Rapid Cycle Analysis to Monitor the Safety of 

COVID-19 Vaccines in Near Real-Time within 

the Vaccine Safety Datalink: 

Myocarditis and Anaphylaxis

Nicola Klein, MD, PhD

Kaiser Permanente Vaccine Study Center

Kaiser Permanente Northern California

Marshfield Clinic Research Institute

Vaccine Safety Datalink – Immunization Safety Office, CDC
• Established in 1990

• Collaborative project between CDC and 9 integrated healthcare organizations 

The Vaccine Safety Datalink (VSD)

2
Aims:

1. To monitor the safety of COVID-19 vaccines weekly using prespecified outcomes of interest among VSD members. 

2. To describe the uptake of COVID-19 vaccines over time 

among eligible VSD members overall and in strata by age, site, 

and race/ethnicity.

Surveillance began in December 2020.

VSD Rapid Cycle Analysis (RCA)

3
# Outcomes Settings Risk Window 

(days) Chart Review Monitoring Only

Exclude if COVID19 in the Prior X 

Days

1 Acute disseminated encephalomyelitis E, I 1-21, 1-42 Yes

2 Acute myocardial infarction – First Ever E, I 1-21, 1-42 30 days

3 Acute respiratory distress syndrome E, I 0-84 Yes 42 days

4 Anaphylaxis – First in 7 days E, I 0-1 Yes Yes

5 Appendicitis E, I 1-21, 1-42

6 Bell’s palsy – First Ever E, I, O 1-21, 1-42 30 days

7 Cerebral venous sinus thrombosis E, I 1-21, 1-42 Yes 30 days

8 Disseminated intravascular coagulation E, I 1-21, 1-42 42 days

9 Encephalitis / myelitis / encephalomyelitis E, I 1-21, 1-42 30 days

10 Guillain-Barré syndrome E, I 1-21, 1-42 Yes

11 Immune thrombocytopenia E, I, O 1-21, 1-42 30 days

12 Kawasaki disease E, I 1-21, 1-42

13 Multisystem inflammatory syndrome in children/adults (MIS-C/MIS-A) E, I 0-84 Yes

14 Myocarditis / pericarditis – First in 60 Days E, I 1-21, 1-42 Yes (subgroup) 30 days

15 Narcolepsy / cataplexy E, I, O 0-84 Yes

16 Pulmonary embolism – First Ever E, I 1-21, 1-42 30 days

17 Seizures E, I 1-21, 1-42 30 days

18 Stroke, hemorrhagic E, I 1-21, 1-42 30 days

19 Stroke, ischemic E, I 1-21, 1-42 30 days

20 Thrombosis with thrombocytopenia syndrome – First Ever E, I 1-21, 1-42 Yes 30 days

21 Thrombotic thrombocytopenic purpura E, I 1-21, 1-42 30 days

22 Transverse myelitis E, I 1-21, 1-42 Yes

23 Venous thromboembolism – First Ever E, I, O 1-21, 1-42 30 days

VSD COVID-19 Vaccine RCA Outcomes

Abbreviations: E=ED, I=Inpatient, O=Outpatient

4
COVID-19 Vaccine Uptake

(Data through 8/21/21)

5
VSD COVID-19 Vaccine Totals

6
VSD COVID-19 Vaccine Totals

7
Primary Analyses

(Data through 8/21/2021)

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• For the primary analysis, the number of outcomes observed in the risk interval 

(1-21 days) after COVID-19 vaccination were compared to the number 

expected.

• The expected was derived from “vaccinated concurrent comparators” who 

were in a comparison interval (days 22-42) after COVID-19 vaccination.

• On each day that an outcome occurred, vaccinees who were in their risk 

interval were compared with similar vaccinees who were concurrently in their 

comparison interval. 

─Comparisons were adjusted for age group, sex, race/ethnicity, VSD site, as well 

as calendar date.

Analytic Strategy

9
Vaccinee with Myocarditis in Risk Interval and a Concurrent Comparator

Comparison Interval 22-42 days post-vaccination 

22 June 3 42

Vaccinated 

May 3

1

Risk Interval 1-21 days post-vaccination

21 June 3

Vaccinated 

May 30

On each calendar day that an outcome occurred 

in a vaccinee (e.g., June 3), we compared 

vaccinees in their risk interval (day 1-21) with 

similar vaccinees in their comparison interval (day 

22-42). 

By similar, we mean they were in the same age 

group and of the same sex, race, and at the same 

VSD site. 

