Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Updated COVID-19 vaccine (2023-2024 Formulation)

Overview

A Grading of Recommendations, Assessment, Development and Evaluation (GRADE) review of the evidence for benefits and harms for updated COVID-19 vaccine (2023-2024 Formulation) was presented to the Advisory Committee on Immunization Practices (ACIP) on September 12, 2023. GRADE evidence type indicates the certainty of estimates from the available body of evidence. Evidence certainty can be high, medium, low, or very low [1].

The policy question under consideration was, “Should vaccination with the updated COVID-19 vaccine (2023-2024 Formulation, monovalent with XBB.1.5 containing component) be recommended for persons aged 6 months and older?” To evaluate the certainty of evidence for anticipated benefits and harms from the updated COVID-19 vaccine, the ACIP COVID-19 Vaccines Work Group (WG) assessed evidence from last year’s updated vaccine (i.e., bivalent COVID-19 vaccine) for two age groups that were defined based on dosage cutoffs: adolescents and adults aged ≥ 12 years and infants and children aged 6 months – 11 years. The potential benefits pre-specified by the ACIP COVID-19 Vaccines WG for adolescents and adults included prevention of medically attended COVID-19 (emergency department [ED]/urgent care [UC] visits) (critical), hospitalization due to COVID-19 (critical), death due to COVID-19 (important), and post-COVID conditions (important). The potential benefits pre-specified by the ACIP COVID-19 Vaccines WG for infants and children included all the benefits in adolescents and adults with the addition of multisystem inflammatory syndrome in children (MIS-C) (important). The two pre-specified harms for both age groups were specified serious adverse events (SAEs) (i.e., myocarditis/pericarditis and anaphylaxis) (critical) and reactogenicity (severe, grade ≥3) (important).

A systematic review of evidence on the benefits and harms of a bivalent COVID-19 vaccine among persons aged ≥6 months was conducted, using domestic data available as of June 29, 2023. The evidence from 2 Phase I open label trials [2, 3], 10 Phase I, II, II/III, or III randomized controlled trials (RCTs) [4-15], 6 vaccine effectiveness studies [16-21], and 3 studies of a single vaccine safety surveillance system [22-24] were assessed using a modified GRADE approach [1]. Pooled effectiveness estimates were calculated when multiple sources had data on an outcome. For benefits, insufficient data was captured in the systematic review to conduct an evidence synthesis for infants and children. Benefits were indirectly inferred from adolescent and adult data. No data met the systematic review criteria for the outcomes of MIS-C or post-COVID conditions.

In terms of benefits for adolescents and adults, the pooled vaccine effectiveness estimates from observational studies found that the bivalent COVID-19 vaccine was associated with a lower risk of medically attended COVID-19 (ED/UC visits) (relative risk [RR] 0.5, 95% confidence interval [CI]: 0.4–0.5; low certainty), hospitalization due to COVID-19 (RR 0.5; 95% CI: 0.4–0.7; low certainty), and death due to COVID-19 (RR 0.4, 95% CI: 0.3–0.6; very low certainty). The certainty assessment regarding death was downgraded due to serious concern for inconsistency. For infants and children, findings in adults were assessed and downgraded for serious concern for indirectness; the certainty assessment for all pooled benefits was very low.

In terms of harms, the available data from observational safety surveillance systems indicated that there was a rare risk of specified serious adverse events, anaphylaxis and myocarditis/pericarditis, following vaccination among both adolescents and adults (low certainty), and infants and children (very low certainty; downgraded due to serious concern for indirectness). Pooled trial data from the original monovalent primary series RCTs indicated that severe reactogenicity (grade ≥3) was associated with vaccination in adolescents and adults (RR 4.8; 95% CI: 4.5–5.2) and infants and children (RR 4.7; 95% CI: 3.4–6.4). There was very serious concern for indirectness in both age groups and the evidence type was low certainty.

Introduction

On September 11, 2023, the U.S. Food and Drug Administration (FDA) approved the Biologics License Application (BLA) for use of updated COVID-19 vaccine (2023-2024 Formulation) for the prevention of COVID-19 in persons aged ≥12 years [25, 26] and issued an Emergency Use Authorization (EUA) [27, 28] for the use of updated COVID-19 vaccine (2023-2024 Formulation) for persons ages 6 months – 11 years. As part of the process employed by the Advisory Committee on Immunization Practices (ACIP), a systematic review and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) assessment of the evidence was conducted and presented to ACIP [1]. There were no conflicts of interest reported by CDC and ACIP COVID-19 Vaccines Work Group members involved in the GRADE analysis.

