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https://doi.org/10.1038/s41591-021-01630-0
1Nuffield 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.
11BHF/University Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK. ✉e-mail: julia.hippisley-cox@phc.ox.ac.uk
By the end of September 2021, more than 6.3 billion doses of
COVID-19 vaccination had been administered worldwide1.
Clinical trials of COVID-19 vaccines were underpowered
to detect the rare adverse events that are important for risk–ben-
efit evaluations and to inform clinical practice postvaccination.
Therefore, identifying such rare adverse events is now a global sci-
entific priority.
As of 4 November 2021, there have been 1,783 reports to the
United States Vaccine Adverse Event Reporting System (VAERS)
of cases of heart inflammation, namely myocarditis or pericarditis,
among people aged 12–29 years who received COVID-19 vaccines,
in particular following mRNA vaccination, that is, BNT162b2 and
mRNA-1273 vaccines2. As of 9 July 2021, the European Medicines
Agency (EMA) has reported 145 cases of myocarditis and 138 cases
of pericarditis out of 177 million doses of the BNT162b2 vaccine, and
9 cases of myocarditis and 19 cases of pericarditis out of 20 million
doses of the mRNA-1273 vaccine3. In Israel, 275 cases of myocarditis
were reported between December 2020 and May 2021 among more
than 5 million people vaccinated with the BNT162b2 vaccine4. No
association between ChAdOx1 vaccine and myocarditis or pericar-
ditis has been reported. The same reports showed that these events
are more likely to occur in adolescent and young adults, mostly after
the second dose. Evaluation of the risks of adverse events following
vaccination or SARS-CoV-2 infection in different age groups pro-
vides crucial information to determine whether the risks from the
vaccine outweighs the risks following a positive SARS-CoV-2 test.
In England, the vaccination campaign began on 8 December
2020 with the BNT162b2 vaccine followed by the ChAdOx1 vaccine
on 4 January 2021. In the first phase, priority was given to the most
vulnerable, in a schedule based primarily on age. The mRNA-1273
vaccine became available in England on 13 April 2021. Since 7 April
2021, ChAdOx1 vaccine has not been recommended for individuals
younger than 30 years of age, and since 7 May 2021 for individuals
younger than 40 years of age.
The English National Immunisation (NIMS) Database of
COVID-19 vaccination includes data on vaccine type, date and
Risks of myocarditis, pericarditis, and cardiac
arrhythmias associated with COVID-19
vaccination or SARS-CoV-2 infection
Martina Patone1, Xue W. Mei 1, Lahiru Handunnetthi 2, Sharon Dixon1, Francesco Zaccardi3,
Manu Shankar-Hari 4,5,6, Peter Watkinson 7,8, Kamlesh Khunti3, Anthony Harnden1,
Carol A. C. Coupland 1,9, Keith M. Channon10, Nicholas L. Mills 4,11, Aziz Sheikh 4 and
Julia Hippisley-Cox 1 ✉
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.
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doses for all people vaccinated in England. We linked NIMS, at
individual patient level, to national data for mortality, hospital
admissions and SARS-CoV-2 infection data to examine the associa-
tions between the first and second dose of ChAdOx1, BNT162b2
or mRNA-1273 vaccines and cardiac adverse events: myocarditis,
pericarditis or cardiac arrhythmias. We used the same population
to investigate the associations between a positive SARS-CoV-2 test
(before or after vaccination) as a secondary exposure and the same
cardiac adverse events. We also assessed risks for the same outcomes
following vaccination or a SARS-CoV-2 positive test in younger
persons (<40 years old). Incidence rate ratios, the rate of hospital
admission or death from each outcome in risk periods after vacci-
nation or a positive test relative to baseline periods, were estimated
using self-controlled case series (SCCS) methodology5,6.
Results
A total of 38,615,491 adults had been vaccinated with at least one
dose of ChAdOx1 (n = 20,615,911), BNT162b2 (n = 16,993,389) or
mRNA-1273 (n = 1,006,191) in England between 1 December 2020
and 24 August 2021 (Table 1). Of these, 32,095,748 had received
two doses of either ChAdOx1 (n = 19,754,224, 95.8%), BNT162b2
(n = 11,972,733, 70.5%) or mRNA-1273 (n = 368,791, 36.7%).
Individuals receiving the ChAdOx1 and BNT162b2 vaccine were
older, on average, than those receiving the mRNA-1273 vaccine,
as expected given that the mRNA-1273 vaccine roll-out began in
April 2021 in the United Kingdom, when higher priority risk groups
(including older people) had already received their vaccine.
Amongst those with at least one dose, there were 3,028,867
(7.8%) individuals who had a SARS-CoV-2 positive test. Of these,
2,315,669 (6.0%) individuals tested positive before vaccination;
while 713,198 (1.8%) and 298,315 (0.7%) tested positive after the
first and second vaccine doses, respectively. Table 1 shows the char-
acteristics of the study population, stratified by vaccine type and
dose, and of those who tested positive for SARS-CoV-2.
During the study period there were 1,615 and 1,574 admissions
or deaths related to myocarditis and pericarditis, respectively (14
patients had both), and 385,508 related to cardiac arrhythmias.
The characteristics of individuals with myocarditis, pericarditis
and cardiac arrhythmias in the 1–28 days postvaccination differed
by condition and according to the vaccine administered (Table 2).
Supplementary Table 1 shows the characteristics of patients who
died for the individual outcomes in the 1–28 days following a first or
second dose of COVID-19 vaccine or SARS-CoV-2 infection. Table
3 and Fig. 1 show the number of patients with outcome events in
each exposure time period and the incidence rate ratios (IRRs) and
95% CIs for outcomes in the exposure risk periods.
Myocarditis. Of the 38,615,491 vaccinated individuals included in
our study, 1,615 (0.004%) were admitted to hospital with, or died
from, myocarditis at any time in the study period (either before or
after vaccination); 397 (0.001%) of these occurred in the 1-28 days
post any dose of vaccine. Of the 1,615 who were admitted or died,
359 (22.2%) had a SARS-CoV-2 positive test, with 287 (17.8%) of
these being before vaccination. There were 114 deaths with myo-
carditis recorded on the death certificate as a cause of death (23
had a SARS-CoV-2 positive test). Of those who have been admitted
with, or died from, myocarditis in the 1-28 days postvaccination,
12.7% (18) and 10.7% (9) had a positive SARS-CoV-2 test before
the first and second dose ChAdOx1 vaccine, respectively, and 7.4%
(7) before the first dose of BNT162b2 vaccine (Table 2).
There was an increased risk of myocarditis at 1–7 days following
the first dose of ChAdOx1 (IRR 1.76; 95% CI 1.29, 2.42), BNT162b2
(IRR 1.45, 95% CI 0.97, 2.12) and mRNA-1273 (IRR 8.38, 95% CI
3.53, 19.91), and the second dose of BNT162b2 (IRR 1.75, 95% CI
1.13, 2.70) and mRNA-1273 (IRR 23.10, 95% CI 6.46, 82.56). There
was an increased risk of myocarditis at 1–7 days (IRR 21.08, 95% CI
15.34, 28.96), 8–14 days (IRR 11.29, 95% CI 7.70, 16.57), 15–21 days
(IRR 5.36, 95% CI 3.24, 8.89) and 21–28 days (IRR 3.08, 95%CI 1.65,
5.75) following a positive test.
Over the 1–28 days postvaccination, we observed an associa-
tion with the first dose of ChAdOx1 (IRR 1.29, 95% CI 1.05, 1.58),
BNT162b2 (IRR 1.31, 95% CI 1.03, 1.66) and mRNA-1273 (IRR
2.97; 95% CI 1.34, 6.58). Following a second dose, the increased
risk was much higher with mRNA-1273 (IRR 9.84, 95% CI 2.69,
36.03) compared with BNT162b2 (IRR 1.30, 95% CI 0.98, 1.72).
The risk of myocarditis was increased in the 1–28 days following a
SARS-CoV-2 positive test (IRR 9.76, 95% CI 7.51, 12.69).
Pericarditis. Of the 38,615,491 vaccinated individuals included in
our study, 1,574 (0.004%) were admitted to hospital with, or died
from, pericarditis at any time in the study period (either before or
after vaccination); 356 (0.001%) of these occurred in the 1-28 days
after any dose of vaccine. Of the 1,574 who were admitted or died,
188 (11.9%) had a SARS-CoV-2 positive test, with 154 (9.8%) of
these being before vaccination. There were 31 deaths with peri-
carditis recorded on the death certificate as cause of death (6 had
a SARS-CoV-2 positive test). Table 2 shows the percentages of
patients with pericarditis events in the risk period who had a posi-
tive SARS-CoV-2 test before vaccination by vaccine type and dose.
