Document text
cdc.gov/coronavirus
Myocarditis and COVID- 19
Vaccine Intervals:
International Data and Policies
Danielle Moulia, MPH
ACIP MeetingFebruary 4, 2021
Discussion background and framework
Goal: Examine international data and policies on preferential
recommendations of an mRNA vaccine product or extended primary series
intervals as they relate to myocarditis and/or pericarditis*
Discussion framework
International data on risk of myocarditis by mRNA vaccine product, focusing on the highest risk group – young males post dose 2
International data on extended primary series interval: risk of myocarditis
and vaccine effectiveness
International policies and recommendations
* Myocarditis and/or pericarditis will be referred to generally as “myocarditis,” unless a specific study is being referenced.
International Data on Risk of Myocarditis
by mRNA Product
US:Summary of findings
VAERS : National, passive surveillance
Among males ages 18 –24 years , the myocarditis* reporting rate after a
second dose of Moderna was 40 per million
VSD: Nine integrated healthcare organizations, active surveillance
Among males ages 18 –39 years , the myocarditis/pericarditis** rate after a
second dose of Moderna was 1.5x (aRR‡: 1.5 [0.86–2.61]) than Pfizer
*As of January 13th, 2022; CDC case definition; 7 -day risk period; **As of January 15th, 2022; CDC case definition, 7 -day risk period
‡Adjusted for VSD site, age, sex, race/ethnicity, and calendar date
VAERS: Vaccine Adverse Events Reporting System VSD: Vaccine Safety Datalink
Source: Su J. Myopericarditis following mRNA COVID -19 vaccination: Updates from the Vaccine Adverse Event Reporting System (VAERS). Sl ides presented to ACIP WG Dec 17, 2020.
Klein, N. Myocarditis Analyses in the Vaccine Safety Datalink: Rapid Cycle Analyses and “Head -to-Head” Product Comparisons. Slid es.
Canada: Summary of findings
Abraham et al . CAEFISS, passive and enhanced surveillance data
Among males ages 18 –29 years the myocarditis/pericarditis* reporting rate
after a second dose of Moderna ( 140 per million doses ) was ~5x(aRR‡: 4.73
[3.19–7.20]) higher than Pfizer ( 25 per million doses )
Buchan et al . Ontario, period of enhanced passive surveillance
Among males ages 18 –24 years, the myocarditis/pericarditis** reporting rate
after a second dose Moderna ( 300 per million doses ) was ~5xhigher than
Pfizer ( 59 per million doses )
*From December 1, 2020 to October 8,2021; Myocarditis/pericarditis meeting level 1 -4 of the Brighton Collaboration case definiti on, 7 day risk period ** From December 14, 2020 to
September 4, 2021, myocarditis/pericarditis meeting level 1 -4 of the Brighton Collaboration case definition, study length risk period; ‡Poisson model conditioned by week
CAEFISS: Canadian Adverse Events Following Immunization Surveillance System
Source: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3988612 .Accessed 1/23/2022
https://www.medrxiv.org/content/10.1101/2021.12.02.21267156v1.article -metrics .Accessed 1/23/2022
United Kingdom: Summary of findings
Yellow Card reporting : Passive and active surveillance of adverse events
Among persons ages 18 –29 years , the myocarditis and pericarditis* reporting
rate after a second dose of Moderna ( 71 per million doses) was ~2.5x higher
than Pfizer (24 per million doses)
Patone et al: Self-controlled case series of myocarditis** hospitalizations in the
UK
Among males ages <40 years, additional events of myocarditis after a second
dose of Moderna ( 101 per million doses) was >8x than Pfizer (12 per million
doses )
*As of January 19, 2022, reports of suspected myocarditis and pericarditis associated with COVID -19 vaccines ; ** As of November 15, 2021, inpatient admission or death due to
primary and secondary ICD -10 of myocarditis, 28 day risk period
Source: https://www.gov.uk/government/publications/coronavirus -covid -19-vaccine -adverse -reactions/coronavirus -vaccine -summary -of-yellow -card -reporting#yellow- card -reports .
Accessed 1/22/2022.