10
Outcome Events in 21-Day Risk Interval after Either Dose of Any mRNA Vaccine

Compared with Outcome Events in Vaccinated Comparators on the Same Calendar Days 

NE= not estimable

1Sequential test requires 1-sided p < 0.0048 (Fisher) for a signal. This keeps the probability of a false positive signal (due to chance alone) below 0.05 in 2 years 

of surveillance. 

2Adjusted for VSD site, 5-year age group, sex, race/ethnicity, and calendar date. Comparison interval is 22–42 days after either dose.

Sequential Test1

Outcome

Event

Events

in Risk Interval

Adjusted 

Rate Ratio2

1-sided

P-value (Fisher)

'Signal’ 1-sided

p < 0.0048

Acute disseminated encephalomyelitis 1 NE 0.794 no

Acute myocardial infarction 655 1.03 0.328 no

Appendicitis 890 0.85 0.998 no

Bell’s palsy 583 1.00 0.527 no

Cerebral venous sinus thrombosis 8 1.66 0.373 no

Disseminated intravascular coagulation 32 0.72 0.903 no

Encephalitis / myelitis / encephalomyelitis 20 1.76 0.188 no

Guillain-Barré syndrome 12 0.63 0.887 no

Immune thrombocytopenia 49 0.91 0.693 no

Kawasaki disease 0 0.00 0.252 no

Myocarditis / pericarditis 115 1.57 0.010 no

Pulmonary embolism 541 0.99 0.582 no

Seizures 312 0.95 0.706 no

Stroke, hemorrhagic 255 0.98 0.593 no

Stroke, ischemic 1152 1.01 0.458 no

Transverse myelitis 1 1.61 0.620 no

Thrombotic thrombocytopenic purpura 7 2.26 0.216 no

Thrombosis with thrombocytopenia syndrome 83 0.91 0.723 no

Venous thromboembolism 668 1.20 0.006 no

11
Myocarditis/pericarditis Chart Review Summary

12–39-Year-Olds after mRNA Vaccines

(Data through 8/21/2021)

12
• Chart review completed for cases through August 21, 2021 for 100/102 cases (2 

pending) 

12–39 year-olds

Cases identified during post-vaccination days 1-98

• Initial chart review followed with adjudication by an infectious disease clinician 

and/or a cardiologist. 

confirm incident following vaccination

confirmed based on CDC definitions 

evaluate level of certainty for myocarditis

Adjudication confirmed 78/100 (78%) post-vaccination 

myocarditis/pericarditis 

 56 confirmed cases among 12–39-year-olds, with onset 0-21 days after dose 1 or 2

Myocarditis/pericarditis Following an mRNA 

Vaccine: Chart Review Summary

13
Confirmed Myocarditis/pericarditis 0-21 Days after Any Dose of 

Either mRNA Vaccine: Descriptive Characteristics by Age Group

12-17 Year-Olds 

(Pfizer) (N=22)

18-29 Year-Olds

(N=21)

30-39 Years-Olds 

(N=13)

Male sex 18 (82%) 20 (95%) 9 (69%)

Race/ethnicity 

White 11 (50%) 11 (52%) 4 (31%)

Black 1 (5%) 0 (0%) 0 (0%)

Asian 0 (0%) 3 (14%) 2 (15%)

Hispanic 8 (36%) 5 (24%) 4 (31%)

Multiple/other 1 (5%) 1 (5%) 1 (8%)

Unknown 1 (5%) 1 (5%) 2 (15%)

History of COVID-19 infection 0 (0%) 2 (10%) 1 (8%)

History of myo/pericarditis 1 (5%) 0 (0%) 3 (23%)

Symptom onset post-vaccination, median (range) 2 days (1-20 days) 1 days (0-11 days) 5 days (1-20 days)

Adjudication diagnosis

Acute myocarditis 11 (50%) 3 (14%) 3 (23%)

Myopericarditis 10 (45%) 16 (76%) 5 (38%)

Acute pericarditis 1 (5%) 2 (10%) 5 (38%)

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Confirmed Myocarditis/pericarditis 0-21 Days after Any Dose of Either 

mRNA Vaccine: Symptoms and Diagnostic Testing by Age Group

Signs and Symptoms 12-17 Year-Olds 

(Pfizer) (N=22)

18-29 Year-Olds

(N=21)

30-39 Years-Olds 

(N=13)

Chest pain/pressure/discomfort 22 (100%) 21 (100%) 13 (100%)

Dyspnea/shortness of breath 14 (64%) 7 (33%) 7 (54%)

Palpitations 1 (5%) 5 (24%) 0 (0%)

Pericardial rub on exam 0 (0%) 0 (0%) 1 (8%)

Other (fever, fatigue, chills, headache, numbness, 

tingling, syncope, nausea, sweating, etc.)