There were reduced risks of pericarditis after a first dose of
ChAdOx1 (IRR 0.59; 95% CI 0.37, 0.94 at 1–7 days, IRR 0.64; 95% CI
0.42, 0.99 at 15–21 days), of BNT162b2 (IRR 0.46; 95% CI 0.24, 0.90
at 8–14 days) and following a second dose of ChAdOx1 (IRR 0.49;
95% CI: 0.29, 0.82 at 22–28 days). There were insufficient numbers
of events to evaluate associations with the mRNA-1273 vaccine by
week. There was an increased risk of hospital admission or death for
pericarditis at 1–7 days (IRR 4.85, 95% CI 2.56, 9.18) and 8–14 days
(IRR 3.81, 95% CI 1.90, 7.63) following a SARS-CoV-2 positive test.
Over the 1–28 days postvaccination, we observed a decreased
risk of pericarditis following the first dose of ChAdOx1 (IRR 0.74,
95%CI 0.59, 0.92), in contrast with an increased risk in the 1–28 days
following a SARS-CoV-2 positive test (IRR 2.79, 95% CI 1.80, 4.32).
No association was observed with the BNT162b2 or mRNA-1273
vaccine.
Cardiac arrhythmia. Of the 38,615,491 vaccinated individuals
included in our study, 385,508 (1.0%) were admitted to hospital
with or died from cardiac arrhythmia at any time in the study period
(either before or after vaccination); 86,754 (0.2%) of these occurred
in the 1-28 days after any dose of vaccine. Of those who were admit-
ted or died 39,897 (10.3%) had a SARS-CoV-2 positive test, with
29,694 (7.7%) having a positive test before vaccination. There were
7,795 deaths with cardiac arrhythmia recorded as the cause of death
(1,108 had a SARS-CoV-2 positive test). Table 2 shows the percent-
ages of patients with cardiac arrhythmia events in the risk period
who had a positive SARS-CoV-2 test before vaccination by vaccine
type and dose.
There were decreased risks of cardiac arrhythmia after the first
dose of ChAdOx1 (IRR 0.95, 95% CI 0.92, 0.97 at 1–7 days and over
subsequent periods) and BNT162b2 (IRR 0.79, 95% CI 0.76, 0.81 at
1–7 days and over subsequent periods) and following a second dose
of ChAdOx1 (IRR 0.84, 95% CI 0.82, 0.87 at 1–7 days; IRR 0.97, 95%
CI 0.94, 0.99 at 8–14 days) and of BNT162b2 (IRR 0.85, 95% CI 0.83,
0.88 at 1–7 days; IRR 0.95, 95% CI 0.92, 0.98 at 8–15 days). There
was an increased risk of cardiac arrhythmia following a second
dose of mRNA-1273 (IRR 1.93, 95% CI 1.25, 2.96 at 1–7 days) and
at 1–7 days (IRR 11.73, 95% CI 11.33, 12.14), 8–14 days (IRR 6.57,
95%CI 6.30, 6.85), 15–21 days (IRR 2.30, 95% CI 2.15, 2.45) and
21–28 days (IRR 1.67, 95% CI 1.55, 1.80) following a SARS-CoV-2
positive test.
Over the 1–28 days post vaccination, we found a decreased
risk of cardiac arrhythmia associated with a first dose of ChAdOx1
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Table 1 | Baseline demographic characteristics of people receiving either ChAdOx1, BNT162b2 or mRNA-1273 vaccines or testing positive for SARS-CoV-2 virus (before or after
vaccination), in England between 1 December 2020 and 24 August 2021. Data are presented as column % (counts)
ChAdOx1 BNT162b2 mRNA-1273 ChAdOx1 BNT162b2 mRNA-1273 Positive SARS-CoV-2 test
(amongst total vaccinated)
One dose (at least) (n=38,615,491) Two doses (n=32,095,748)
Total number of people 20,615,911 16,993,389 1,006,191 19,754,224 11,972,733 368,791 3,028,867
Sex
Women 43.3 (8,918,403) 42.6 (7,233,091) 29.9 (300,567) 43.3 (8,559,325) 47.2 (5,650,542) 33.9 (125,120) 45.7 (1,385,137)
Men 34.9 (7,191,428) 31.8 (5,401,842) 28.5 (286,893) 34.9 (6,900,964) 32.6 (3,906,666) 26.4 (97,524) 32.2 (974,389)
Not recorded 21.9 (4,506,080) 25.6 (4,358,456) 41.6 (418,731) 21.7 (4,293,935) 20.2 (2,415,525) 39.6 (146,147) 22.1 (669,341)
Age
Mean age (s.d.) 55.2 (14.8) 47.8 (21.7) 32.3 (9.4) 55.4 (14.7) 55.5 (20.4) 39.6 (7.3) 44.5 (17.8)
16–29 years 5.2 (1,064,443) 25.2 (4,285,600) 41.4 (416,982) 5.0 (988,291) 10.4 (1,244,710) 6.9 (25,382) 24.4 (738,170)
30–39 years 7.8 (1,598,406) 23.2 (3,945,405) 36.4 (366,327) 7.6 (1,494,285) 20.7 (2,475,091) 43.8 (161,412) 19.0 (574,710)
40+ years 87.1 (17,953,062) 51.6 (8,762,384) 21.2 (222,882) 87.4 (17,271,648) 68.9 (8,252,932) 49.3 (181,997) 56.6 (1,715,987)
Ethnicity
White 55.5 (11,449,387) 52.3 (8,887,419) 40.1 (403,362) 55.8 (11,019,453) 57.8 (6,921,753) 43.0 (158,719) 52.6 (1,593,727)
Indian 1.5 (319,328) 1.7 (288,641) 0.7 (7,406) 1.5 (304,100) 1.8 (217,910) 0.8 (2,975) 2.4 (72,852)
Pakistani 1.0 (214,193) 1.1 (183,917) 0.7 (6,724) 1.0 (191,755) 0.9 (105,414) 0.4 (1,474) 2.1 (64,153)
Bangladeshi 0.4 (81,004) 0.4 (62,128) 0.3 (3,287) 0.4 (74,743) 0.3 (34,927) 0.2 (684) 0.7 (21,585)
Other Asian 0.7 (137,542) 0.8 (134,649) 0.7 (6,648) 0.7 (129,169) 0.8 (90,508) 0.7 (2,488) 1.1 (31,933)
Black Caribbean 0.5 (99,666) 0.4 (62,101) 0.3 (2,734) 0.5 (91,098) 0.4 (47,767) 0.2 (664) 0.5 (14,152)
Black African 0.7 (149,358) 0.7 (115,282) 0.6 (5,929) 0.7 (134,635) 0.6 (73,472) 0.5 (1,679) 0.9 (27,757)
Chinese 0.3 (53,279) 0.3 (43,014) 0.3 (3,261) 0.3 (51,338) 0.3 (30,662) 0.5 (1,691) 0.2 (4,585)
Other ethnic group 1.8 (366,361) 1.9 (321,150) 1.9 (19,313) 1.7 (342,040) 1.7 (208,462) 1.8 (6,795) 2.3 (69,725)
Ethnicity not recorded 37.6 (7,745,793) 40.6 (6,895,088) 54.4 (547,527) 37.5 (7,415,893) 35.4 (4,241,858) 52.0 (191,622) 37.3 (1,128,398)
Number of doses
One dose only 4.1 (835,832) 29.5 (5,007,083) 63.3 (637,335) – – – 25.1 (759,352)
Cardiac inflammation in the previous 2yearsa
Previous myocarditis <0.1 (1,840) <0.1 (1,485) <0.1 (56) <0.1 (1,747) <0.1 (1,220) <0.1 (15) <0.1 (451)
Previous pericarditis <0.1 (1,849) <0.1 (1,508) <0.1 (31) <0.1 (1,771) <0.1 (1,285) <0.1 (8) <0.1 (346)
Previous cardiac arrhythmia 2.6 (538,564) 2.9 (500,295) 0.3 (2,969) 2.6 (505,794) 3.9 (466,724) 0.3 (1,005) 3.1 (92,985)
aTwo years before 1 December 2020
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Table 2 | Demographic characteristics of patients who experienced the individual outcomes in the 1–28days following a first or second dose of COVID-19 vaccine or SARS-CoV-2
infection amongst the vaccinated population in England from 1 December 2020 to 24 August 2021 (cells with an asterisk are suppressed)
Myocarditis Pericarditis
1–28 days post first dose 1–28 days post second dose 1–28 days
post test 1–28 days post first dose 1–28 days post second dose 1-28 days
post test
ChAdOx1n
CoV-19
vaccine
BNT162b2
mRNA
vaccine
mRNA-1273 ChAdOx1n
CoV-19
vaccine