ACIP adopted a modified GRADE approach in 2010 as the framework for evaluating the scientific evidence that informs recommendations for vaccine use. ACIP has made modifications to the GRADE approach by presenting assessed evidence as high, moderate, low, and very low certainty. Additionally, instead of presenting the overall certainty of evidence across all outcomes, ACIP presents the certainty of evidence for the benefits and harms separately. ACIP includes an option “ACIP recommends the intervention for individuals based on shared clinical decision-making” instead of providing a conditional recommendation for or against an intervention. GRADE was used to evaluate the benefits and harms of an updated (i.e., bivalent) COVID-19 vaccine, which was determined by ACIP COVID-19 WG to be the most directly applicable to the 2023-2024 vaccine due to its updated formulation, among adolescents and adults aged ≥12 years and infants and children aged 6 months – 11 years. Evidence of benefits and harms were reviewed based on the modified GRADE approach [1].

The policy question under consideration was, “Should vaccination with the updated COVID-19 vaccine (2023-2024 Formulation, monovalent with XBB.1.5 containing component) be recommended for persons aged 6 months and older?” To evaluate the certainty of evidence for anticipated benefits and harms from the updated COVID-19 vaccine (2023-2024 Formulation), the ACIP COVID-19 Vaccines Work Group (WG) assessed evidence from last years updated vaccine (i.e., bivalent COVID-19 vaccine) for two age groups that were defined based on dosing cutoffs: adolescents and adults aged ≥ 12 years and infants and children ages 6 months – 11 years (Table 1).

Methods

We conducted a systematic review of evidence on the benefits and harms of a bivalent COVID-19 vaccine (see Appendix 2 for databases and search strategies). We assessed outcomes and evaluated the quality of evidence using the GRADE approach. Patient-important outcomes (including benefits and harms) for assessment were selected a priori by the WG during WG calls.

We identified RCTs through clinicaltrials.gov. Relevant Phase I, II, II/III or III RCTs of Moderna or Pfizer-BioNTech COVID-19 vaccine were included if they: 1) involved human subjects; 2) reported primary data; 3) included persons (aged ≥6 months) at risk for SARS-CoV-2 infection; 4) included data relevant to the safety outcome being measured (reactogenicity). We identified relevant observational studies through an ongoing systematic review conducted by the International Vaccine Access Center (IVAC) and the World Health Organization (WHO) [29]. Relevant observational studies, using cohort or test-negative case-control designs, were restricted to the defined population, intervention, comparison, and outcome outlined in the policy questions. We included studies conducted in the United States with a majority of their study period between September 2, 2022 and April 19, 2023. Outcomes were assessed starting at least 7 days after a dose. We included only bivalent COVID-19 vaccine effectiveness estimates, which could be combined vaccine effectiveness for multiple bivalent COVID-19 vaccines, or single bivalent COVID-19 vaccines. We included studies of general populations and special populations. In addition, efforts were made to obtain unpublished and other relevant data by hand-searching reference lists, and consulting with vaccine manufacturers and subject matter experts. We included observational safety data from one vaccine safety surveillance system based on input from CDC’s Immunization Safety Office (ISO). Characteristics of all included studies and surveillance systems are shown in Appendix 1.

Two reviewers evaluated all studies for study limitations (risk of bias) using the Cochrane Risk of Bias (RoB) tool for RCTs and the Newcastle-Ottawa Scale (NOS) for observational studies. RoB is comprised of a series of questions structured into domains focusing on different aspects of trial design, conduct, and reporting. Based on question responses, judgement can be “low”, “moderate”, or “high” risk of bias. NOS is a 9-point scale which assesses study limitations related to participant selection and comparability, and assessment of outcome (cohort studies) or ascertainment of exposure (case-control studies). Studies with NOS scores <7 were considered to have serious study limitations.

From the RCT data, risk ratios (RRs) were calculated from numerators and denominators available in the body of evidence. Vaccine effectiveness estimates were defined as 100% x (1-RR). Vaccine effectiveness estimates and 95% CIs were taken from the published/preprint studies, as defined by the authors using a variety of study designs and analytical approaches; adjusted estimates were used when available. When multiple studies were available, pooled estimates were calculated using random effects (>3 studies) or fixed effects (≤3 studies) meta-analysis (R meta package). When multiple studies provided estimates based on overlapping study populations, the study with the most comprehensive population and follow-up time was selected for inclusion in the pooled estimate. When a single study provided estimates for non-overlapping study populations at distinct timepoints following a bivalent dose, all estimates were included in the pooled vaccine effectiveness estimate. The evidence certainty assessment for randomized and observational studies addressed risk of bias, inconsistency, indirectness, imprecision, and other characteristics. The GRADE assessment across the body of evidence for each outcome was presented in an evidence profile.

Results

The results of the GRADE assessment were presented to ACIP on September 12, 2023.

Outcomes of interest included individual benefits and harms. Indirect effects of vaccination (e.g., societal benefits) were not considered as part of GRADE. Benefits of interest deemed critical for all age groups were prevention of medically attended COVID-19 (emergency department [ED]/urgent care [UC] visits) and prevention of hospitalization due to COVID-19 (Table 2). Other important benefits included prevention of death due to COVID-19 and prevention of post-COVID conditions. For infants and children, the important benefit of the prevention of multisystem inflammatory syndrome in children (MIS-C) was also included. The critical harm of interest was specified serious adverse events (SAEs), (i.e., myocarditis/pericarditis and anaphylaxis) reactogenicity grade ≥3 was deemed an important harm.

After screening 255 publications, 217 were excluded from full-text review because they were in a different population (e.g., a different country or study period, n=204), or a different outcome (e.g., symptomatic COVID-19, n=13). Of the 38 publications that were deemed eligible for full-text review, 17 were excluded because the study period or design did not meet the inclusion criteria upon full-text review. The remaining 21 publications, which reported data on 19 studies or surveillance systems, were included in the evidence synthesis and GRADE evidence assessment (Appendix 1). Data were reviewed from 12 RCT publications, 6 vaccine effectiveness studies, and 3 vaccine safety studies from a single surveillance system, the Vaccine Safety Datalink (VSD). For benefits, insufficient data was captured in the systematic review to conduct an evidence synthesis for infants and children. Benefits were indirectly inferred from adolescent and adult data.

Two observational vaccine effectiveness studies reported data on medically attended COVID-19 (ED/UC visits) (Table 3a), six reported data on hospitalization due to COVID-19 (Table 3b), two reported data on death due to COVID-19 (Table 3c), and no studies reported data on prevention of post-COVID-conditions or MIS-C. The pooled vaccine effectiveness estimates from the observational studies demonstrated that the updated COVID-19 vaccine reduced medically attended COVID-19 (ED/UC visits) (pooled vaccine effectiveness: 53%, 95% CI: 50–56%; based on 2 studies) [16, 18]. The pooled vaccine effectiveness against hospitalization due to COVID-19 was 48% (95% CI: 30–61%), based on 8 estimates from 4 studies [17, 18, 20, 21] (2 studies were excluded from the meta-analysis due to overlapping populations). The pooled vaccine effectiveness for prevention of death due to COVID-19 was 61% (95% CI: 41–74%), based on 2 studies [18, 20].

Observational data on serious adverse events were reviewed. An analysis from VSD evaluated chart-reviewed cases of myocarditis and pericarditis occurring in a 0–7-day risk interval among persons aged 5–39 years following a booster dose of the original monovalent vaccine and a booster dose of the bivalent vaccine (Table 3d) [23, 24]. The rate of myocarditis and pericarditis per million doses varied by age group, gender, vaccine, and dose. For adolescents and adults, the highest rate of myocarditis and pericarditis was observed among males ages 16 – 17 years receiving the original monovalent Pfizer booster dose (188.0 [95% CI: 86.0–356.9]). The highest rate following a bivalent booster dose was observed among males 30 – 39 years receiving the Moderna vaccine (23.9 [95% CI: 0.6–133.2]), however due to low uptake of the bivalent booster, rates of myocarditis and pericarditis should be interpreted with caution. For children ages 5 – 11 years, there were no cases of myocarditis or pericarditis observed. An analysis of data from VSD evaluated chart-reviewed cases of anaphylaxis among all vaccinated persons aged ≥12 years following either dose of the original monovalent primary series. Based on events occurring in a 0–1-day risk interval after vaccination, the estimated incidence of confirmed anaphylaxis was 5.1 (95% CI: 3.3–7.4) per million doses of Moderna and 4.8 (95% CI: 3.2–6.9) per million doses of Pfizer [22]. Six randomized controlled trials among adolescents and adults [2-9] and 4 among infants and children [10-15] reported on grade ≥3 systemic or local reactions following either dose of a primary series of the original monovalent vaccine. Grade ≥3 reactions occurred more frequently in the vaccine than placebo groups in both age groups (Table 3e).