13 (59%) 12 (57%) 8 (62%)

Diagnostic Testing

Troponin levels obtained 22 (100%) 21 (100%) 13 (100%)

Abnormal troponin level 21 (95%) 19 (90%) 7 (54%)

ECG completed 22 (100%) 21 (100%) 13 (100%)

Abnormal findings 16 (73%) 19 (90%) 12 (92%)

Echocardiogram completed 21 (95%) 20 (95%) 11 (85%)

Abnormal findings 9/21 (43%) 6/20 (30%) 9/11 (82%)

Cardiac MRI completed 4 (19%) 7 (33%) 1 (8%)

Abnormal findings 4/4 (100%) 6/7 (86%) 1/1 (100%)

15
12-17 Year-Olds 

(Pfizer) (N=22)

18-29 Year-Olds

(N=21)

30-39 Years-Olds 

(N=13)

Highest level of care

Outpatient 0 (0%) 2 (10%) 0 (0%)

Emergency department 3 (14%) 1 (5%) 3 (23%)

Admitted to hospital 12 (55%) 18 (86%) 10 (77%)

Admitted to ICU 7 (32%) 0 (0%) 0 (0%)

Length of stay

0 days (same day discharge) 2 (9%) 3 (14%) 3 (23%)

1 day 5 (23%) 9 (43%) 7 (54%)

2 days 6 (27%) 7 (33%) 0 (0%)

3 days 4 (18%) 2 (10%) 1 (8%)

4 days 3 (14%) 0 (0%) 0 (0%)

5 days 2 (9%) 0 (0%) 0 (0%)

≥6 days 0 (0%) 0 (0%) 2 (15%)

Discharged to home 22 (100%) 21 (100%) 13 (100%)

Follow-up visit noted at the time of chart review 15 (68%) 20 (95%) 12 (92%)

Confirmed Myocarditis/pericarditis 0-21 Days after Any Dose of Either 

mRNA Vaccine: Level of Care and Discharge Status by Age Group

16
Subgroup Analysis of Confirmed 

Myocarditis/pericarditis after mRNA Vaccines 

among 12-39 Year-Olds 

(Data Through 8/21/2021)

17
Day of Onset of Confirmed Myocarditis/pericarditis among 

12-39 Year-Olds after Either Dose of an mRNA Vaccine

18
NE= not estimable 

1Comparison interval is 22–42 days after either dose.

2Adjusted for VSD site, 5-year age group, sex, race/ethnicity, and calendar date. 

Analysis

Vaccine Dose Events

in Risk

Interval

Events in 

Comparison 

Interval1

Adjusted 

Rate Ratio2

95%

Confidence

Interval

2-Sided

P-value

Excess Cases in Risk 

Period per 1 Million 

Doses

Both mRNA Both Doses 51 5 5.63 2.31 - 16.44 <.001 8.9

Dose 1 11 5 3.81 1.14 - 14.26 0.029 3.3

Dose 2 36 4 8.31 3.07 - 28.28 <.001 15.5

Pfizer Both Doses 31 5 3.62 1.39 - 11.11 0.007 7.2

Dose 1 6 5 2.26 0.56 - 9.30 0.251 2.1

Dose 2 21 4 5.74 1.98 - 20.52 <.001 13.6

Moderna Both Doses 20 0 NE 3.32 - NE <.001 12.7

Dose 1 5 0 NE 0.89 - NE 0.065 6.1

Dose 2 15 0 NE 3.79 - NE <.001 19.8

Confirmed Myocarditis/Pericarditis in the 0-21 Day Risk Interval, among 

12–39-year-olds by Product and Dose

Compared with Outcome Events in Vaccinated Comparators on the Same Calendar Days 

19
Analysis

Vaccine Dose Events

in Risk

Interval

Events in 

Comparison 

Interval1

Adjusted 

Rate Ratio2

95%

Confidence

Interval

2-Sided

P-value

Excess Cases in Risk 

Period per 1 Million 

Doses

Both mRNA Both Doses 44 5 15.55 6.07 - 47.22 <.001 8.6

Dose 1 6 4 6.73 1.43 - 35.12 0.015 2.0

Dose 2 34 4 23.84 8.49 - 83.64 <.001 15.9

Pfizer Both Doses 25 4 11.34 3.70 - 42.24 <.001 7.1

Dose 1 2 4 2.38 0.21 - 20.11 0.454 0.7

Dose 2 19 3 22.88 6.60 - 106.13 <.001 14.4

Moderna Both Doses 19 0 NE 9.04 – NE <.001 12.0

Dose 1 4 0 NE 2.17 - NE 0.008 4.9

Dose 2 15 0 NE 9.36 – NE <.001 19.7

NE= not estimable

1Comparison interval is 22–42 days after either dose.