BNT162b2
mRNA
vaccine
mRNA-1273 Positive
SARS-CoV-2
test
ChAdOx1n
CoV-19
vaccine
BNT162b2
mRNA
vaccine
mRNA-1273 ChAdOx1n
CoV-19
vaccine
BNT162b2
mRNA
vaccine
mRNA-
1273 Positive
SARS-CoV-2
test
Total number of people 142 94 9 84 64 * 134 102 59 * 117 75 027
Sex
Women 40.8 (58) 50.0 (47) * 27.4 (23) 42.2 (27) * 39.6 (53) 26.5 (27) 37.3 (22) 0 27.4 (32) 30.7 (23) 0 44.4 (12)
Men 58.5 (83) 50.0 (47) * 71.4 (60) 57.8 (37) * 60.4 (81) 72.5 (74) 62.7 (37) * 72.6 (85) 69.3 (52) 0 55.6 (15)
Not recorded 0.7 (1) 0 0 1.2 (1) 0 0 0 1.0 (1) 0 0 0 0 0 0
Age
Mean age (s.d.) 58.1 (18.2) 55.2 (22.0) 26.0 (9.9) 54.8 (18.3) 61.0 (22.8) 32.5 (10.7) 62.2 (17.0) 57.4 (13.8) 56.7 (20.1) 28.0 (5.3) 57.7 (16.6) 63.2 (18.7) - 54.7 (14.5)
16–29 years 6.3 (9) 11.7 (11) 66.7 (6) 11.9 (10) 12.5 (8) * 5.2 (7) * 10.2 (6) * 7.7 (9) * 0 *
29–39 years 8.5 (12) 23.4 (22) * 13.1 (11) 15.6 (10) * 7.5 (10) * 16.9 (10) * 6.8 (8) * 0 *
40+ years 85.2 (121) 64.9 (61) * 75.0 (63) 71.9 (46) * 87.3 (117) 93.1 (95) 72.9 (43) 0 85.5 (100) 86.7 (65) 0 88.9 (24)
Number of doses
First dose only 44.4 (63) 52.1 (49) 100.0 (9) – – – 19.4 (26) 17.6 (18) 32.2 (19) * – – – 22.2 (6)
SARS-CoV-2
Positive SARS-CoV-2 test
before vaccine
12.7 (18) 7.4 (7) * 10.7 (9) * 0 79.1 (106) 10.8 (11) 11.9 (7) 0 9.4 (11) * 0 70.4 (19)
Arrythmia
Sex
Total number of
people
24,225 18,359 156 23,019 20,947 48 8,940
Women 48.1 (11,651) 47.2 (8,655) 50.0 (78) 47.2 (10,872) 47.3 (9,907) 60.4 (29) 43.8 (3,913)
Men 51.9 (12,568) 52.8 (9,699) 50.0 (78) 52.8 (12,143) 52.7 (11,038) 39.6 (19) 56.2 (5,026)
Not recorded <0.1 (6) <0.0 (5) 0 <0.1 (4) <0.1 (2) 0 <0.1 (1)
Age
Mean age (s.d.) 70.1 (16.2) 72.9 (18.1) 35.0 (11.4) 70.1 (15.3) 76.0 (14.5) 43.4 (9.5) 65.7 (18.0)
18–29 years 2.1 (498) 4.4 (810) 35.9 (56) 1.8 (416) 1.5 (315) * 3.7 (333)
29–39 years 2.8 (674) 4.5 (829) 33.63 (52) 2.5 (574) 2.3 (487) 33.3 (16) 6.0 (535)
40+ years 95.2 (23,053) 91.1 (16,720) 30.8 (48) 95.7 (22,029) 96.2 (20,145) 62.5 (30) 90.3 (8,072)
Number of doses
First dose only 18.5 (4,475) 20.6 (3,792) 60.3 (94) – – – 17.0 (1,519)
SARS-CoV-2
Positive
SARS-CoV-2 test
before vaccine
6.6 (1,559) 3.8 (694) 9.0 (14) 5.5 (1,269) 2.8 (580) 0 75.6 (6,761)
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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
Baseline 550 409.0 1.00 398 3 07. 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 1 7.7 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 92.9 3.81 (1.90, 7.63)
15–21 days: first dose/positive test 23 1 7.6 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)
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(IRR 0.94, 95% CI 0.93, 0.96) and BNT162b2 (IRR 0.89, 95% CI
0.87, 0.90) and following a second dose of ChAdOx1 (IRR 0.95, 95%
CI 0.94, 0.96) and BNT162b2 (IRR 0.95, 95% CI 0.93, 0.96). There
was an increased risk of cardiac arrhythmia following a second dose
of mRNA-1273 (IRR 1.46, 95% CI, 1.08, 1.98) and a SARS-CoV-2
positive test (IRR 5.35, 95% CI 5.21, 5.50).
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
after each exposure by sex and in those aged under 40 years or
40 years and older. Supplementary Tables 2 and 3a show the IRRs
estimated for each week in the 1–28 days following exposure in
these subgroups. Whilst the findings generally mirrored those
reported in the overall 1–28 day period in each subgroup, given the
small numbers of events in some weeks, care is needed in the inter-
pretation. Here, we report the results of the subgroup analyses only
for myocarditis.
In those aged under 40 years, we observed increased risks of
myocarditis in the 1–28 days following a first dose of BNT162b2
(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
1.91, 6.04) and of mRNA-1273 (IRR 20.71, 95% CI 4.02, 106.68) and
following a SARS-CoV-2 positive test (IRR 4.06, 95%CI 2.21, 7.45).
No association was found with the ChAdOx1 vaccine. In those
aged 40 years or older, the risk of myocarditis was increased in the
1–28 days following a first dose of ChAdOx1 (IRR 1.33, 95% CI
1.06, 1.67) and a SARS-CoV-2 positive test (IRR 12.18, 95% CI 9.01,
16.46). No association was found with the BNT162b2 vaccine and
numbers of events were insufficient to evaluate associations with
the mRNA-1273 vaccine.
In women, we found an increased risk of myocarditis 1–28 days
following a first dose of ChAdOx1 (IRR 1.40, 95% CI 1.01, 1.93)
and BNT162b2 (IRR 1.54, 95% CI 1.08, 2.20), and following a
SARS-CoV-2 positive test (IRR 11.00, 95% CI 7.12, 16.99). There
were insufficient numbers of events to evaluate associations with
the mRNA-1273 vaccine for women. In men, we found an increased
risk of myocarditis at 1–28 days following a first and second dose
of mRNA-1273 (IRR 3.79, 95% CI 1.59, 9.04 and IRR 12.27, 95%CI
2.77, 54.37, respectively) and following a SARS-CoV-2 positive test
(IRR 9.06, 95% CI 6.51, 12.62). No association was found with the
ChAdOx1 or BNT162b2 vaccines.
Supplementary Table 3b shows the IRRs of these outcomes esti-
mated in the 1–28 days following exposure when restricting to dif-
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).
Subgroup analyses by previous SARS-CoV-2 infection. Supple-
mentary Table 4 shows the estimated IRRs for myocarditis, peri-
carditis or cardiac arrhythmias in the 1–28 day risk period after
each vaccination in those who did not have a SARS-CoV-2 posi-
tive test before vaccination. These results generally agreed with the
main analyses. We did not observe any increased risk of myocar-
ditis, pericarditis or arrhythmia following a first or second dose of
ChAdOx1 or BNT162b2 vaccine in those who tested positive before
vaccination, but there was a decreased risk of cardiac arrythmias
following a first dose of either vaccine (Supplementary Table 5).
There were insufficient numbers of events to evaluate associations
with the mRNA-1273 vaccine in this subgroup.
Subgroup analyses by categories of cardiac arrhythmia. Cardiac
arrhythmias (n = 385,508) were categorized as atrial fibrillation or
flutter (n = 229,248, 59.4%), atrio-ventricular (AV) block and related
conduction disorders (n = 114,701, 29.7%), ventricular tachycar-
dia (n = 8,211, 2.1%), ventricular fibrillation (n = 2,910, 0.7%) and
other, including supraventricular tachycardia (n = 130,485, 33.8%).
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)
Day 0: first dose/positive test 289 553.9 0.33 (0.30, 0.38) 232 497.0 0.33 (0.29, 0.37) 9 4.5 1.32 (0.69, 2.54) 3,847 86.7 69.83 (67.32, 72.43)
1–7 days: first dose/positive test 5,873 3,872.1 0.95 (0.92, 0.97) 3,958 3,471.4 0.79 (0.76, 0.81) 38 31.6 0.80 (0.58, 1.11) 4,593 613.3 11.73 (11.33, 12.14)
8–14 days: first dose/positive test 5,981 3,867.0 0.93 (0.90, 0.95) 4,837 3,458.9 0.92 (0.89, 0.95) 40 31.4 0.88 (0.64, 1.21) 2,643 624.7 6.57 (6.30, 6.85)
15–21 days: first dose/positive test 6,243 3,863.0 0.95 (0.92, 0.97) 4,971 3,404.5 0.92 (0.90, 0.95) 43 32.1 1.02 (0.75, 1.38) 966 638.8 2.30 (2.15, 2.45)
22–28 days: first dose/positive test 6,128 3,857.0 0.92 (0.89, 0.94) 4,593 3,150.5 0.89 (0.86, 0.91) 35 29.1 0.90 (0.64, 1.26) 738 653.8 1.67 (1.55, 1.80)
−28 to −1 days: second dose 18,595 13,728.4 0.75 (0.74, 0.77) 15,010 10,907.1 0.75 (0.74, 0.77) 38 43.2 0.66 (0.47, 0.92)
Day 0: second dose 265 502.4 0.30 (0.26, 0.33) 257 444.6 0.32 (0.29, 0.37) * * n/a
1–7 days: second dose 5,236 3,517.4 0.84 (0.82, 0.87) 4,737 3,112.3 0.85 (0.83, 0.88) 22 11.2 1.93 (1.25, 2.96)
8–14 days: second dose 5,931 3,517.4 0.97 (0.94, 0.99) 5,288 3,112.3 0.95 (0.92, 0.98) 13 11.2 1.39 (0.80, 2.42)
15–21 days: second dose 6,019 3,517.4 1.00 (0.97, 1.03) 5,495 3,112.3 0.99 (0.96, 1.02) 6 11.2 0.84 (0.37, 1.89)
22–28 days: second dose 5,833 3,510.8 0.99 (0.97, 1.02) 5,427 3,098.4 0.99 (0.96, 1.02) 7 9.8 1.43 (0.67, 3.03)
1–28 days: first dose/positive test 24,225 15,459.0 0.94 (0.93, 0.96) 18,359 13,485.4 0.89 (0.87, 0.90) 156 124.1 0.90 (0.76, 1.06) 8,940 2,530.5 5.35 (5.21, 5.50)
1–28 days: second dose 23,019 14,063.1 0.95 (0.94, 0.96) 20,947 12,435.3 0.95 (0.93, 0.96) 48 43.4 1.46 (1.08, 1.98)
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 (Continued)
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Over the 1–28 days postexposure, we observed an increased risk
of atrial fibrillation or flutter arrhythmia at 15–21 days following
a first dose of mRNA-1273 vaccine (IRR 2.06, 95% CI 1.11, 3.82);
of ventricular fibrillation at 22–28 days following a second dose of
ChAdOx1 vaccine (IRR 1.35, 95% CI 1.05, 1.74) and of other car-
diac arrhythmia at 1–7 days following a second dose of mRNA-1273
vaccine (IRR 2.32, 95% CI 1.49, 3.62). There was an increased risk
of all cardiac arrhythmia subgroups in the 1–28 days following a
SARS-CoV-2 positive test (Supplementary Table 6).
Robustness of results. We found no increased risk of celiac disease
(negative control) across the prespecified time periods for the
vaccine exposures, with the exception of the 15–21 days after the
second dose of ChAdOx1 (IRR 1.20; 95% CI: 1.05, 1.36). We also
found a decreased risk on the day of vaccination, as expected given
the healthy vaccinee effect. Anaphylaxis (positive control) showed
the expected increased risk on the day of vaccination (both first
and second dose), but not at later periods following the ChAdOx1
and BNT162b2 vaccinations (Supplementary Table 7). There were
insufficient numbers of events to evaluate associations between ana-
phylaxis and the mRNA-1273 vaccine. See Methods for clarification
of the choice of controls outcomes.
Supplementary Table 8a and Extended Data Figs. 1–3 show the
results for several sensitivity analyses. Overall, our main findings
were not sensitive to censoring due to death, and IRRs for the sec-
ond dose of vaccination agree with main results when we removed
those who had the outcome after the first dose of any vaccine, but
before the second.
As expected, sensitivity analyses 6–8 show that, by reducing
the length of the prerisk period, we could exaggerate the relative
incidence associated with vaccine exposure and understate the
relative incidence associated with infection exposure, whereas
increasing the length of the prerisk period has the opposite effect
(Supplementary Table 8b).
A sensitivity analysis restricting the study period up to 17 May
2021, when the Centres for Disease Control and Prevention (CDC)
announced cases of myocarditis after the BNT162b2 vaccine,
showed no increased incidence of myocarditis in the 1–7 days fol-
lowing a second dose of BNT162b2 (IRR 1.07, 95% CI 0.59, 1.97).
The age distribution of those vaccinated with ChAdOx1 in these
two time periods was similar, but those vaccinated with BNT162b2
were older in the restricted study period (13.8% versus 29.7% were
younger than 40 years; Supplementary Table 9).
Hospital duration of stay for myocarditis. The median hospital
duration of stay for those with myocarditis in the 28 days postvac-
cination was 3 days (interquartile range (IQR): 1, 9) for ChAdOx1,
3 days (IQR: 1, 7) for BNT162b2 and 4 days (IQR: 3, 6) for mRNA-
1273, with means of 8.3, 5.7 and 4.5 days, respec tively. This compares
with a median of 4 days (IQR: 1, 9) and mean of 7.6 days for those
whose admissions had not occurred in the 28 days post vaccination.
Absolute measures of effect of vaccination and SARS-CoV-2
infection. We estimated the number of exposures needed for one
excess event and the excess number of events per 1 million exposed
for each outcome (Fig. 2 and Supplementary Table 10). In the
0.5
1.5
3.0
7.0
16.0
0.5
1.5
3.0
7.0
16.0
0.5
1.5
3.0
7.0
16.0
0.5
1.5
3.0
7.0
16.0
Myocarditis Pericarditis Cardiac arrhythmia
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
ChadOx1
vaccine
BNT162b2
vaccine
mRNA-1,273
vaccine
SARS-CoV-2
diagnosis
IRR (95% CI)
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
22–28days) after first or second dose of ChAdOx1, BNT162b2 and mRNA-1273 vaccines and a SARS-CoV-2 positive test for the prerisk period (28days
before exposure). Horizontal bold line in each panel indicates 1.