Patone M. 2021 MedRxiv preprint. https://www.medrxiv.org/content/10.1101/2021.12.23.21268276v1.full.pdf . Accessed 1/22/2022.
Nordic Countries : Nordic cohort, myocarditis results
Presented to VaST on 1/10/2022
All residents ages 12 years and older in Denmark, Finland, Norway, and
Sweden (23.1M) from December 2020 –October 2022
Inpatient care for myocarditis and pericarditis
Within a 7 -day risk period after either dose, the rate ratio of myocarditis
for Moderna vaccine vs. an unvaccinated comparator was higher than
Pfizer vaccine vs. an unvaccinated comparator
–The highest rate ratios observed were among those receiving a
second dose of Moderna in a heterologous mRNA primary series
VaST: Vaccine Technical Advisory Workgroup
Source: Hovi et al., Slides not publicly available.
Denmark: SARS -CoV-2 vaccination and myocarditis or
myopericarditis: population -based cohort study
Design: Retrospective cohort
Period: October 2020 –October 2021
Population: 5M persons living in Denmark ages ≥12 years
Outcome: Hospital diagnosis of myocarditis or pericarditis, increased
troponin levels, and a hospital stay lasting >24 hours, 28 -day risk period
Adjusted using: Cox proportional hazard model with covariates for age,
sex, vaccine priority group, season, and clinical comorbidities
Source: Husby et al., SARS -CoV-2 vaccination and myocarditis or myopericarditis: population -based cohort study BMJ 2021; 375 :e068665 doi:10.1136/bmj -2021- 068665
Denmark: SARS -CoV-2 vaccination and myocarditis or
myopericarditis: population -based cohort study
Population Product Absolute Rate per
100,000 dosesaHR, Unvaccinated
Comparator
12–39 years Pfizer, after any dose 1.6 (1.0 to 2.6) 1.48 (0.74 to 2.98)
Moderna, after any dose 5.7 (3.3 to 9.3) 5.24 (2.47 to 11.12)
Males, ≥12
yearsPfizer, after any dose 1.5 (1.0 to 2.2) 0.82 (0.50 to 1.34)
Moderna, after any dose 6.3 (3.6 to 10.2) 3.22 (1.75 to 5.93)
Females, ≥12
yearsPfizer, after any dose 1.3 (0.8 to 1.9) 3.73 (1.82 to 7.65)
Moderna, after any dose 2.0 (0.7 to 4.8) 6.33 (2.11 to 18.96)
Males, 12 –39
yearsPfizer, post dose 2 1.8 (0.8 to 3.4)* 1.54 (0.62 to 3.81)*
Moderna, post dose 2 9.4 (5.0 to 16.0)* 9.80 (4.20 to 22.84) *
*conducted as part of a post hoc analysis
aHR: Adjusted hazards ratio. Adjusted for age, sex, vaccine priority group, season, and clinical comorbidities.
Source: Husby et al., SARS -CoV-2 vaccination and myocarditis or myopericarditis: population -based cohort study. BMJ 2021; 375: e068665 doi:10.1136/bmj -2021- 068665.
France and Germany : Summary of findings
Germany :National, passive surveillance
Among males ages 18 –29 years, the myocarditis/pericarditis*
reporting rate after any dose of Moderna ( 117 per million doses)
was >2x higher than Pfizer ( 47 per million doses )
France :Regional, enhanced passive surveillance
Among males ages 18 –24 years, the myocarditis** reporting rate
after a second dose of Moderna ( 139 per million doses) was ~3x
higher than Pfizer (43 per million doses )
*As of September 30, 2021; all reports post mRNA vaccination; **As of September 20, 2021; all reports post mRNA vaccine
Source: https://www.rki.de/DE/Content/Infekt/EpidBull/Archiv/2021/Ausgaben/46_21.pdf . Accessed 1/23/2022.
https://www.omedit -auvergne -rhone -alpes.ars.sante.fr/index.php/system/files/2021 -10/ANSM_Rapport_CRPV_Moderna_22102021.pdf . Accessed 1/23/2022.
https://ansm.sante.fr/uploads/2021/10/22/20211021- covid -19-vaccins -pfizer -focus -1-2.pdf . Accessed 1/23/2022.
Myocarditis rate ratios (Moderna vs. Pfizer) country,
subgroup, and dose
Klein, USA, M 18 –39y, post dose 2₽Buchan, Canada -Ontario, M 18 –24y, post dose 2*
France, M 18– 24y, post dose 2*Abraham, Canada , M 18 –29y, post dose 2‡
Husby , Denmark, M 12 –39y, post dose 2*
Rate Ratio0 5 10 15 20
*Unadjusted rate ratio; ‡Adjusted with a Poisson model conditioned by calendar week of vaccine administration; ₽ Adjusted for VSD site, age, sex, race/ethnicity, and calendar date
Source . Husby et al., SARS -CoV-2 vaccination and myocarditis or myopericarditis: population -based cohort study. BMJ 2021; 375: e068665 doi:10.1136/bmj -2021- 068665
https://ansm.sante.fr/uploads/2021/10/22/20211021- covid -19-vaccins -pfizer -focus -1-2.pdf. Accessed 1/23/2022 .
Klein, N. Myocarditis Analyses in the Vaccine Safety Datalink: Rapid Cycle Analyses and “Head -to-Head” Product Comparisons. Slid es.
https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3988612 .Accessed 1/23/2022
https://www.medrxiv.org/content/10.1101/2021.12.02.21267156v1.article -metrics .Accessed 1/23/2022
Summary of findings: Myocarditis risk by mRNA product
Risk of myocarditis may be higher for Moderna than Pfizer vaccine
Limitations: observational data; rates not readily comparable due to
differences in:
–Case definition and risk interval length
–Subpopulations
–Case ascertainment
–Calendar time and vaccine implementation factors, including extended primary series intervals
A limited number of geographic locations are administering both Moderna and Pfizer and had data available.
International Data on Risk of Myocarditis
with an Extended Primary Series Interval
Ontario, Canada : Myocarditis/pericarditis by interval
Design: Retrospective, population- based cohort, using provincial vaccine registry
and passive vaccine safety surveillance
Period: December 14, 2020 to September 4, 2021
Population: Adults ages ≥18 years receiving dose 2 on or after June 1, 2021 in
Ontario; 19,740,741 doses of mRNA vaccines
Outcome: Myocarditis/pericarditis meeting level 1 –3 of the Brighton Collaboration
case definition
Analysis: Crude reporting rates; overall rate following dose 2 by product estimated
using Poisson regression, adjusted for dose 1 product and interval
–Dosing intervals : ≤30 days (≤4 weeks), 31 –55 days (5– 7 weeks), ≥56 days (≥8
weeks)
Source: Buchan S et al. Dec 2021, MedRxiv preprint.
Ontario, Canada: Reporting rate of myocarditis/pericarditis per million
doses among males ages 18 –24 years by vaccine product* and interval
Source: Buchan S et al. Dec 2021, MedRxiv preprint.
*Moderna -Pfizer not shown here because there were no reported events in males ages 18 –24 years; a smaller number of males in this age group received this schedule (n=8,853).020040060080010001200140016001800
≤4 weeks 5-7 weeks ≥8 weeks ≤4 weeks 5-7 weeks ≥8 weeks ≤4 weeks 5-7 weeks ≥8 weeks
Pfizer —Pfizer Moderna —Moderna Pfizer —ModernaRate (95% CI) per million doses
Males ages 18 -24 y n=235,819 n=93,616 n=85,893
Summary of data: Myocarditis risk with extended
primary series interval
Rates of myocarditis may be lower with extended primary
series interval
Reduced rates of myocarditis with extended interval were
observed with Moderna and Pfizer vaccines
Source : Buchan S. Dec 2021, MedRxiv preprint.