2Adjusted for VSD site, 5-year age group, sex, race/ethnicity, and calendar date. 

Confirmed Myocarditis/Pericarditis in the 0-7 Day Risk Interval, among 

12–39-year-olds by Product and Dose

Compared with Outcome Events in Vaccinated Comparators on the Same Calendar Days 

20
NE= not estimable

1Comparison interval is 22–42 days after either dose.

2Adjusted for VSD site, 5-year age group, sex, race/ethnicity, and calendar date.

Analysis

Vaccine Dose Events

in Risk

Interval

Events in 

Comparison 

Interval1

Adjusted 

Rate Ratio2

95%

Confidence

Interval

2-Sided

P-value

Excess Cases in Risk 

Period per 1 Million 

Doses

Both mRNA Both Doses 29 5 10.4 3.9 - 32.54 <.001 6.7

Dose 1 5 4 6.34 1.27 - 34.08 0.024 2.1

Dose 2 24 4 13.8 4.73 - 49.64 <.001 11.9

Pfizer Both Doses 10 4 4.82 1.26 - 20.91 0.021 3.4

Dose 1 1 4 1.76 0.05 - 18.77 0.662 0.4

Dose 2 9 3 9.12 2.14 - 48.59 0.002 7.2

Moderna Both Doses 19 0 NE 9.04 – NE <.001 12.0

Dose 1 4 0 NE 2.17 – NE 0.008 4.9

Dose 2 15 0 NE 9.36 - NE <.001 19.7

Confirmed Myocarditis/Pericarditis in the 0-7 Day Risk Interval, among 

18–39-year-olds by Product and Dose

Compared with Outcome Events in Vaccinated Comparators on the Same Calendar Days 

21
Analysis

Vaccine Dose Events

in Risk

Interval

Events in 

Comparison 

Interval1

Adjusted 

Rate Ratio2

95%

Confidence

Interval

2-Sided

P-value

Excess Cases in Risk 

Period per 1 Million 

Doses

Days 0-21 Both Doses 18 0 NE 3.07 - NE <.001 20.9

Dose 1 3 0 NE 0.39 - NE 0.172 6.6

Dose 2 11 0 NE 4.22 – NE <.001 37.0

Days 0-7 Both Doses 15 0 NE 8.19 – NE <.001 16.7

Dose 1 1 0 NE 0.02 - NE 0.706 2.1

Dose 2 10 0 NE 13.53 - NE <.001 33.7

NE= not estimable

1Comparison interval is 22–42 days after either dose.

2Adjusted for VSD site, 5-year age group, sex, race/ethnicity, and calendar date. 

Confirmed Myocarditis/Pericarditis, among 12–17-year-olds (Pfizer only) in 

the 0-7 and 0-21 Day Risk Interval by Dose

Compared with Outcome Events in Vaccinated Comparators on the Same Calendar Days 

22
• As of August 27, 2021, chart reviews have been completed for 29/34 cases 

time-eligible for 3-month follow-up review.

• Of these, 24 had at least 1 follow-up visit at least 7 days since the initial 

encounter.

• These 24 cases were reviewed to obtain information regarding

symptoms and diagnostic evaluation at most recent follow-up visit 

recovery status for

• ongoing symptoms

• medication

• exercise restrictions

Myocarditis/pericarditis Following an mRNA 

Vaccine: 3-month Follow-up Chart Review

23
12-17 Year-Olds (N=3)* 18-29 Year-Olds (N=11) 30-39 Years-Olds (N=10)

Time from symptom onset to most recent follow-up visit 

(median, range) 53 days (13-57 days) 31 days (11-99 days) 86 days (10-152 days)

Follow-up visit at least 3 months since initial encounter 0 (0%) 3 (27%) 5 (50%)

No new or worsening symptoms noted 2 (67%) 8 (73%) 8 (80%)

Any new or worsening symptom 1 (33%) 3 (27%) 2 (20%)

Chest pain/pressure/discomfort 1 2 2

Shortness of breath/pain with breathing 1 1 1

Palpitations 1 1 0

Fatigue 1 1 1

Elevated heart rate 1 1 1 

Other (orthostatic hypotension, dizziness, etc.) 1 0 0 

Troponin levels obtained 3 (100%) 5 (45%) 4 (40%)

Abnormal troponin level 0 2 2

ECG completed 2 (67%) 7 (64%) 2 (20%)