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Table 4 | IRRs (95% CI) by age group (aged 40years or younger, older than 40years) 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)
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)
Age<40years
Myocarditis Baseline 95 1.00 120 1.00 16 1.00 37 1.00
−28 to −1 days: first dose/positive test 8 0.36 (0.17, 0.77) 15 0.95 (0.54, 1.66) * 0.76 (0.17, 3.50) 7 1.75 (0.76, 4.05)
Day 0: first dose/positive test * n /a * 3.29 (0.80, 13.45) * n/a 5 32.71 (12.49, 85.68)
1–28 days: first dose/positive test 21 0.92 (0.55, 1.55) 33 1.83 (1.20, 2.79) 8 3.89 (1.60, 9.44) 17 4.06 (2.21, 7.45)
−28 to −1 days: second dose 5 0.40 (0.16, 1.01) 7 0.93 (0.42, 2.09) * 4.82 (0.82, 28.17)
Day 0: second dose * n /a *n/a *n/a
1–28 days: second dose 21 1.50 (0.88, 2.55) 18 3.40 (1.91, 6.04) * 20.71 (4.02, 106.68)
Pericarditis Baseline 57 1.00 107 1.00 11 1.00 26 1.00
−28 to −1 days: first dose/positive test 7 0.46 (0.21, 1.04) 16 0.86 (0.50, 1.49) * 1.79 (0.48, 6.62) 5 2.05 (0.75, 5.56)
Day 0: first dose/positive test * n /a *n /a *n/a * 21.12 (4.86, 91.77)
1–28 days: first dose/positive test 7 0.51 (0.23, 1.16) 16 0.89 (0.51, 1.54) * 2.49 (0.67, 9.32) * 0.99 (0.29, 3.33)
−28 to −1 days: second dose 6 0.58 (0.24, 1.39) 7 0.90 (0.40, 2.01) * n /a
Day 0: second dose * n /a *n/a *n/a
1–28 days: second dose 17 1.79 (0.97, 3.28) 10 1.26 (0.62, 2.54) * n/a
Cardiac arrhythmia Baseline 5520 1.00 11,531 1.00 924 1.00 2,290 1.00
−28 to −1 days: first dose/positive test 1036 0.86 (0.80, 0.92) 1,787 0.90 (0.85, 0.95) 147 1.00 (0.84, 1.19) 283 1.22 (1.08, 1.39)
Day 0: first dose/positive test 17 0.39 (0.24, 0.62) 25 0.36 (0.25, 0.54) 6 1.25 (0.56, 2.79) 189 21.35 (18.37, 24.80)
1–28 days: first dose/positive test 1172 0.94 (0.88, 1.01) 1,639 0.90 (0.85, 0.95) 108 0.90 (0.73, 1.10) 868 3.38 (3.12, 3.66)
−28 to −1 days: second dose 839 0.77 (0.71, 0.83) 659 0.75 (0.69, 0.82) 18 0.67 (0.41, 1.08)
Day 0: second dose 20 0.51 (0.33, 0.80) 15 0.46 (0.27, 0.76) * n/a
1–28 days: second dose 990 0.97 (0.90, 1.04) 802 1.04 (0.96, 1.12) 18 1.46 (0.90, 2.38)
Age>= 40
Myocarditis Baseline 455 1.00 278 1.00 6 1.00 82 1.00
−28 to −1 days: first dose/positive test 73 0.76 (0.58, 1.00) 34 0.68 (0.47, 1.00) * n/a 25 3.22 (2.02, 5.15)
Day 0: first dose/positive test * 0.66 (0.16, 2.67) * n /a *n /a 31 94.81 (61.39, 146.42)
1–28 days: first dose/positive test 121 1.33 (1.06, 1.67) 61 1.12 (0.83, 1.52) * n/a 117 12.18 (9.01, 16.46)
−28 to −1 days: second dose 53 0.70 (0.51, 0.95) 41 0.93 (0.65, 1.32) * n /a
Day 0: second dose * 0.73 (0.18, 2.95) * n/a *n/a
1–28 days: second dose 63 0.87 (0.65, 1.15) 46 0.96 (0.69, 1.34) * n /a
Pericarditis Baseline 524 1.00 307 1.00 * 1.00 69 1.00
−28 to −1 days: first dose/positive test 57 0.59 (0.44, 0.78) 26 0.60 (0.39, 0.90) * n/a 24 4.30 (2.63, 7.03)
Day 0: first dose/positive test * n /a *n /a *n/a 9 42.16 (20.65, 86.07)
1–28 days: first dose/positive test 95 0.79 (0.62, 1.00) 43 0.80 (0.57, 1.12) * n /a 24 3.72 (2.30, 6.00)
−28 to −1 days: second dose 52 0.40 (0.30, 0.55) 28 0.41 (0.28, 0.61) * n/a
Day 0: second dose * n /a * 1.07 (0.34, 3.35) * n/a
1–28 days: second dose 100 0.82 (0.65, 1.04) 65 0.88 (0.66, 1.16) * n/a
Continued
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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)
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 0n/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
Table 4 | IRRs (95% CI) by age group (aged 40years or younger, older than 40years) 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)
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1–28 days following the first dose of the ChAdOx1, BNT162b2 and
mRNA-1273 vaccine, an extra two (95% CI 0, 3), one (95%CI 0,
2) and six (95% CI 2, 8) myocarditis events per 1 million exposed
would be anticipated, respectively. In the 1–28 days following the
second dose of mRNA-1273, an extra ten (95% CI 7, 11) myocarditis
events per 1 million persons would be anticipated. This compares
with an extra 40 (95% CI 38, 41) myocarditis events per 1 million in
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
aged under 40 years. For this age group, we estimated 2 (95% CI 1, 3)
and 8 (95%CI 4, 9) excess cases of myocarditis per 1 million people
receiving a first dose of BNT162b2 and mRNA-1273, respectively,
and 3 (95% CI 2, 4) and 15 (95%CI 12, 16) excess cases of myocar-
ditis per 1 million people receiving a second dose of BNT162b2 and
mRNA-1273, respectively. This compares with ten (95% CI 7, 11)
extra cases of myocarditis following a SARS-CoV-2 positive test in
those aged under 40 years.
Discussion
This is the largest study to date of acute cardiac outcomes after
SARS-CoV-2 vaccination or infec tion, the first to compare the risk of
cardiac events between different vaccine products and SARS-CoV2
infection and the first to investigate the association between cardiac
events and the ChAdOx1 vaccine.
Our findings are relevant to the public, clinicians and policy
makers. First, there was an increase in the risk of myocarditis
within a week of receiving the first dose of both adenovirus and
mRNA vaccines, and a higher increased risk after the second dose
of both mRNA vaccines. In contrast, we found no evidence of an
increase in the risk of pericarditis or cardiac arrhythmias follow-
ing vaccination, except in the 1–28 days following a second dose
of the mRNA-1273 vaccine. Second, in the same population, there
was a greater risk of myocarditis, pericarditis and cardiac arrhyth-
mia following SARS-CoV-2 infection. Third, the increased risk of
myocarditis after vaccination was higher in persons aged under 40
years. We estimated extra myocarditis events to be between 1 and
10 per million persons in the month following vaccination, which
was substantially lower than the 40 extra events per million persons
observed following SARS-CoV-2 infection.
We assessed the temporal association between COVID-19 vacci-
nation and cardiac adverse events using hospital admissions with
diagnoses of myocarditis or pericarditis, and cardiac arrhythmias.
Myocarditis is an inflammatory disorder of the myocardium that
commonly results from viral infection, systemic immune-mediated
diseases or immunomodulatory treatments7. It occurs more com-
monly in men, which may be a consequence of different effects
of sex hormones on the immune system8. Several cases have
been reported in patients hospitalized with SARS-CoV-2 infec-
tion, and screening for cardiac involvement using cardiac troponin
testing has demonstrated that myocardial injury is common
and associated with poor outcomes9. Irrespective of the underly-
ing etiology of myocarditis, those who develop important ventri-
cular impairment are at increased risk of cardiogenic shock and
mortality10, highlighting the importance of ascertaining whether
myocarditis may be temporally associated with vaccination for
SARS-CoV-2.
Whereas myocarditis is a specific form of cardiac inflammation,
pericarditis reflects inflammation localized to the pericardium, and
the occurrence of cardiac arrhythmias, although associated with
both, is not a specific indictor of cardiac inflammation. Thus, nei-
ther pericarditis nor any category of cardiac arrhythmia were asso-
ciated specifically with COVID-19 vaccination10–12. Myocarditis
is underdiagnosed in practice13, with clinical bias being directed
towards myocardial ischemia or infarction. Thus, our use of diag-
nostic codes for myocarditis from routine data suggest that the
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)
Pericarditis Baseline 375 1.00 272 1.00 10 1.00 66 1.00
−28 to −1 days: first dose/positive test 41 0.53 (0.38, 0.74) 28 0.63 (0.42, 0.93) * 1.94 (0.60, 6.26) 21 3.76 (2.24, 6.31)
Day 0: first dose/positive test * n /a *n /a *n/a 6 27.82 (11.86, 65.26)
1–28 days: first dose/positive test 74 0.82 (0.62, 1.07) 37 0.73 (0.51, 1.04) * 1.96 (0.52, 7.34) 15 2.20 (1.24, 3.90)
−28 to −1 days: second dose 46 0.51 (0.37, 0.71) 24 0.50 (0.33, 0.78) * n/a
Day 0: second dose * n /a *n/a *n/a
1–28 days: second dose 85 0.99 (0.77, 1.28) 52 1.01 (0.73, 1.38) * n/a
Cardiac arrhythmia Baseline 61,748 1.00 57,988 1.00 463 1.00 6,994 1.00
−28 to −1 days: first dose/positive test 9,387 0.79 (0.77, 0.80) 6,670 0.73 (0.72, 0.75) 73 0.91 (0.71, 1.17) 3,332 5.09 (4.88, 5.32)
Day 0: first dose/positive test 127 0.29 (0.24, 0.34) 115 0.32 (0.27, 0.39) * 1.11 (0.36, 3.46) 2,122 81.29 (77.32, 85.47)
1–28 days: first dose/positive test 12,568 0.95 (0.93, 0.97) 9,699 0.93 (0.91, 0.95) 78 1.13 (0.89, 1.45) 5,026 6.55 (6.31, 6.80)
−28 to −1 days: second dose 9,784 0.76 (0.74, 0.78) 8,004 0.78 (0.76, 0.80) 16 0.60 (0. 36, 1.01)
Day 0: second dose 147 0.31 (0.27, 0.37) 141 0.35 (0.29, 0.41) * n/a
1–28 days: second dose 12,143 0.95 (0.93, 0.97) 11,038 0.96 (0.94, 0.98) 19 1.18 (0.73, 1.89)
n/a, not applicable.