GRADE Summary

The initial GRADE evidence level was high for RCTs and low for the observational data. In terms of benefits, the observational data among adolescents and adults indicated that the vaccine reduces the risk of medically attended COVID-19 (ED/UC visits), and no serious concerns impacting certainty were identified for this outcome (low certainty). Observational data among adolescents and adults for hospitalization due to COVID-19 indicated a similar risk reduction with vaccination, and there were no serious concerns in the certainty assessment (low certainty). The observational data among adolescents and adults indicated a reduction in risk of death due to COVID-19 and was downgraded once for serious concern of inconsistency (very low certainty). Among infants and children, the findings for all three benefits were the same, however all were downgraded for serious concern for indirectness and the certainty assessment was very low.

Observational data on specified serious adverse events (i.e., myocarditis/pericarditis and anaphylaxis) demonstrated these events were rare and there were no serious concerns in the certainty assessment for adolescents and adults (low certainty), however there were serious concerns due to indirectness in the certainty assessment for infants and children (very low certainty). There were very serious concerns for indirectness due to differences in intervention and population that reduced the certainty of estimates of reactogenicity from RCTs (low certainty) in both age groups.

The summary of evidence types is shown in Tables 5a and 5b. The final certainty assessments for adults and adolescents were low for prevention of medically attended COVID-19, low for prevention of hospitalization due to COVID-19, very low for prevention of death due to COVID-19, low for specified serious adverse events, and low for reactogenicity. The final certainty assessments for infants and children were very low for prevention of medically attended COVID-19, prevention of hospitalization due to COVID-19, and prevention of death due to COVID-19, very low for specified serious adverse events, and low for reactogenicity.

References

1. Ahmed, F., et al., Methods for developing evidence-based recommendations by the Advisory Committee on Immunization Practices (ACIP) of the U.S. Centers for Disease Control and Prevention (CDC). Vaccine, 2011. 29(49): p. 9171-6.
2. Anderson, E.J., et al., Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults. N Engl J Med, 2020. 383(25): p. 2427-2438.
3. Jackson, L.A., et al., An mRNA Vaccine against SARS-CoV-2 – Preliminary Report. N Engl J Med, 2020. 383(20): p. 1920-1931.
4. Chu, L., et al., A preliminary report of a randomized controlled phase 2 trial of the safety and immunogenicity of mRNA-1273 SARS-CoV-2 vaccine. Vaccine, 2021. 39(20): p. 2791-2799.
5. Baden, L.R., et al., Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med, 2021. 384(5): p. 403-416.
6. El Sahly, H.M., et al., Efficacy of the mRNA-1273 SARS-CoV-2 Vaccine at Completion of Blinded Phase. N Engl J Med, 2021. 385(19): p. 1774-1785.
7. Walsh, E.E., et al., Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates. New England Journal of Medicine, 2020. 383(25): p. 2439-2450.
8. Polack, F.P., et al., Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. New England Journal of Medicine, 2020. 383(27): p. 2603-2615.
9. Thomas, S.J., et al., Six Month Safety and Efficacy of the BNT162b2 mRNA COVID-19 Vaccine. medRxiv, 2021: p. 2021.07.28.21261159.
10. Moderna, Personal Communication, June 2021-May 2022. 2021.
11. Moderna, Personal Communication, March 22-May 26, 2022. 2022.
12. Moderna, Personal Communication, March 22-June 3, 2022. 2022.
13. Pfizer-BioNTech, Personal Communication, March 22-June 8, 2022. 2022.
14. Woodworth, K.R., et al., The Advisory Committee on Immunization Practices’ Interim Recommendation for Use of Pfizer-BioNTech COVID-19 Vaccine in Children Aged 5-11 Years – United States, November 2021. MMWR Morb Mortal Wkly Rep, 2021. 70(45): p. 1579-1583.
15. Oliver, S.E., et al., The Advisory Committee on Immunization Practices’ Interim Recommendation for Use of Pfizer-BioNTech COVID-19 Vaccine – United States, December 2020. MMWR Morb Mortal Wkly Rep, 2020. 69(50): p. 1922-1924.
16. Tenforde, M.W., et al., Early Estimates of Bivalent mRNA Vaccine Effectiveness in Preventing COVID-19-Associated Emergency Department or Urgent Care Encounters and Hospitalizations Among Immunocompetent Adults – VISION Network, Nine States, September-November 2022. MMWR Morb Mortal Wkly Rep, 2023. 71(53): p. 1637-1646.
17. Surie, D., et al., Early Estimates of Bivalent mRNA Vaccine Effectiveness in Preventing COVID-19-Associated Hospitalization Among Immunocompetent Adults Aged ≥65 Years – IVY Network, 18 States, September 8-November 30, 2022. MMWR Morb Mortal Wkly Rep, 2022. 71(5152): p. 1625-1630.
18. Tseng, H.F., et al., Effectiveness of mRNA-1273 bivalent (Original and Omicron BA.4/BA.5) COVID-19 vaccine in preventing hospitalizations for COVID-19, medically attended SARS-CoV-2 infections, and hospital death in the United States. medRxiv, 2023: p. 2023.05.25.23290456.
19. Lin, D.-Y., et al., Effectiveness of Bivalent Boosters against Severe Omicron Infection. New England Journal of Medicine, 2023. 388(8): p. 764-766.
20. Lin, D.-Y., et al., Durability of Bivalent Boosters against Omicron Subvariants. New England Journal of Medicine, 2023. 388(19): p. 1818-1820.
21. Link-Gelles, R., et al., Estimates of Bivalent mRNA Vaccine Durability in Preventing COVID-19-Associated Hospitalization and Critical Illness Among Adults with and Without Immunocompromising Conditions – VISION Network, September 2022-April 2023. MMWR Morb Mortal Wkly Rep, 2023. 72(21): p. 579-588.
22. Klein, N.P., et al., Surveillance for Adverse Events After COVID-19 mRNA Vaccination. Jama, 2021. 326(14): p. 1390-1399.
23. Klein, N.P., Goddard, K, COVID-19 Vaccine Safety Surveillance Summary from VSD RCA. 2023.
24. Goddard, K., Hanson, K., Lewis, N., Weintraub, E., Fireman, B., Klein, N.P., Incidence of Myocarditis/Pericarditis Following mRNA COVID-19 Vaccination Among Children and Younger Adults in the United States. Annals of Internal Medicine, 2022. 175(12): p. 1169-1771.
25. U.S. Food and Drug Administration, September 11, 2023 Approval Letter – Spikevax. 2023.
26. U.S. Food and Drug Administration, September 11, 2023 Approval Letter – Comirnaty. 2023.
27. U.S. Food and Drug Administration, Pfizer-BioNTech COVID-19 Vaccine Emergency Use Authorization. 2023.
28. U.S. Food and Drug Administration, Moderna COVID-19 Vaccine Emergency Use Authorization. 2023.
29. International Vaccine Access Center (IVAC). VIEW-hub. 2023.

Table 1: Policy Question and PICO

Table 1a: Policy Question and PICO for Adolescents and Adults

Abbreviations: PICO: population, intervention, comparison, outcomes.

Table 1b: Policy Question and PICO for Infants and Children

Abbreviations: PICO: population, intervention, comparison, outcomes.

Table 2: Outcomes and Rankings

Table 2a: Outcomes and Rankings for Adolescents and Adults

^aThree options: 1. Critical; 2. Important but not critical; 3. Not important for decision making

Table 2b: Outcomes and Rankings for Infants and Children

^aThree options: 1. Critical; 2. Important but not critical; 3. Not important for decision making

Table 3a: Summary of Studies Reporting Medically Attended COVID-19 (Emergency Department/Urgent Care Visits)

^aPre-print article

^bErrata published on March 17, 2023.

Table 3b: Summary of Studies Reporting Hospitalization due to COVID-19

^a Vaccine effectiveness estimates were not included in the pooled analysis used for GRADE due to overlapping population with another study.

^b Preprint article

^c Updated analysis presented to ACIP on April 19, 2023: “COVID-19 Vaccine Effectiveness Updates”.

^d Errata published on March 17, 2023.

^e Study included vaccine effectiveness estimates for immunocompromised patients that were not included in the pooled analysis.

Table 3c: Summary of Studies Reporting Death due to COVID-19

^a Preprint article

Table 3d: Summary of Studies Reporting Specified Serious Adverse Events (anaphylaxis and myocarditis/pericarditis)

^aRates of myocarditis and pericarditis following an original monovalent booster were published by Goddard et al in 2022. This analysis was updated in May 2023 and rates following a bivalent booster were presented at the September 12, 2023 ACIP meeting.