Abnormal findings 0 4 2

Echocardiogram completed 2 (67%) 3 (27%) 3 (30%)

Abnormal findings 1 1 0

Cardiac MRI completed 1 (33%) 0 0

Abnormal findings 0 N/A N/A

Confirmed Myocarditis/pericarditis 0-21 Days after Any Dose of Either mRNA 

Vaccine by Age Group: Cases with at least 1 follow-up visit since initial episode

* The 3 cases had all been in the ICU at their initial encounter.
12-17 Year-Olds 

(N=3)

18-29 Year-Olds

(N=11)

30-39 YearsOlds (N=10)

Current Status (not mutually exclusive)

Recovered, no medication, exercise restriction or symptoms 0 8 (73%) 1 (10%)

Still symptomatic 1 (33%) 1 (9%) 4 (50%)

Still on medication (primarily NSAIDS, Colchicine) 0 2 (18%) 3 (30%)

Still on exercise/physical activity restrictions 3 (100%) 2 (18%) 0 

Confirmed Myocarditis/pericarditis 0-21 Days after Any Dose of Either mRNA 

Vaccine by Age Group: Current Status at Most Follow-up Recent Visit

25
Anaphylaxis Chart Review Summary

(Data Through 7/31/2021)

26
• Chart review completed for 213/216 cases through July 31, 2021*

• 66/213 (31%) cases confirmed as post-vaccination anaphylaxis with day 0-1 ED visit

*Full review 

not completed 

until 30 days 

after the event

Anaphylaxis Chart Review Summary

Pfizer (N=37) Moderna (N=26) Janssen (N=3)

Age in years, median (range) 42 (15-74) 40 (18-76) 43 (30-65)

Female sex 36 (97%) 23 (88%) 3 (100%)

Minutes to symptom onset, median (range) 10 (0-300) 10 (2-39) --

Symptom onset within 15 minutes 25 (68%) 18 (69%) 1 (33%)

Symptom onset within 30 minutes 32 (86%) 23 (88%) 2 (67%)

Prior history of allergies 29 (78%) 20 (77%) 1 (33%)

Prior history of anaphylaxis 20 (54%) 6 (23%) 1 (33%)

Dose 1 31 (84%) 21 (81%) N/A

Brighton Collaboration case definition level

1 15 (41%) 6 (23%) 0 (0%)

2 22 (59%) 19 (73%) 3 (100%)

3 0 (0%) 1 (4%) 0 (0%)

Cases (95% CI) per million doses 5.0 (3.5-6.9) 4.9 (3.2-7.2) 7.6 (1.6-22.3)

Cases (95% CI) per million doses in females 9.0 (6.3-12.5) 8.0 (5.0-11.9) 16.3 (3.4-47.6)

Cases (95% CI) per million first doses 8.1 (5.5-11.5) 7.7 (4.8-11.8) --

Cases (95% CI) per million first doses in females 14.6 (9.8-20.8) 12.2 (7.2-19.2) -- 27
• In the VSD, rate of anaphylaxis after mRNA vaccines is ~ 5 cases / 

million doses.

• No signals for myocarditis/pericarditis or for any other outcome in the 21 

days after both mRNA doses in the overall VSD population, including all 

ages ≥12 years.

• In the subgroup aged 12–39 years, the rate ratio for 

myocarditis/pericarditis was elevated after both Pfizer and Moderna

during days 0-21 after vaccination, and especially during days 0-7.

• In subgroup analyses, both mRNA vaccines were associated with 

myocarditis/pericarditis in persons aged 12-39 years. 

Summary

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• Kaiser Permanente Northern California:

• Laurie Aukes, Berwick Chan, Bruce Fireman, Kristin Goddard, Ned Lewis, Karen Nunley, Pat Ross, Arnold Yee, 

Ousseny Zerbo, Nandini Bahkshi

• Marshfield Clinic Research Institute:

• Jim Donahue, Ed Belongia, Tom Boyce, Kayla Hanson, Burney Kieke, Dave McClure, Erica Scotty

• CDC Immunization Safety Office:

• Eric Weintraub, Tat’Yana Kenigsberg, Mike McNeil, Jonathan Duffy, Frank Destefano, Tanya Myers, Tom 

Shimabukuro, Matt Oster

• VSD Sites

• HealthPartners Institute, Minneapolis, Minnesota

• Kaiser Permanente Colorado, Denver, Colorado

• Kaiser Permanente Northwest, Portland, Oregon

• Kaiser Permanente Southern California, Los Angeles, California

• Kaiser Permanente Washington, Seattle, Washington

• Denver Health, Denver, Colorado

Acknowledgements

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