Table 4 | IRRs (95% CI) by age group (aged 40years or younger, older than 40years) 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)
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ascertainment of cardiac inflammation after COVID-19 vaccina-
tion is likely to be under- rather than over-represented14,15.
Although no cases of myocarditis were observed in the random-
ized trials of vaccine, this condition is uncommon, and postmarket
authorization surveillance may be required. Our observation of an
increased risk within 7 days of receiving the vaccine is consistent
with the presentation of viral myocarditis, where viral symptoms are
often reported in the week leading up to presentation. Furthermore,
myocarditis following vaccination has been reported with other
vaccines, for example, in healthy adults after receipt of live vac-
cinia virus vaccines16,17 Whilst the mechanisms of myocarditis fol-
lowing exposure to SARS-CoV2 infection and vaccination are not
known, it seems likely that systemic complications of infection are
a consequence of an immune-mediated, virus-independent immu-
nopathologic process18. However, vaccine mediated expression of
SARS-CoV-2 surface spike protein on the surface of cardiomyo-
cytes could potentially trigger an immunologic response resulting
in organ-specific cell death19,20
Our findings are consistent with those from a case-control study
of 884,828 persons receiving the BNT162b2 vaccine in Israel21. That
study observed an association with myocarditis in the 42 days fol-
lowing vaccination (risk ratio of 3.24), but no association with peri-
carditis or cardiac arrhythmia. Two further studies from Israel add
to our observations by providing clinical review to ensure robust
case ascertainment22 and reporting investigations and outcomes in
individual patients with myocarditis following the BNT162b2 vac-
cine23. Witberg et al.21,22 observed a small excess in events 3–5 days
following the second dose of BNT162b2 vaccine, but most were mild
presentations and just one classified as fulminant22. Mevorach et al.
observed an incidence ratio of 5.34 for myocarditis in 5,442,696
persons following BNT162b2, although this was attenuated when
restricted to the 136 definite and probable cases of myocarditis23.
Risk of myocarditis was restricted to males under the age of 40 years
and only observed following the second dose. Similarly, two studies
from the United States have reported an incident rate ratio of 2.7
for myocarditis in the 10 days following the second dose of both
mRNA vaccines24 and an estimated 6.3 and 10.1 extra cases per
million doses in the 1- to 21-day period following the first and
second dose of both mRNA vaccines, respectively, in those younger
than 40 years25.
Our findings extend these observations by including 38 million
adults in England receiving both mRNA and adenovirus-mediated
vaccine. There were 1,615 myocarditis events in our study popula-
tion, enabling a granular evaluation of subgroups and the tempo-
ral association in the weeks following vaccination. We observed a
small excess in myocarditis events after both the first and second
dose of vaccine, but this risk was restricted to a 7-day period fol-
lowing vaccination. This observation was not limited to the mRNA
vaccines as we also found an excess in myocarditis events following
the first dose of ChAdOx1 vaccine. The excess risk was observed in
men and women but was only consistently observed following both
mRNA vaccines in those younger than 40 years, although this may,
in part, reflect the small number of individuals over the age of 40
years receiving the mRNA-1273 vaccine in England.
Whilst myocarditis can be life-threatening, most vaccine-
associated myocarditis events have been mild and self-limiting22.
The risk observed here is small and confined to the 7-day period
following vaccination, whereas the lifetime risk of morbidity and
mortality following SARS-CoV-2 infection is substantial. Indeed,
myocardial injury is very common in persons admitted to hospi-
tal with SARS-CoV-2 infection26, when evaluated systematically
using high-sensitivity cardiac troponin tests27. Moreover, evidence
of myocardial injury, irrespective of whether due to myocarditis or
myocardial ischemia, is associated with a higher risk of in-hospital
death28. We estimate that the absolute number of excess myocarditis
events in the 28 days following a first dose of adenovirus or mRNA
vaccine is between one and six per million persons vaccinated,
and the excess risk following the second dose of the mRNA-1283
vaccine is ten per million. By contrast, we estimate 40 excess myo-
carditis events per million in the 28 days following SARS-CoV-2
0
10
20
30
40
ChAdOx1 (first dose)
ChAdOx1 (second dose)
BNT162b2 (first dose)
BNT162b2 (second dose)
mRNA-1,273 (first dose)
mRNA-1,273 (second dose)
SARS-CoV-2 positive test
Myocarditis
Excess events
0
5
10
15
ChAdOx1 (first dose)
ChAdOx1 (second dose)
BNT162b2 (first dose)
BNT162b2 (second dose)
mRNA-1,273 (first dose)
mRNA-1,273 (second dose)
SARS-CoV-2 positive test
Myocarditis (<40)
Excess events
0
2
4
6
ChAdOx1 (first dose)
ChAdOx1 (second dose)
BNT162b2 (first dose)
BNT162b2 (second dose)
mRNA-1,273 (first dose)
mRNA-1,273 (second dose)
SARS-CoV-2 positive test
Pericarditis
Excess events
0
1,000
2,000
3,000
ChAdOx1 (first dose)
ChAdOx1 (second dose)
BNT162b2 (first dose)
BNT162b2 (second dose)
mRNA-1,273 (first dose)
mRNA-1,273 (second dose)
SARS-CoV-2 positive test
Cardiac arrhythmia
Excess events
Number of excess events in the 1–28 days postvaccination/SARS-CoV-2 positive test per 1 million vaccinated/infected
Fig. 2 | Number of excess events due to exposure per 1million exposed, as reported in Supplementary Table 10. When IRR did not show a significant
increase of incidence over the 1–28days postvaccination or a SARS-CoV-2 positive test, absolute measures are not given.
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420
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infection. The risks are more evenly balanced in younger persons
aged up to 40 years, where we estimated the excess in myocarditis
events following SARS-CoV-2 infection to be 10 per million with
the excess following a second dose of mRNA-1273 vaccine being
15 per million. Further research is required to understand why the
risk of myocarditis seems to be higher following mRNA-1273 vac-
cine. Although the wider societal benefits of controlling the spread
of virus to those who are more vulnerable are substantial, these data
may help inform public health policy and the choice of vaccine
offered to younger adults.
This study has several strengths. First, the United Kingdom
offered an ideal place to carry out this study given that three vacci-
nations have been rolled out at speed and scale. Second, this was a
population-based study of data recorded prospectively and avoided
recall and selection biases linked to case reports. Third, the large
sample size provided sufficient power to investigate these rare out-
comes, which could not be assessed through clinical trials. Fourth,
the SCCS study design removes potential confounding from fixed
characteristics, and the breakdown of our study period into weekly
blocks accounted for temporal confounding. Of note, the esti-
mated IRRs are consistently less than 1 in the pre-exposure period
before vaccination and greater than 1 in the prerisk period before
a SARS-CoV-2 positive test. This was expected since events are
unlikely to happen shortly before vaccination (relatively healthy
people are receiving the vaccine) and more likely to happen before a
SARS-CoV-2 positive test (as a standard procedure, patients admit-
ted to hospital are tested for SARS-CoV-2). We also assessed the
robustness of our results through analyses of control outcomes and
several sensitivity analyses.
There are some limitations that we should acknowledge. First,
although we used an established methodology for evaluating vac-
cine safety, we cannot determine whether our findings are causal.
Second, we relied on hospital admission codes and death certifica-
tion to define our outcome measures. As such, we are not able to
determine what proportion of patients underwent cardiac imaging
or biopsy to confirm the diagnosis of myocarditis. It remains pos-
sible that our findings have been influenced by referral bias, with
troponin testing performed more widely following vaccination
due to media reports of vaccine-associated myocarditis. Our sen-
sitivity analysis restricted to those persons vaccinated before the
CDC announcement does not discount this possibility, although
the different results could also be explained by the fact that the
population who received the BNT162b2 vaccine were older in the
restricted study period. Third, the mRNA-1273 vaccine roll-out
began in April 2021 in the United Kingdom; as a consequence, the
number of events in patients who received this vaccine was low.
Although the signal associated with myocarditis is strong for this
vaccine, care is needed in the interpretation, and it would be use-
ful to replicate our results in similarly large datasets internation-
ally. Fourth, we are unclear about the biological plausibility of the
observed reduced risks of pericarditis and arrhythmia linked to
vaccination and, although these findings are consistent of those of
Barda et al.21, they should be interpreted with caution. Fifth, in this
study, we performed several comparisons, which may lead to some
erroneous inferences. As a consequence, careful interpretation is
needed, especially for the borderline associations found. Finally, it is
also important to note that control outcomes were chosen to assess
the validity of the association between cardiac adverse events and
vaccination. Control outcomes for a SARS-CoV-2 positive test are
more challenging to find, as the entire health system is affected by
the pandemic. Caution is needed in interpretation of the findings
for a SARS-CoV-2 positive test in light of this.
In summary, this population-based study quantifies for the
first time the risk of several rare cardiac adverse events associated
with three COVID-19 vaccines as well as SARS-CoV-2 infection.
Vaccination for SARS-CoV-2 in adults was associated with a small
increase in the risk of myocarditis within a week of receiving the
first dose of both adenovirus and mRNA vaccines, and after the
second dose of both mRNA vaccines. By contrast, SARS-CoV-2
infection was associated with a substantial increase in the risk of
hospitalization or death from myocarditis, pericarditis and cardiac
arrhythmia.
Online content
Any methods, additional references, Nature Research report-
ing summaries, source data, extended data, supplementary infor-
mation, acknowledgements, peer review information; details of
author contributions and competing interests; and statements of
data and code availability are available at https://doi.org/10.1038/
s41591-021-01630-0.
Received: 15 October 2021; Accepted: 15 November 2021;
Published online: 14 December 2021
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Methods
Ethical approval. National Health Service Research Ethics Committee approval
was obtained from East Midlands-Derby Research Ethics Committee [reference
04/03/2021].
Data. We used the National Immunisation Database (NIMS) database of COVID-
19 vaccination to identify vaccine exposure. This includes vaccine type, date and
doses for all people vaccinated in England. We linked NIMS vaccination data,
at individual level, to national data for mortality (Office for National Statistics),
hospital admissions (Hospital Episode Statistics) and SARS-CoV-2 infection data
(Second Generation Surveillance System).
Study design. The SCCS design was used; this design was developed originally
to examine vaccine safety5,6. The analyses are conditional on each case, so any
fixed characteristics during the study period, such as sex, ethnicity or chronic
conditions, are inherently controlled for. Any time-varying factors, like seasonal
variation, need to be adjusted for in the analyses.
Study period and population. We examined the associations between ChAdOx1,
BNT162b2 or mRNA-1273 vaccines and selected cardiac conditions during the
ongoing COVID-19 vaccination programme in England, which commenced on
8 December 2020. Separate analyses were carried out in cases with each cardiac
outcome of interest. People were considered eligible for inclusion in each study
cohort if they had received at least one vaccine dose, were at least 16 years old and
were admitted to hospital with, or died from, the outcome of interest between 1
December 2020 and 24 August 2021 (last data update). Patients were followed
up from the study start (1 December 2020) to the earliest of the end of the study
period or when they died. Patients with a hospital admission for the same outcome
in the 2 years before the start of the study period were excluded.
Outcomes. The outcomes in this study are selected cardiac conditions with
previous indications of association with SARS-CoV-2 infection or COVID-19
vaccination. These included myocarditis, pericarditis and arrythmia. We used the
International Classification of Diseases-10 codes to define each outcome, as listed
in Supplementary Table 11. The outcomes were identified as the first hospital
admission due to the event of interest, or death recorded on the death certificate
with the International Classification of Diseases-10 code related to the outcome
of interest within the study period. A histogram showing the number of admissions
in England from 1 April 2019 to 24 August 2021 is presented in Extended Data
Fig. 4.
Exposures. The exposure variables were a first or second dose of the ChAdOx1,
BNT162b2 or mRNA-1273 vaccines, or SARS-CoV-2 infection, defined as the first
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
time periods: 0, 1–7, 8–14, 15–21 and 22–28 days after each exposure date, under
the assumption that the adverse events under consideration are unlikely to be
related to exposure later than 28 days postexposure. We assumed that the risks
may be different after each vaccine dose (first and second), and hence we allowed
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
after the second dose. To avoid overlapping risk periods, we assumed that later
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.
A prerisk interval of 1–28 days before each exposure date was included to account
for potential bias that might arise if the occurrence of the outcome temporarily
influenced the likelihood of exposure. The baseline period for the vaccination
exposures comprised the remaining time from 1 December 2020 until 29 days
before the first dose date and from 29 days after the first dose until 29 days before
the second dose (if applicable), and from 29 days after the second dose until 24
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.
Seasonality and COVID-19 pandemic period. Hospital admissions were likely
influenced by the pressure on the health systems due to COVID-19, which was
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.
Statistical analysis. We described characteristics of each cohort (vaccinated
patients with the outcomes of interest) in terms of age, sex and ethnic group. The
SCCS models were fitted using a conditional Poisson regression model with an
offset for the length of the exposure risk period. Separate analyses were carried out
for each cardiac outcome of interest. IRR, the relative rate of hospital admissions or
deaths due to each outcome of interest in exposure risk periods relative to baseline
periods, and their 95% CI were estimated by the SCCS model adjusted for week
as a time-varying covariate. Exposure terms for vaccines and for a SARS-CoV-2
positive test were included in the same model.
We investigated if the associations between vaccine exposures and outcomes
are sex- or age-dependent by running subgroups analyses amongst those aged
under 40 years and those aged 40 years and older and by gender. We also conducted
analyses restricted to those with a SARS-CoV-2 infection before vaccination and
those without SARS-CoV-2 infection. Finally, we performed subgroup analyses by
prespecified categories of cardiac arrythmia as reported in Supplementary Table 11.
We conducted sensitivity analyses to assess the robustness of results to
assumptions, such as that the occurrence of an outcome event did not influence
the probability of subsequent exposures by (1) excluding those who died from
the outcome and (2) restricting analysis to the period postvaccination, without
censoring at death. To assess potential reporting delays in the data by (3) restricting
the study to the period up to 1 August 2021. To include only time unaffected by
any notoriety bias by (4) restricting the study to the period up to 17 May 2021,
when CDC announced cases of myocarditis after BNT162b2 vaccine and (5)
removing patients who had outcomes in the 28 days after a first dose, but before a
second dose, since they are less likely to have a second dose if they experienced an
adverse event after the first.
To compare the choice of different pre-exposure risk periods, we also included
three extra sensitivity analyses using different lengths for the prerisk period: (6)
including the prerisk period in the baseline, (7) including only the 1–14 days
before exposure in the prerisk period and (8) including a longer prerisk period
of 59 days.
Stata v.17 was used for these analyses.
Absolute risk. Absolute risk differences cannot be obtained using SCCS. We
supplemented our estimates of IRRs with measures of effect using a method29
developed to estimate the number of exposures needed to produce one excess
adverse outcome and the excess number of events per 1 million exposed for each
outcome.
SCCS assumptions. Independence between outcome and exposure. We assumed
that patients who experienced an outcome before vaccination were likely to delay
vaccination until symptoms had improved. erefore, we included a prerisk period
in the analyses, lasting from 1 to 28 days before vaccination, which removes this
period from the baseline period (Extended Data Fig. 6). Hospital admissions
for the events of interest can trigger COVID-19 testing. Such events may well
be caused by SARS-CoV-2 infection, but the reverse causality involved in their
detection induces bias. To reduce the bias, which could over or underestimate the
eect of infection, we decided to allocate day 0 to a risk period on its own30.
Event-dependent observation periods. We tested this assumption with sensitivity
analyses 1 and 2. These further analyses agreed with the main analysis, suggesting
that there should be little concern for these outcomes.
Negative and positive control outcomes. We examined the association of
exposures with celiac disease as a negative control outcome31, which is assumed not
to be associated with exposure to vaccination or SARS-CoV-2 infection; and with
anaphylaxis as a positive control outcome given that it could occur shortly after
vaccination with either vaccine32.
Reporting Summary. Further information on research design is available in the
Nature Research Reporting Summary linked to this article.
Data availability
The data that support the findings of this study—NIMS Database of COVID-19,
mortality (Office of National Statistics), hospital admissions (Hospital Episode
Statistics) and SARS-CoV-2 infection data (PHE)—are not publicly available
because they are based on deidentified national clinical records. Due to national
and organizational data privacy regulations, individual-level data such as those
used for this study cannot be shared openly.
Code availability
The code used for this study has been deposited in the git repository of the research
group, which is protected by privacy. Access to the code is available from the
authors on request for noncommercial, academic and research use only.
References
29. Wilson, K. & Hawken, S. Drug safety studies and measures of eect using
the self-controlled case series design. Pharmacoepidemiol. Drug Saf. 22,
108–110 (2013).
30. Fonseca-Rodríguez, O. et al. Avoiding bias in self-controlled case series
studies of coronavirus disease 2019. Stat Med. 40, 6197–6208 (2021).
31. Lipsitch et al. Negative controls: a tool for detecting confounding and bias in
observational studies. Epidemiology 21, 383–388 (2010).