International Data on Vaccine Effectiveness
with an Extended Primary Series Interval
British Columbia and Quebec, Canada: Vaccine
effectiveness by primary series interval
Design: Test-negative case -control design to estimate vaccine effectiveness
Period: May 30 to October 2, 2021
Population: Community -dwelling adults ages ≥18 years in British Columbia (BC) and
Quebec, Canada; 1,235,447 specimens, including 44,673 test -positive cases and
2,460 hospitalizations
Outcome: Infections and hospitalizations due to SARS -CoV- 2, confirmed by RT -PCR
Analysis: Multivariable logistic regression to estimate odds ratios:
–Adjusted for age group (18 –49, 50– 69, 70– 79, ≥80 years); sex; epi week of the
analysis period (weeks 22 –39, categorical); and region of the province
–Dosing intervals: 3 –4 weeks, 5 –6 weeks, 7 –8 weeks, 9 –11 weeks, 12– 15 weeks,
16+ weeks
Source: Skowronski DM. 2021, MedRxiv preprint .
85 8591 91
8891 9193979998
959498
50556065707580859095100
0 2 4 6 8British Columbia
VE against infection VE against hospitalizationBritish Columbia and Quebec, Canada: Vaccine
effectiveness of any two doses of mRNA vaccines by
primary series interval
Source: Skowronski DM. 2021, MedRxiv preprint . 3–4w 5– 6w 7– 8w 9– 11w 12– 15w ≥16w ≥7w
Time between dose 1 and dose 2 (weeks)Adjusted two dose VE (%: 95% CI)
VE against infection VE against Hospitalization798589 89 89908987979897969597
50556065707580859095100
0 1 2 3 4 5 6 7 8Quebec
3–4w 5– 6w 7– 8w 9– 11w 12– 15w ≥16w ≥7w
Time between dose 1 and dose 2 (weeks)
England: Serological responses and vaccine
effectiveness by primary series interval
Design: Test-negative case -control design to estimate vaccine effectiveness
Period: October 2020 to June 2021
Population: Symptomatic adults ages ≥50 years attending community testing (n=308,764
unvaccinated persons; n=16,237 persons received Pfizer primary series vaccine); serological
responses of 421 immunocompetent adults ages 50 –89 years given two doses of Pfizer at
different intervals
Outcome: Testing SARS -CoV -2 positive by PCR through NHS, following COVID -19 compatible
symptoms; serological responses 14 –34 days post -dose 2
Analysis: Logistic regression to estimate odds ratios by vaccination status
–Adjusted for a week of onset, age group, gender, region, index of multiple deprivation, ethnicity,
health/social care worker, care home resident, flagged as clinically at extremely increased risk for COVID -
19 illness, and flagged as extended risk groups among adults ages <65 years
–Dosing intervals: 3 –4, 5–6, 7–8, 9–12 and > 12weeks
Source: Amirthalingam G. 2021, Nat Commun.
Pfizer vaccine
effectiveness against
symptomatic SARS -
CoV-2 infection was
higher with an extended interval (>6
weeks) compared to a
standard interval (3– 4
weeks) for all age groups.
Source: Amirthalingam G. 2021, Nat Commun.
Age: ≥80 ≤Jan4 | ≥80 >Jan 4 | 65 –79 | 50 –64
100%
90%
80%
70%
60%
50%
40%30%
20%
10%0%Post Dose 2 Vaccine Effectiveness (95% CI)
3-4 9- 12 | 3 -4 9- 12 >12 | 3- 4 7- 8 9- 12 >12 | 3 -4 5- 6 7- 8 9- 12 >12
Interval between Dose 1 and 2 (weeks)England:
Pfizer vaccine
effectiveness by
primary series
interval
Summary: Immunogenicity with extended primary
series interval
Payne et al. (UK ): Among SARS- CoV- 2 infection naïve persons in an observational
cohort, serological responses were higher after an extended dosing interval (6 –14
week) compared to a standard interval (3 –4 week).
–Among persons with an extended interval, there were higher antibody and B
cell responses, as well as sustained B and T cell responses, compared to a
standard interval.
–An extended interval may promote efficient T cell expansion and long -term
memory cell persistence.
Amirthalingam et al. (England), Parry et al. (England), & Grunau et al (Canada):
Neutralizing antibody titers were higher following an e xtended dosing interval with
mRNA vaccine, compared to a standard interval.
Source: Payne R. 2021, Cell.; Amirthalingam G. 2021, Nat Commun.; Parry H. 2022, Npj Vaccines.; Grunau B. 2022, Clin Inf Dis.
