable to do normal activities, and 360 411 (12·3%) were unable to work (table 5). After dose two of mRNA-1273, 903 095 (32·8%) of 2 753 894 participants were unable to do normal activities, and 550 955 (20·0%) were unable to work (table 5). Less than 1·0% reported receiving medical care after receiving either dose of either vaccine (table 5). A very small proportion reported an emergency room visit or hospitalisation (table 5).
When stratified by sex, female participants reported a health impact more frequently than did male participants, peaking on day 1 after vaccination (appendix p 11). Following dose two of mRNA-1273 vaccine, 522 192 (41·4%) of 1 262 711 female participants reported an inability to do normal activities in the day 1 survey, and 296 178 (23·5%) reported an inability to work (appendix pp 9, 11). Among male recipients of dose two of mRNA-1273, on the day 1 survey 167 957 (25·6%) of 655 688 were unable to do normal activity and 110 868 (16·9%) were unable to work (appendix pp 9, 11).

Discussion

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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Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine.