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https://doi.org/10.1038/s41591-021-01630-0
Although myocarditis and pericarditis were not observed as adverse events in coronavirus disease 2019 (COVID-19) vaccine
trials, there have been numerous reports of suspected cases following vaccination in the general population. We undertook
a self-controlled case series study of people aged 16 or older vaccinated for COVID-19 in England between 1 December 2020
and 24 August 2021 to investigate hospital admission or death from myocarditis, pericarditis and cardiac arrhythmias in the
1–28 days following adenovirus (ChAdOx1, n = 20,615,911) or messenger RNA-based (BNT162b2, n = 16,993,389; mRNA-1273,
n = 1,006,191) vaccines or a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive test (n = 3,028,867). We
found increased risks of myocarditis associated with the first dose of ChAdOx1 and BNT162b2 vaccines and the first and second
doses of the mRNA-1273 vaccine over the 1–28 days postvaccination period, and after a SARS-CoV-2 positive test. We esti-
mated an extra two (95% confidence interval (CI) 0, 3), one (95% CI 0, 2) and six (95% CI 2, 8) myocarditis events per 1 million
people vaccinated with ChAdOx1, BNT162b2 and mRNA-1273, respectively, in the 28 days following a first dose and an extra
ten (95% CI 7, 11) myocarditis events per 1 million vaccinated in the 28 days after a second dose of mRNA-1273. This compares
with an extra 40 (95% CI 38, 41) myocarditis events per 1 million patients in the 28 days following a SARS-CoV-2 positive test.
We also observed increased risks of pericarditis and cardiac arrhythmias following a positive SARS-CoV-2 test. Similar associa-
tions were not observed with any of the COVID-19 vaccines, apart from an increased risk of arrhythmia following a second dose
of mRNA-1273. Subgroup analyses by age showed the increased risk of myocarditis associated with the two mRNA vaccines
was present only in those younger than 40.
B
y the end of September 2021, more than 6.3 billion doses of than 5 million people vaccinated with the BNT162b2 vaccine4. No
COVID-19 vaccination had been administered worldwide1. association between ChAdOx1 vaccine and myocarditis or pericar-
Clinical trials of COVID-19 vaccines were underpowered ditis has been reported. The same reports showed that these events
to detect the rare adverse events that are important for risk–ben- are more likely to occur in adolescent and young adults, mostly after
efit evaluations and to inform clinical practice postvaccination. the second dose. Evaluation of the risks of adverse events following
Therefore, identifying such rare adverse events is now a global sci- vaccination or SARS-CoV-2 infection in different age groups pro-
entific priority. vides crucial information to determine whether the risks from the
As of 4 November 2021, there have been 1,783 reports to the vaccine outweighs the risks following a positive SARS-CoV-2 test.
United States Vaccine Adverse Event Reporting System (VAERS) In England, the vaccination campaign began on 8 December
of cases of heart inflammation, namely myocarditis or pericarditis, 2020 with the BNT162b2 vaccine followed by the ChAdOx1 vaccine
among people aged 12–29 years who received COVID-19 vaccines, on 4 January 2021. In the first phase, priority was given to the most
in particular following mRNA vaccination, that is, BNT162b2 and vulnerable, in a schedule based primarily on age. The mRNA-1273
mRNA-1273 vaccines2. As of 9 July 2021, the European Medicines vaccine became available in England on 13 April 2021. Since 7 April
Agency (EMA) has reported 145 cases of myocarditis and 138 cases 2021, ChAdOx1 vaccine has not been recommended for individuals
of pericarditis out of 177 million doses of the BNT162b2 vaccine, and younger than 30 years of age, and since 7 May 2021 for individuals
9 cases of myocarditis and 19 cases of pericarditis out of 20 million younger than 40 years of age.
doses of the mRNA-1273 vaccine3. In Israel, 275 cases of myocarditis The English National Immunisation (NIMS) Database of
were reported between December 2020 and May 2021 among more COVID-19 vaccination includes data on vaccine type, date and
1
Nuffield Department of Primary Health Care Sciences, University of Oxford, Oxford, UK. 2Wellcome Centre for Human Genetics, University of Oxford,
Oxford, UK. 3Leicester Real World Evidence Unit, Diabetes Research Centre, University of Leicester, Leicester, UK. 4Usher Institute, University of Edinburgh,
Edinburgh, UK. 5Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK. 6School of Immunology and Microbial Sciences, King’s College
London, London, UK. 7Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. 8NIHR Biomedical Research Centre, Oxford
University Hospitals NHS Trust, Oxford, UK. 9Division of Primary Care, School of Medicine, University of Nottingham, Nottingham, UK. 10British Heart
Foundation Centre of Research Excellence, NIHR Oxford Biomedical Research Centre, University of Oxford, John Radcliffe Hospital, Oxford, UK.
11
BHF/University Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK. ✉e-mail: julia.hippisley-cox@phc.ox.ac.uk
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Table 3 | IRR (95% CI) for individual outcomes in predefined risk periods immediately before and after exposure to vaccination and before and after a positive SARS-CoV-2 test
result, adjusted for calendar time from 1 December 2020 to 24 August 2021 (cells with an asterisk are suppressed). n/a, not applicable; pyrs, person-years
ChAdOx1nCoV-19 vaccine BNT162b2 mRNA vaccine mRNA-1273 vaccine Positive SARS-CoV-2 test
Events pyrs IRR (95% CI) Events pyrs IRR (95% CI) Events pyrs IRR (95% CI) Events pyrs IRR (95% CI)
Myocarditis
Articles
Baseline 550 409.0 1.00 398 307.7 1.00 22 20.4 1.00 119 216.7 1.00
−28 to −1 days: first dose/positive test 81 70.4 0.74 (0.58, 0.95) 49 49.0 0.75 (0.55, 1.01) * * 0.41 (0.09, 1.87) 32 21.0 2.84 (1.89, 4.28)
Day 0: first dose/positive test * * 0.54 (0.14, 2.19) * * 1.24 (0.40, 3.88) * * n/a 36 0.8 78.21 (52.90, 115.62)
1–7 days: first dose/positive test 47 17.6 1.76 (1.29, 2.42) 27 12.5 1.45 (0.97, 2.17) 7 0.7 8.38 (3.53, 19.91) 68 5.8 21.08 (15.34, 28.96)
8–14 days: first dose/positive test 35 17.6 1.22 (0.85, 1.74) 23 12.5 1.23 (0.80, 1.90) * * n/a 37 5.9 11.29 (7.70, 16.57)
15–21 days: first dose/positive test 30 17.6 1.03 (0.71, 1.51) 21 12.4 1.14 (0.73, 1.78) * * n/a 18 6.0 5.36 (3.24, 8.89)
22–28 days: first dose/positive test 30 17.5 1.03 (0.71, 1.51) 23 12.0 1.33 (0.86, 2.04) * * n/a 11 6.1 3.08 (1.65, 5.75)
−28 to −1 days: second dose 58 58.3 0.65 (0.49, 0.87) 48 33.3 0.96 (0.70, 1.32) * * 2.19 (0.45, 10.69)
Day 0: second dose * * 0.64 (0.16, 2.56) * * n/a * * n/a
1–7 days: second dose 13 14.8 0.60 (0.34, 1.04) 23 9.3 1.75 (1.13, 2.70) * * 23.10 (6.46, 82.56)
8–14 days: second dose 28 14.8 1.31 (0.88, 1.93) 15 9.3 1.16 (0.69, 1.97) * * n/a
15–21 days: second dose 19 14.8 0.91 (0.57, 1.45) 14 9.3 1.14 (0.66, 1.97) * * n/a
22–28 days: second dose 24 14.8 1.16 (0.76, 1.76) 12 9.1 1.01 (0.57, 1.82) * * n/a
1–28 days: first dose/positive test 142 70.2 1.29 (1.05, 1.58) 94 49.4 1.31 (1.03, 1.66) 9 2.9 2.97 (1.34, 6.58) 134 23.9 9.76 (7.51, 12.69)
1–28 days: second dose 84 59.2 1.00 (0.78, 1.27) 64 37.1 1.30 (0.98, 1.72) * * 9.84 (2.69, 36.03)
Pericarditis
Baseline 581 405.2 1.00 414 285.9 1.00 12 11.2 1.00 95 115.4 1.00
−28 to −1 days: first dose/positive test 64 70.7 0.54 (0.42, 0.71) 42 47.2 0.63 (0.45, 0.87) * * 1.62 (0.52, 5.07) 29 10.0 3.57 (2.30, 5.55)
Day 0: first dose/positive test * * n/a * * 0.74 (0.18, 2.98) * * n/a 11 0.4 35.04 (18.47, 66.46)
1–7 days: first dose/positive test 19 17.7 0.59 (0.37, 0.94) 11 12.0 0.59 (0.32, 1.07) * * n/a 11 2.8 4.85 (2.56, 9.18)
8–14 days: first dose/positive test 34 17.7 1.00 (0.70, 1.44) 9 12.0 0.46 (0.24, 0.90) * * n/a 9 2.9 3.81 (1.90, 7.63)
15–21 days: first dose/positive test 23 17.6 0.64 (0.42, 0.99) 19 11.9 0.98 (0.62, 1.57) * * n/a * * 1.63 (0.59, 4.45)
22–28 days: first dose/positive test 26 17.6 0.71 (0.47, 1.06) 20 11.6 1.02 (0.65, 1.61) * * n/a * * 1.15 (0.36, 3.66)
−28 to −1 days: second dose 58 61.0 0.43 (0.32, 0.57) 35 36.5 0.47 (0.33, 0.67) * * n/a
Day 0: second dose * * n/a * * 0.99 (0.32, 3.09) * * n/a
1–7 days: second dose 37 15.6 1.12 (0.79, 1.58) 12 10.1 0.58 (0.33, 1.04) * * n/a
8–14 days: second dose 29 15.6 0.89 (0.61, 1.31) 16 10.1 0.80 (0.48, 1.32) * * n/a
15–21 days: second dose 36 15.6 1.13 (0.80, 1.60) 21 10.1 1.05 (0.67, 1.64) * * n/a
22–28 days: second dose 15 15.5 0.49 (0.29, 0.82) 26 10.1 1.34 (0.89, 2.02) * * n/a
1–28 days: first dose/positive test 102 70.6 0.74 (0.59, 0.92) 59 47.4 0.77 (0.58, 1.02) * * 1.64 (0.45, 5.94) 27 11.7 2.79 (1.80, 4.32)
1–28 days: second dose 117 62.4 0.91 (0.73, 1.13) 75 40.4 0.93 (0.72, 1.21) * * n/a
Cardiac arrhythmia
Baseline 118,356 88,084.1 1.00 113,968 81,778.6 1.00 1,221 867.6 1.00 15,119 24,323.4 1.00
−28 to −1 days: first dose/positive test 17,562 15,500.4 0.78 (0.76, 0.79) 12,767 13,158.8 0.72 (0.70, 0.73) 184 126.8 0.90 (0.77, 1.05) 6,618 2,223.6 4.82 (4.68, 4.97)
(Continued)
IRR (95% CI) was an increased risk of cardiac arrhythmia following a second dose
Positive SARS-CoV-2 test
Subgroup analyses by age group and sex. Table 4 shows the IRRs
for the outcomes in the overall 1–28 day risk periods before and
2,530.5
638.8
653.8
624.7
613.3
86.7
pyrs
8,940
2,643
4,593
3,847
for myocarditis.
mRNA-1273 vaccine
(IRR 1.83, 95% CI 1.20, 2.79) and of mRNA-1273 (IRR 3.89, 95%
CI 1.60, 9.44), after a second dose of BNT162b2 (IRR 3.40, 95% CI
124.1
43.4
43.2
pyrs
31.4
31.6
29.1
32.1
11.2
11.2
11.2
1.91, 6.04) and of mRNA-1273 (IRR 20.71, 95% CI 4.02, 106.68) and
4.5
9.8
*
48
43
38
38
35
22
13
9
6
7
*
3,098.4
3,458.9
3,471.4
3,150.5
3,112.3
3,112.3
3,112.3
444.6
497.0
of mRNA-1273 (IRR 3.79, 95% CI 1.59, 9.04 and IRR 12.27, 95%CI
Events
18,359
15,010
5,288
4,837
4,593
5,495
3,958
5,427
4,737
4,971
232
257
ferent age groups (16–29, 29–39 and 40 plus years). The increased
risk of myocarditis associated with either messenger RNA-based
vaccine consistently occurs in the younger population (<40 years).
14,063.1
3,863.0
3,867.0
3,857.0
3,510.8
3,872.1
3,517.4
3,517.4
3,517.4
23,019
18,595
6,243
5,236
5,873
5,833
6,019
5,981
6,128
5,931
289
265
16.0
ChadOx1
7.0
vaccine
3.0
1.5
0.5
16.0
BNT162b2
vaccine
7.0
3.0
1.5
0.5
16.0
7.0
vaccine
3.0
1.5
0.5
SARS-CoV-2
16.0
diagnosis
7.0
3.0
1.5
0.5
28 to 1: first dose
0: first dose
1–7: first dose
8–14: first dose
15–21: first dose
22–28: first dose
28 to 1: second dose
0: second dose
1–7: second dose
8–14: second dose
15–21: second dose
22–28: second dose
28 to 1: first dose
0: first dose
1–7: first dose
8–14: first dose
15–21: first dose
22–28: first dose
28 to 1: second dose
0: second dose
1–7: second dose
8–14: second dose
15–21: second dose
22–28: second dose
28 to 1: first dose
0: first dose
1–7: first dose
8–14: first dose
15–2: first dose
22–28: first dose
28 to 1: second dose
0: second dose
1–7: second dose
8–14: second dose
15–21: second dose
22–28: second dose
Time period (days since exposure)
Fig. 1 | IRRs with 95% CIs for cardiac adverse events following each exposure. IRRs are presented for predefined risk periods (0, 1–7, 8–14, 15–21 and
22–28 days) after first or second dose of ChAdOx1, BNT162b2 and mRNA-1273 vaccines and a SARS-CoV-2 positive test for the prerisk period (28 days
before exposure). Horizontal bold line in each panel indicates 1.
Over the 1–28 days postexposure, we observed an increased risk As expected, sensitivity analyses 6–8 show that, by reducing
of atrial fibrillation or flutter arrhythmia at 15–21 days following the length of the prerisk period, we could exaggerate the relative
a first dose of mRNA-1273 vaccine (IRR 2.06, 95% CI 1.11, 3.82); incidence associated with vaccine exposure and understate the
of ventricular fibrillation at 22–28 days following a second dose of relative incidence associated with infection exposure, whereas
ChAdOx1 vaccine (IRR 1.35, 95% CI 1.05, 1.74) and of other car- increasing the length of the prerisk period has the opposite effect
diac arrhythmia at 1–7 days following a second dose of mRNA-1273 (Supplementary Table 8b).
vaccine (IRR 2.32, 95% CI 1.49, 3.62). There was an increased risk A sensitivity analysis restricting the study period up to 17 May
of all cardiac arrhythmia subgroups in the 1–28 days following a 2021, when the Centres for Disease Control and Prevention (CDC)
SARS-CoV-2 positive test (Supplementary Table 6). announced cases of myocarditis after the BNT162b2 vaccine,
showed no increased incidence of myocarditis in the 1–7 days fol-
Robustness of results. We found no increased risk of celiac disease lowing a second dose of BNT162b2 (IRR 1.07, 95% CI 0.59, 1.97).
(negative control) across the prespecified time periods for the The age distribution of those vaccinated with ChAdOx1 in these
vaccine exposures, with the exception of the 15–21 days after the two time periods was similar, but those vaccinated with BNT162b2
second dose of ChAdOx1 (IRR 1.20; 95% CI: 1.05, 1.36). We also were older in the restricted study period (13.8% versus 29.7% were
found a decreased risk on the day of vaccination, as expected given younger than 40 years; Supplementary Table 9).
the healthy vaccinee effect. Anaphylaxis (positive control) showed
the expected increased risk on the day of vaccination (both first Hospital duration of stay for myocarditis. The median hospital
and second dose), but not at later periods following the ChAdOx1 duration of stay for those with myocarditis in the 28 days postvac-
and BNT162b2 vaccinations (Supplementary Table 7). There were cination was 3 days (interquartile range (IQR): 1, 9) for ChAdOx1,
insufficient numbers of events to evaluate associations between ana- 3 days (IQR: 1, 7) for BNT162b2 and 4 days (IQR: 3, 6) for mRNA-
phylaxis and the mRNA-1273 vaccine. See Methods for clarification 1273, with means of 8.3, 5.7 and 4.5 days, respectively. This compares
of the choice of controls outcomes. with a median of 4 days (IQR: 1, 9) and mean of 7.6 days for those
Supplementary Table 8a and Extended Data Figs. 1–3 show the whose admissions had not occurred in the 28 days post vaccination.
results for several sensitivity analyses. Overall, our main findings
were not sensitive to censoring due to death, and IRRs for the sec- Absolute measures of effect of vaccination and SARS-CoV-2
ond dose of vaccination agree with main results when we removed infection. We estimated the number of exposures needed for one
those who had the outcome after the first dose of any vaccine, but excess event and the excess number of events per 1 million exposed
before the second. for each outcome (Fig. 2 and Supplementary Table 10). In the
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Table 4 | IRRs (95% CI) by age group (aged 40 years or younger, older than 40 years) and sex (women and men) for the outcomes in predefined risk periods immediately before and
after exposure to vaccination and before and after a positive SARS-CoV-2 test result, adjusted for calendar time from 1 December 2020 to 24 August 2021 (cells with an asterisk are
suppressed) (Continued)
ChAdOx1nCoV-19 vaccine BNT162b2 mRNA vaccine mRNA-1273 vaccine Positive SARS-CoV-2 test
Time period events IRR (95% CI) events IRR (95% CI) events IRR (95% CI) events IRR (95% CI)
Articles
Cardiac arrhythmia Baseline 112,836 1.00 102,437 1.00 297 1.00 12,829 1.00
−28 to −1 days: first dose/positive test 16,526 0.75 (0.74, 0.76) 10,980 0.68 (0.67, 0.70) 37 0.64 (0.46, 0.91) 6,335 5.35 (5.18, 5.52)
Day 0: first dose/positive test 272 0.33 (0.29, 0.37) 207 0.32 (0.28, 0.37) * 1.50 (0.48, 4.69) 3,658 76.38 (73.54, 79.34)
1–28 days: first dose/positive test 23,053 0.94 (0.93, 0.96) 16,720 0.88 (0.87, 0.90) 48 0.91 (0.67, 1.24) 8,072 5.71 (5.54, 5.87)
−28 to −1 days: second dose 17,756 0.76 (0.74, 0.77) 14,351 0.75 (0.74, 0.77) 20 0.62 (0.39, 0.98)
Day 0: second dose 245 0.29 (0.25, 0.32) 242 0.32 (0.28, 0.36) * n/a
1–28 days: second dose 22,029 0.95 (0.94, 0.97) 20,145 0.94 (0.93, 0.96) 30 1.40 (0.95, 2.07)
Women
Myocarditis Baseline 230 1.00 163 1.00 6 1.00 40 1.00
−28 to −1 days: first dose/positive test 32 0.68 (0.45, 1.01) 15 0.51 (0.29, 0.87) * n/a 14 3.23 (1.71, 6.10)
Day 0: first dose/positive test * 1.39 (0.34, 5.63) * 1.94 (0.48, 7.87) * n/a 13 70.71 (36.93, 135.37)
1–28 days: first dose/positive test 58 1.40 (1.01, 1.93) 47 1.54 (1.08, 2.20) * n/a 53 11.00 (7.12, 16.99)
−28 to −1 days: second dose 18 0.51 (0.31, 0.85) 17 0.86 (0.51, 1.47) * n/a
Day 0: second dose * n/a * n/a * n/a
1–28 days: second dose 23 0.63 (0.40, 0.99) 27 1.25 (0.81, 1.95) * n/a
Pericarditis Baseline 205 1.00 142 1.00 * 1.00 29 1.00
−28 to −1 days: first dose/positive test 23 0.57 (0.36, 0.90) 14 0.61 (0.35, 1.08) * n/a 8 3.12 (1.37, 7.11)
Day 0: first dose/positive test * n/a * n/a * n/a 5 50.44 (18.80, 135.30)
1-28 days: first dose/positive test 27 0.57 (0.37, 0.88) 22 0.84 (0.53, 1.34) * n/a 12 4.29 (2.13, 8.63)
−28 to −1 days: second dose 12 0.26 (0.14, 0.47) 11 0.40 (0.21, 0.75)
Day 0: second dose * n/a * 1.82 (0.45, 7.41)
1–28 days: second dose 32 0.74 (0.50, 1.11) 23 0.80 (0.50, 1.27)
Cardiac arrhythmia Baseline 56,585 1.00 55,963 1.00 758 1.00 8,125 1.00
−28 to −1 days: first dose/positive test 8,174 0.73 (0.71, 0.75) 6,097 0.68 (0.66, 0.70) 111 0.90 (0.73, 1.10) 3,286 4.37 (4.19, 4.56)
Day 0: first dose/positive test 162 0.38 (0.33, 0.45) 117 0.33 (0.28, 0.40) 6 1.46 (0.65, 3.26) 1,725 56.62 (53.68, 59.73)
1–28 days: first dose/positive test 11,651 0.93 (0.91, 0.95) 8,655 0.85 (0.83, 0.87) 78 0.75 (0.59, 0.95) 3,913 4.33 (4.17, 4.51)
−28 to −1 days: second dose 8,811 0.75 (0.73, 0.77) 7,006 0.73 (0.71, 0.75) 22 0.71 (0.46, 1.11)
Day 0: second dose 118 0.28 (0.23, 0.33) 116 0.31 (0.25, 0.37) * n/a
1–28 days: second dose 10,872 0.95 (0.93, 0.97) 9,907 0.94 (0.92, 0.96) 29 1.77 (1.19, 2.61)
Men
Myocarditis Baseline 318 1.00 234 1.00 16 1.00 79 1.00
−28 to −1 days: first dose/positive test 49 0.73 (0.53, 1.01) 34 0.89 (0.62, 1.30) * 0.59 (0.13, 2.74) 18 2.45 (1.44, 4.18)
Day 0: first dose/positive test * n/a * n/a * n/a 23 77.15 (47.39, 125.59)
1–28 days: first dose/positive test 83 1.21 (0.93, 1.59) 47 1.16 (0.84, 1.61) 8 3.79 (1.59, 9.04) 81 9.06 (6.51, 12.62)
−28 to −1 days: second dose 40 0.78 (0.55, 1.11) 31 1.10 (0.74, 1.64) * 3.61 (0.69, 18.95)
Day 0: second dose * n/a 0 n/a * n/a
1–28 days: second dose 60 1.26 (0.94, 1.71) 37 1.39 (0.96, 2.02) * 12.27 (2.77, 54.37)
Continued
1.00
the 1–28 days following a SARS-CoV-2 positive test.
Subgroup analyses by age showed that the increased risk of events
associated with the two mRNA vaccines was present only in those
events
6,994
5,026
3,332
2,122
aged under 40 years. For this age group, we estimated 2 (95% CI 1, 3)
66
21
15
6
1.00
n/a
n/a
n/a
n/a
n/a
Discussion
This is the largest study to date of acute cardiac outcomes after
SARS-CoV-2 vaccination or infection, the first to compare the risk of
events
463
16
19
*
*
*
*
*
*
1.00
n/a
n/a
11,038
8,004
9,699
6,670
141
115
28
24
52
37
was substantially lower than the 40 extra events per million persons
observed following SARS-CoV-2 infection.
1.00
1.00
n/a
n/a
12,568
61,748
12,143
9,784
9,387
375
85
74
41
*
Baseline
suppressed) (Continued)
Number of excess events in the 1–28 days postvaccination/SARS-CoV-2 positive test per 1 million vaccinated/infected
30
10 4 2,000
Excess events
Excess events
Excess events
Excess events
20
5 2 1,000
10
0 0 0 0
ascertainment of cardiac inflammation after COVID-19 vaccina- for myocarditis in the 10 days following the second dose of both
tion is likely to be under- rather than over-represented14,15. mRNA vaccines24 and an estimated 6.3 and 10.1 extra cases per
Although no cases of myocarditis were observed in the random- million doses in the 1- to 21-day period following the first and
ized trials of vaccine, this condition is uncommon, and postmarket second dose of both mRNA vaccines, respectively, in those younger
authorization surveillance may be required. Our observation of an than 40 years25.
increased risk within 7 days of receiving the vaccine is consistent Our findings extend these observations by including 38 million
with the presentation of viral myocarditis, where viral symptoms are adults in England receiving both mRNA and adenovirus-mediated
often reported in the week leading up to presentation. Furthermore, vaccine. There were 1,615 myocarditis events in our study popula-
myocarditis following vaccination has been reported with other tion, enabling a granular evaluation of subgroups and the tempo-
vaccines, for example, in healthy adults after receipt of live vac- ral association in the weeks following vaccination. We observed a
cinia virus vaccines16,17 Whilst the mechanisms of myocarditis fol- small excess in myocarditis events after both the first and second
lowing exposure to SARS-CoV2 infection and vaccination are not dose of vaccine, but this risk was restricted to a 7-day period fol-
known, it seems likely that systemic complications of infection are lowing vaccination. This observation was not limited to the mRNA
a consequence of an immune-mediated, virus-independent immu- vaccines as we also found an excess in myocarditis events following
nopathologic process18. However, vaccine mediated expression of the first dose of ChAdOx1 vaccine. The excess risk was observed in
SARS-CoV-2 surface spike protein on the surface of cardiomyo- men and women but was only consistently observed following both
cytes could potentially trigger an immunologic response resulting mRNA vaccines in those younger than 40 years, although this may,
in organ-specific cell death19,20 in part, reflect the small number of individuals over the age of 40
Our findings are consistent with those from a case-control study years receiving the mRNA-1273 vaccine in England.
of 884,828 persons receiving the BNT162b2 vaccine in Israel21. That Whilst myocarditis can be life-threatening, most vaccine-
study observed an association with myocarditis in the 42 days fol- associated myocarditis events have been mild and self-limiting22.
lowing vaccination (risk ratio of 3.24), but no association with peri- The risk observed here is small and confined to the 7-day period
carditis or cardiac arrhythmia. Two further studies from Israel add following vaccination, whereas the lifetime risk of morbidity and
to our observations by providing clinical review to ensure robust mortality following SARS-CoV-2 infection is substantial. Indeed,
case ascertainment22 and reporting investigations and outcomes in myocardial injury is very common in persons admitted to hospi-
individual patients with myocarditis following the BNT162b2 vac- tal with SARS-CoV-2 infection26, when evaluated systematically
cine23. Witberg et al.21,22 observed a small excess in events 3–5 days using high-sensitivity cardiac troponin tests27. Moreover, evidence
following the second dose of BNT162b2 vaccine, but most were mild of myocardial injury, irrespective of whether due to myocarditis or
presentations and just one classified as fulminant22. Mevorach et al. myocardial ischemia, is associated with a higher risk of in-hospital
observed an incidence ratio of 5.34 for myocarditis in 5,442,696 death28. We estimate that the absolute number of excess myocarditis
persons following BNT162b2, although this was attenuated when events in the 28 days following a first dose of adenovirus or mRNA
restricted to the 136 definite and probable cases of myocarditis23. vaccine is between one and six per million persons vaccinated,
Risk of myocarditis was restricted to males under the age of 40 years and the excess risk following the second dose of the mRNA-1283
and only observed following the second dose. Similarly, two studies vaccine is ten per million. By contrast, we estimate 40 excess myo-
from the United States have reported an incident rate ratio of 2.7 carditis events per million in the 28 days following SARS-CoV-2
Outcomes. The outcomes in this study are selected cardiac conditions with SCCS assumptions. Independence between outcome and exposure. We assumed
previous indications of association with SARS-CoV-2 infection or COVID-19 that patients who experienced an outcome before vaccination were likely to delay
vaccination. These included myocarditis, pericarditis and arrythmia. We used the vaccination until symptoms had improved. Therefore, we included a prerisk period
International Classification of Diseases-10 codes to define each outcome, as listed in the analyses, lasting from 1 to 28 days before vaccination, which removes this
in Supplementary Table 11. The outcomes were identified as the first hospital period from the baseline period (Extended Data Fig. 6). Hospital admissions
admission due to the event of interest, or death recorded on the death certificate for the events of interest can trigger COVID-19 testing. Such events may well
with the International Classification of Diseases-10 code related to the outcome be caused by SARS-CoV-2 infection, but the reverse causality involved in their
of interest within the study period. A histogram showing the number of admissions detection induces bias. To reduce the bias, which could over or underestimate the
in England from 1 April 2019 to 24 August 2021 is presented in Extended Data effect of infection, we decided to allocate day 0 to a risk period on its own30.