Summary of data: Vaccine effectiveness with extended
primary series interval
Extended primary series interval may improve immunogenicity and
vaccine effectiveness.
–Neutralizing antibody titers were higher following an e xtended dosing interval
(6–14 week) with mRNA vaccine, compared to a standard interval (3 –4 week). 1-4
–mRNA vaccine effectiveness against infection and hospitalization was 5 –10%
higher with an extended interval (7 –8 weeks vs. 3 –4 weeks). 5
Limitation: Data collected prior to Omicron surge
1 Payne R. 2021, Cell.
2Grunau B. 2022, Clin Infect Dis.
3 Amirthalingam G. 2021, Nat Commun
4Parry H. 2022, Npj Vaccines
5Skowronski DM. 2021, MedRxiv preprint .
International Policies and
Recommendations
Canada
NACI strongly recommends a complete mRNA COVID- 19
vaccine series for persons ages ≥12 years.
–Ages 12 –29 years: Pfizer is preferred for the primary series.
–Ages 18 –20 years: Pfizer may be preferred for a booster.
mRNA vaccine productImmunization
scheduleMinimum
intervalAuthorized intervalOptimal interval
Pfizer -BioNTech
Comirnaty2-dose schedule 19 days 21 days 8 weeks
Moderna Spikevax 2-dose schedule 21 days 28 days 8 weeks
Source: National Advisory Committee on Immunization: Updated Guidance on the use of COVID- 19 Vaccines. (slides)
https://www.canada.ca/en/public -health/services/diseases/coronavirus -disease -covid -19/vaccines/safety- side-effects.html#myocardi tis-and-pericarditis . Accessed 1/23/2022
https://www.canada.ca/en/public -health/services/publications/healthy -living/canadian -immunization -guide -part-4-active -vaccines/p age-26-covid -19-vaccine.html#a5.4 . Accessed 2/1/2022.
United Kingdom
Preferential recommendation for Pfizer in persons ages 12–17
years
Interval : at least 8 weeks
–Ages 16–17 years, at higher risk*: at least 8 weeks
–Ages 16–17 years, not at high risk: 12 week
–Ages 12–15 years, higher risk of severe COVID- 19: at least 8 weeks
–Ages 12–15 years, contact of immunosuppressed person: 8 weeks
–Ages 12–15 years, not high risk, no contacts: 12 weeks
*In a recognized clinical risk group (see table 3) and those who work in health and social care should receive two doses of vac cine at an interval of at least eight weeks. This includes those
aged 16 to 17 years who expect to share living accommodation on most days (and therefore for whom continuing close contact is unavoidable) with individuals of any age who are
immunosuppressed
Source: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1045852/Greenbook- chapter -14a-11Jan22.pdf . Accessed 1/22/2022
Nordic countries
Sweden : Pfizer is recommended for persons ages 12 –30 years over Moderna.
Interval : 3–4 weeks
Norway : Pfizer should be offered to persons ages 12 –30 years. Children and
adolescents ages 5 –15 years may receive 1 or 2 doses based on parents' decision;
persons ages ≥ 16 years should receive 2 doses
Interval : 3–12 weeks
–Persons ages 16 –18 years: 8– 12 weeks
–Children ages 5 –15 years with severe underlying conditions: 8 –12 weeks, but
can be adapted down to 3 weeks based on medical assessment
Source: https://www.fhi.no/en/id/vaccines/coronavirus -immunisation -programme/coronavirus -vaccine/#vaccination -of-children -and- adolescents . Accessed 1/22/2022
https://www.lakemedelsverket.se/en/coronavirus/covid -19-vaccine . Accessed 1/23/2022
https://thl.fi/en/web/infectious -diseases- and-vaccinations/what -s-new/coronavirus -covid -19-latest -updates/vaccines -and-coronavir us/getting -vaccinated -against -covid -19-how- why-and- when-
https://www.sst.dk/en/English/Corona -eng/Vaccination -against -covid -19/COVID -19-vaccines -in-Denmark
Nordic Countries
Finland : Boys and men ages 12 –30 years only offered Pfizer. Girls and
women ages >12 years are offered Pfizer or Moderna.