32. Kounis, N. G. Allergic reactions to current available COVID-19 vaccinations:
pathophysiology, causality, and therapeutic considerations. Vaccines (Basel) 9,
221 (2021).
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Acknowledgements
This project involves data derived from patient-level information collected by the
National Health Service (NHS), as part of the care and support of cancer patients. The
SARS-Cov-2 test data are collated, maintained and quality assured by Public Health
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
registration data are used by permission from NHS Digital who retain the copyright for
that data. NHS Digital and PHE bear no responsibility for the analysis or interpretation
of the data. K.K. is supported by the National Institute for Health Research (NIHR)
Applied Research Collaboration East Midlands (ARC-EM) and NIHR Lifestyle BRC.
M.S.-H. is supported by the National Institute for Health Research Clinician Scientist
Award (NIHR-CS-2016-16-011). J.H.-C. and K.M.C. are supported by the NIHR
Oxford Biomedical Research Centre. N.L.M. and K.M.C. are supported by the British
Heart Foundation (Chair Awards CH/F/21/90010, CH/16/1/32013), Programme Grant
(RG/20/10/34966) and Research Excellence Awards (RE/18/5/34216, RE18/3/34214).
A.S. is supported by the Health Data Research United Kingdom BREATHE Hub. This
research is part of the Data and Connectivity National Core Study, led by Health Data
Research United Kingdom in partnership with the office of National Statistics and funded
by United Kingdom Research and Innovation (grant MC_PC_20029). The investigators
acknowledge the philanthropic support of the donors to the University of Oxford’s
COVID-19 Research Response Fund. The views expressed in this publication are those
of the author(s) and not necessarily those of the NHS, the United Kingdom NIHR or the
Department of Health. The funders of this study had no role in the design and conduct
of the study and did not review or approve the manuscript. The views expressed are those
of the authors and not necessarily the funders. M.P., J.H.-C. and C.A.C.C. had full access
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
questions for consideration and also supported analysis. Patient and Public Involvement
and Engagement advisers were supportive of the vital importance of reporting on cardiac
risks associated with both vaccination against COVID-19 and COVID-19 itself.
Author contributions
M.P., J.H.-C. and C.A.C.C. led the study conceptualization, development of the research
question and analysis plan. J.H.-C. obtained funding, designed the analysis, obtained
data approvals and contributed to interpretation of the analysis. M.P. undertook the
data specification, curation, analysis. M.P. and N.L.M. wrote the first draft of the paper.
S.D. undertook and reported on the Patient and Public Involvement and Engagement.
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
to the discussion on protocol development and provided critical feedback on drafts of the
manuscript. All authors approved the protocol, contributed to the critical revision of the
manuscript and approved the final version of the manuscript.
Competing interests
A.S. is a member of the Scottish Government Chief Medical Officer’s COVID-19
Advisory Group, the Scottish Government’s Standing Committee on Pandemics
and AstraZeneca’s Thrombotic Thrombocytopenic Advisory Group. All roles are
unremunerated. J.H.-C. reports grants from NIHR Biomedical Research Centre, Oxford,
John Fell Oxford University Press Research Fund and Cancer Research United Kingdom
(CR-UK) grant no. C5255/A18085, through the CR-UK Oxford Centre, and grants
from the Oxford Wellcome Institutional Strategic Support Fund (204826/Z/16/Z) and
other research councils during the conduct of the study. J.H.-C. is an unpaid director of
QResearch, a not-for-profit organization that is a partnership between the University
of Oxford and EMIS Health who supplied the QResearch database used for this work.
J.H.-C. is a founder and shareholder of ClinRisk Ltd and was its medical director until 31
May 2019. ClinRisk Ltd produces open and closed source software to implement clinical
risk algorithms (outside this work) into clinical computer systems. J.H.-C. is chair of
the NERVTAG risk stratification subgroup and a member of Scientific Advisory Group
for Emergencies COVID-19 groups and the NHS group advising on prioritization of
use of monoclonal antibodies in SARS-CoV-2 infection. A.H. is a member of the Joint
Committee on Vaccination and Immunisation. K.K. is a member of the Governments
Scientific Advisory Group for Emergencies. All other authors declare no competing
interests related to this paper.
Additional information
Extended data is available for this paper at https://doi.org/10.1038/s41591-021-01630-0.
Supplementary information The online version contains supplementary material
available at https://doi.org/10.1038/s41591-021-01630-0.
Correspondence and requests for materials should be addressed to Julia Hippisley-Cox.
Peer review information Nature Medicine thanks Karina Top, Leslie T. Cooper and the
other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Jennifer Sargent was the primary editor on this article and managed its editorial process
and peer review in collaboration with the rest of the editorial team.
Reprints and permissions information is available at www.nature.com/reprints.
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Articles
Nature MediciNe
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Myocarditis Pericarditis Cardiac arrhythmia
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Main Analysis
ChadOx1
Sensitivity 1
ChadOx1
Sensitivity 2
ChadOx1
Sensitivity 3
ChadOx1
Sensitivity 4
ChadOx1
Sensitivity 5
ChadOx1
Sensitivity 6
ChadOx1
Sensitivity 7
ChadOx1
Sensitivity 8
ChadOx1
Incidence rate ratio (95% CI)
Time period (days since exposure)
Extended Data Fig. 1 | See next page for caption.
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Extended Data Fig. 1 | Incidence rate ratios (IRRs) with 95% confidence intervals associated with ChAdOx1 vaccine (sensitivity analyses). Incidence
rate ratios (IRRs) with 95% confidence intervals for single outcomes in predefined risk periods immediately before and after 1st and 2nd dose of ChAdOx1
vaccine computed using an underlying population of size n=38,615,491 vaccinated individuals and different sensitivity analyses. Horizontal bold line
indicates 1.
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Articles
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Myocarditis Pericarditis Cardiac arrhythmia
?28 to ?1:1d
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Main analysis
BNT162b2
Sensitivity 1
BNT162b2
Sensitivity 2
BNT162b2
Sensitivity 3
BNT162b2
Sensitivity 4
BNT162b2
Sensitivity 5
BNT162b2
Sensitivity 6
BNT162b2
Sensitivity 7
BNT162b2
Sensitivity 8
BNT162b2
Incidence rate ratio (95% CI)
Time period (days since exposure)
Extended Data Fig. 2 | See next page for caption.
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Extended Data Fig. 2 | Incidence rate ratios (IRRs) with 95% confidence intervals associated with BNT162b2 vaccine (sensitivity analyses). Incidence
rate ratios (IRRs) with 95% confidence intervals for single outcomes in predefined risk periods immediately before and after 1st and 2nd dose of BNT162b2
vaccine computed using an underlying population of size n=38,615,491 vaccinated individuals and different sensitivity analyses. Horizontal bold line
indicates 1.
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Articles
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Myocarditis Pericarditis Cardiac arrhythmia
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Main analysis
mRNA 1273
Sensitivity 1
mRNA 1273
Sensitivity 2
mRNA 1273
Sensitivity 3
mRNA 1273
Sensitivity 4
mRNA 1273
Sensitivity 5
mRNA 1273
Sensitivity 6
mRNA 1273
Sensitivity 7
mRNA 1273
Sensitivity 8
mRNA 1273
Incidence rate ratio (95% CI)
Time period (days since exposure)
Extended Data Fig. 3 | See next page for caption.
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Extended Data Fig. 3 | Incidence rate ratios (IRRs) with 95% confidence intervals associated with mRNA-1273 vaccine (sensitivity analyses). Incidence
rate ratios (IRRs) with 95% confidence intervals for single outcomes in predefined risk periods immediately before and after 1st and 2nd dose of mRNA-
1273 vaccine computed using an underlying population of size n=38,615,491 vaccinated individuals and different sensitivity analyses. Horizontal bold line
indicates 1.
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0 100 200 300
Number admissions
Apr19
Jul19
Oct19
Jan20
Apr20
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Oct20
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Apr21
Jul21
Oct21
Myocarditis
0 100 200 300
Number admissions
Apr19
Jul19
Oct19
Jan20
Apr20
Jul20
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Apr21
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Pericarditis
0 5.0e+04 1.0e+05 1.5e+05
Number admissions
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Jul19
Oct19
Jan20
Apr20
Jul20
Oct20
Jan21
Apr21
Jul21
Oct21
Cardiac arrhythmia
Number of admissions in England from 1 April 2019 to 24 August 2021.
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.
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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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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
the 28 prior to vaccination and yellow area shows the 28 days postvaccination.
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Number of events prior and post each COVID 19 vaccine (1st or 2nd dose) in England
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