Fig. 4.
Event-dependent observation periods. We tested this assumption with sensitivity
Exposures. The exposure variables were a first or second dose of the ChAdOx1, analyses 1 and 2. These further analyses agreed with the main analysis, suggesting
BNT162b2 or mRNA-1273 vaccines, or SARS-CoV-2 infection, defined as the first that there should be little concern for these outcomes.
SARS-CoV-2 positive test in the study period. All exposures were included in the
same model. We defined the exposure risk intervals as the following prespecified Negative and positive control outcomes. We examined the association of
time periods: 0, 1–7, 8–14, 15–21 and 22–28 days after each exposure date, under exposures with celiac disease as a negative control outcome31, which is assumed not
the assumption that the adverse events under consideration are unlikely to be to be associated with exposure to vaccination or SARS-CoV-2 infection; and with
related to exposure later than 28 days postexposure. We assumed that the risks anaphylaxis as a positive control outcome given that it could occur shortly after
may be different after each vaccine dose (first and second), and hence we allowed vaccination with either vaccine32.
for a dose effect, by defining a separate risk interval after each dose: 0, 1–7, 8–14,
15–21 or 22–28 days after the first dose and 0, 1–7, 8–14, 15–21 or 22–28 days Reporting Summary. Further information on research design is available in the
after the second dose. To avoid overlapping risk periods, we assumed that later Nature Research Reporting Summary linked to this article.
exposures (second dose) take precedence over earlier ones (first dose), except for
the 28-day prerisk period for the second dose, as shown in Extended Data Fig. 5. Data availability
A prerisk interval of 1–28 days before each exposure date was included to account The data that support the findings of this study—NIMS Database of COVID-19,
for potential bias that might arise if the occurrence of the outcome temporarily mortality (Office of National Statistics), hospital admissions (Hospital Episode
influenced the likelihood of exposure. The baseline period for the vaccination Statistics) and SARS-CoV-2 infection data (PHE)—are not publicly available
exposures comprised the remaining time from 1 December 2020 until 29 days because they are based on deidentified national clinical records. Due to national
before the first dose date and from 29 days after the first dose until 29 days before and organizational data privacy regulations, individual-level data such as those
the second dose (if applicable), and from 29 days after the second dose until 24 used for this study cannot be shared openly.
August 2021 or the censored date if earlier. A SARS-CoV-2 positive test was
considered as a separate exposure in the models, which allowed overlapping risk
windows with vaccination exposure. Code availability
The code used for this study has been deposited in the git repository of the research
Seasonality and COVID-19 pandemic period. Hospital admissions were likely group, which is protected by privacy. Access to the code is available from the
influenced by the pressure on the health systems due to COVID-19, which was authors on request for noncommercial, academic and research use only.
not uniform during the pandemic period. To allow for these underlying seasonal
effects, we split the study observation period into weeks and adjusted for week as a
factor variable in the statistical models. References
29. Wilson, K. & Hawken, S. Drug safety studies and measures of effect using
Statistical analysis. We described characteristics of each cohort (vaccinated the self-controlled case series design. Pharmacoepidemiol. Drug Saf. 22,
patients with the outcomes of interest) in terms of age, sex and ethnic group. The 108–110 (2013).
SCCS models were fitted using a conditional Poisson regression model with an 30. Fonseca-Rodríguez, O. et al. Avoiding bias in self-controlled case series
offset for the length of the exposure risk period. Separate analyses were carried out studies of coronavirus disease 2019. Stat Med. 40, 6197–6208 (2021).
for each cardiac outcome of interest. IRR, the relative rate of hospital admissions or 31. Lipsitch et al. Negative controls: a tool for detecting confounding and bias in
deaths due to each outcome of interest in exposure risk periods relative to baseline observational studies. Epidemiology 21, 383–388 (2010).
periods, and their 95% CI were estimated by the SCCS model adjusted for week 32. Kounis, N. G. Allergic reactions to current available COVID-19 vaccinations:
as a time-varying covariate. Exposure terms for vaccines and for a SARS-CoV-2 pathophysiology, causality, and therapeutic considerations. Vaccines (Basel) 9,
positive test were included in the same model. 221 (2021).
Acknowledgements L.H., K.M.C., F.Z., X.W.M., N.L.M., K.K., M.S.-H., P.W., A.H., S.D. and A.S. contributed
This project involves data derived from patient-level information collected by the to the discussion on protocol development and provided critical feedback on drafts of the
National Health Service (NHS), as part of the care and support of cancer patients. The manuscript. All authors approved the protocol, contributed to the critical revision of the
SARS-Cov-2 test data are collated, maintained and quality assured by Public Health manuscript and approved the final version of the manuscript.
England (PHE). Access to the data was facilitated by the PHE Office for Data Release.