Interval : 6–12 weeks for persons ages ≥5 years
Denmark : Both Pfizer and Moderna vaccines are approved for persons
ages ≥12 years.
Interval : 3–6 weeks (median interval: 5 weeks)
Singapore and Taiwan
Singapore : Children under age 18 years should receive Pfizer vaccine.
Interval : At least 21 days; guidance notes myocarditis risk may decrease with
a longer interval, but encourages a second dose at 21 days due to Omicron
Taiwan : Both Pfizer and Moderna vaccines are approved for persons ages
≥12 years.
Interval : At least 12 weeks
Source: https://www.cdc.gov.tw/En/Bulletin/Detail/YPIDZwC4HjqBMtGi4jynHQ?typeid=158 . Accessed 1/31/22
https://www.moh.gov.sg/covid -19/vaccination/faqs ---children -related -vaccination -matters . Accessed 1/31/22
Australia
Both Pfizer and Moderna vaccines are approved for persons ages 12
years and older.
Interval : At least 3 weeks (Pfizer) or 4 weeks (Moderna)
–Children ages 5 –11 years (Pfizer): 8 weeks
•Can be shortened in special circumstances to a minimum of 3 weeks, such as in an outbreak response, prior to the initiation
of significant immunosuppression, or international travel
Source: https://www.health.gov.au/initiatives -and- programs/covid -19-vaccines/advice -for-providers/clinical- guidance/doses -and-administra tion. Accessed 1/30/2022.
https://www.health.gov.au/sites/default/files/documents/2021/12/atagi -recommendations -on-pfizer -covid -19-vaccine -use-in-children -aged -5-to-11-years_0.pdf . Accessed 1/30/2022.
France and Germany
France : HAS recommends persons under the age of 30 years be
given Pfizer over Moderna when available.
Interval : 6 weeks
Germany : STIKO recommends persons under the age of 30
years be given Pfizer over Moderna.
Interval : 3–6 weeks
HAS: Haute Autorité de Santé; STIKO: Standing Committee on Vaccination
Source: https://www.nitag -resource.org/sites/default/files/2021 -12/48_21.pdf . Accessed 1/23/2022.
https://www.rki.de/DE/Content/Infekt/EpidBull/Archiv/2021/46/Art_03.html . Accessed 1/23/2022.
https://www.reuters.com/business/healthcare -pharmaceuticals/french -health- authority -advises -against -moderna -covid -19-vaccine -under -30s-2021- 11-09/. Accessed 1/23/2022.
Limitations
Not a systematic review; data are biased toward findings that influenced
national vaccine policy
Limited number of countries are administering both Moderna and Pfizer
Caution should be used when comparing myocarditis/pericarditis rates across studies as surveillance systems, case definitions and risk intervals,
subpopulation age ranges, and vaccine implementation differ substantially
National vaccine policies have evolved; some policies extending the primary
series interval evolved from implementation strategies to reach the most people with a first dose
Conclusion
Observational data suggest myocarditis/pericarditis may be associated with
–Moderna vs. Pfizer in persons ages 18 –29 years, especially males
–Shorter primary series interval
Several countries have implemented policies or recommendations to
lengthen the interval between doses (range: 6 -12 weeks) in the primary
series and/or preferentially recommend use of Pfizer among males and/or
persons aged <30 years, which may mitigate the risk of
myocarditis/pericarditis and improve vaccine effectiveness
Acknowledgements
Katie Curran
Sara Oliver
Megan Wallace
Monica Godfrey
Amy Blain
Amimah Asif
Sarah Mbaeyi
Evelyn Twentyman
Tara Jatloui
Susan Goldstein
Jack Gersten
Jefferson Jones
Eddie Shanley
Anthony FioreStephen Hadler
Valerie Morelli
JoEllen Wolicki
Elisha Hall
Erin Ricketts
Faisal Minhaj
Heather Scobie
VTF ACIP WG Team
ACIP COVID -19 Vaccines Work Group
Vaccine Task Force
Epi Task Force
Data Analytics and Visualization Task Force
Respiratory Viruses Branch
For more information, contact CDC
1-800- CDC- INFO (232- 4636)
TTY: 1 -888- 232- 6348 www.cdc.gov
The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.