The Hospital Episode Statistics, Secondary Users Service (SUS-PLUS) datasets and civil Competing interests
registration data are used by permission from NHS Digital who retain the copyright for A.S. is a member of the Scottish Government Chief Medical Officer’s COVID-19
that data. NHS Digital and PHE bear no responsibility for the analysis or interpretation Advisory Group, the Scottish Government’s Standing Committee on Pandemics
of the data. K.K. is supported by the National Institute for Health Research (NIHR) and AstraZeneca’s Thrombotic Thrombocytopenic Advisory Group. All roles are
Applied Research Collaboration East Midlands (ARC-EM) and NIHR Lifestyle BRC. unremunerated. J.H.-C. reports grants from NIHR Biomedical Research Centre, Oxford,
M.S.-H. is supported by the National Institute for Health Research Clinician Scientist John Fell Oxford University Press Research Fund and Cancer Research United Kingdom
Award (NIHR-CS-2016-16-011). J.H.-C. and K.M.C. are supported by the NIHR (CR-UK) grant no. C5255/A18085, through the CR-UK Oxford Centre, and grants
Oxford Biomedical Research Centre. N.L.M. and K.M.C. are supported by the British from the Oxford Wellcome Institutional Strategic Support Fund (204826/Z/16/Z) and
Heart Foundation (Chair Awards CH/F/21/90010, CH/16/1/32013), Programme Grant other research councils during the conduct of the study. J.H.-C. is an unpaid director of
(RG/20/10/34966) and Research Excellence Awards (RE/18/5/34216, RE18/3/34214). QResearch, a not-for-profit organization that is a partnership between the University
A.S. is supported by the Health Data Research United Kingdom BREATHE Hub. This of Oxford and EMIS Health who supplied the QResearch database used for this work.
research is part of the Data and Connectivity National Core Study, led by Health Data J.H.-C. is a founder and shareholder of ClinRisk Ltd and was its medical director until 31
Research United Kingdom in partnership with the office of National Statistics and funded May 2019. ClinRisk Ltd produces open and closed source software to implement clinical
by United Kingdom Research and Innovation (grant MC_PC_20029). The investigators risk algorithms (outside this work) into clinical computer systems. J.H.-C. is chair of
acknowledge the philanthropic support of the donors to the University of Oxford’s the NERVTAG risk stratification subgroup and a member of Scientific Advisory Group
COVID-19 Research Response Fund. The views expressed in this publication are those for Emergencies COVID-19 groups and the NHS group advising on prioritization of
of the author(s) and not necessarily those of the NHS, the United Kingdom NIHR or the use of monoclonal antibodies in SARS-CoV-2 infection. A.H. is a member of the Joint
Department of Health. The funders of this study had no role in the design and conduct Committee on Vaccination and Immunisation. K.K. is a member of the Governments
of the study and did not review or approve the manuscript. The views expressed are those Scientific Advisory Group for Emergencies. All other authors declare no competing
of the authors and not necessarily the funders. M.P., J.H.-C. and C.A.C.C. had full access interests related to this paper.
to all the study data and J.H.-C. had final responsibility for submission. This project is
supported by a patient and public involvement advisory panel, which we thank for its
continued support and guidance. The input of the panel has helped us identify priority Additional information
questions for consideration and also supported analysis. Patient and Public Involvement Extended data is available for this paper at https://doi.org/10.1038/s41591-021-01630-0.
and Engagement advisers were supportive of the vital importance of reporting on cardiac
Supplementary information The online version contains supplementary material
risks associated with both vaccination against COVID-19 and COVID-19 itself.
available at https://doi.org/10.1038/s41591-021-01630-0.
Correspondence and requests for materials should be addressed to Julia Hippisley-Cox.
Author contributions
M.P., J.H.-C. and C.A.C.C. led the study conceptualization, development of the research Peer review information Nature Medicine thanks Karina Top, Leslie T. Cooper and the
question and analysis plan. J.H.-C. obtained funding, designed the analysis, obtained other, anonymous, reviewer(s) for their contribution to the peer review of this work.
data approvals and contributed to interpretation of the analysis. M.P. undertook the Jennifer Sargent was the primary editor on this article and managed its editorial process
data specification, curation, analysis. M.P. and N.L.M. wrote the first draft of the paper. and peer review in collaboration with the rest of the editorial team.
S.D. undertook and reported on the Patient and Public Involvement and Engagement. Reprints and permissions information is available at www.nature.com/reprints.
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Number admissions
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Number admissions
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Jul20
Jul21
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Oct20
Oct21
Apr19
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Apr21
Cardiac arrhythmia
Extended Data Fig. 4 | Number of admissions to hospital for single outcomes by month between April 2019 and August 2021. Number of admissions to
hospital for single outcomes by month between April 2019 and August 2021.
Extended Data Fig. 5 | Schematic presentation of the SCCS study design. Extended Data Fig. 5: Schematic presentation of the SCCS study design.
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the 28 prior to vaccination and yellow area shows the 28 days postvaccination.
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Extended Data Fig. 6 | Number of hospital admissions or deaths for each outcome prior and post each vaccine dose by vaccine type. Pink area shows
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