Table 3e: Summary of Studies Reporting Reactogenicity^a

^aReactogenicity outcome includes local and systemic events, grade ≥3. Grade 3: prevents daily routine activity or requires use of a pain reliever. Grade 4: requires emergency room visit or hospitalization.

^bAdditional data provided by sponsor.

^cRisk of bias was not formally assessed for these small studies with no comparator; these were not included in the quantitative estimate used for GRADE.

Table 4: Grade Summary of Findings Table

Table 4a: Grade Summary of Findings Table: Adolescents and Adults (Ages ≥12)

Explanations 

1. The body of evidence includes preprints.
2. The body of evidence includes a manufacturer-funded study.
3. One study contained data only for Moderna mRNA COVID vaccine. This was deemed unlikely to lead to a substantial risk of bias in the magnitude of effect.
4. Pooled RR based on a fixed effects meta-analysis, using adjusted vaccine effectiveness estimates on a log scale.A fixed effects model was used for this analysis due to imprecise estimates of the between-studies variance.
5. Absolute risk was calculated using the observed risk among a single observational cohort in the available body of evidence. Absolute risk estimates should be interpreted in this context.
6. Six studies were available in the body of evidence. Two were excluded because the study population was already represented.
7. Although I² value was high (92.6%), no serious concern for inconsistency was present because all studies showed consistent magnitudes of effect at similar time points post bivalent dose.
8. Measurement of outcomes differed by study (COVID-19 was not necessarily confirmed as the cause of hospitalizations), but this was deemed not serious.
9.  The denominator from one cohort study was based on census population estimates.
10. Pooled RR based on a random effects meta-analysis, using adjusted vaccine effectiveness estimates on a log scale.
11. Serious concern for inconsistency was present. The magnitude of effect and 95% CIs from the two studies in the body of evidence varied widely, possibly reflecting differences in study methods.
12. Indirectness was noted for anaphylaxis as rates were from the primary series. Primary series rates of anaphylaxis are likely an overestimate of the rate in the current phase of COVID-19 after an updated vaccine, and this was deemed not serious.
13. An analysis from Vaccine Safety Datalink (VSD) evaluated chart-reviewed cases of myocarditis occurring among persons aged 12 – 39 years following a monovalent booster dose and a bivalent dose. Based on events occurring in a 7-day risk interval after vaccination vs. a comparison interval in vaccinated individuals. Among adolescents aged 12 – 17 years who received a bivalent booster dose of Pfizer-BioNTech, there were 0 cases of myocarditis among 55,549 males and 0 cases among 57,776 females (rate per million doses in men was 0 [95% CI: 0 – 5] and women was 0 [95% CI: 0 – 52]). Among adults aged 18 – 49 years there were 2 myocarditis cases in 221,576 males, and 0 in 319,676 females. Among Pfizer-BioNTech recipients, rates per million doses were: 17 (95% CI: 1 – 92) in males ages 18 – 29 years; 0 (95% CI: 0 – 32) in females ages 18 – 29 years; 0 (95% CI: 0–31) in males ages 30 – 39 years and 0 (95% CI: 0 – 23) in females ages 30 – 39 years. Among Moderna recipients, rates per million doses were: 0 (95% CI: 0 – 135) in males ages 18 – 29 years; 0 (95% CI: 0–85) in females ages 18 – 29 years; 24 (95% CI: 1 – 133) in males ages 30 – 39 years and 0 (95% CI: 0–54) in females ages 30 – 39 years. Among adolescents ages 12 – 15 years who received a monovalent booster dose of Pfizer-BioNTech, there were 5 cases of myocarditis among 81,613 males and 0 cases among 84,114 females (rate per million doses in males was 61 [95% CI: 20 – 143] and in females was 0 [95% CI: 0 – 36]). Among adolescents ages 16 – 17 years, there were 9 cases of myocarditis among 47,874 males and 2 cases among 55,004 females (rate per million doses in males was 188 [95% CI: 86 – 357] and in females was 36 [95% CI: 4 – 131]). Among adults ages 18 – 29 years, there were 7 cases of myocarditis among 166,973 males and 1 case among 240,226 females (rate per million doses in males was 42 [95% CI: 17 – 86] and in females was 4 [95% CI: 0 – 23]).  Among adults ages 30 – 39 years, there were 3 cases of myocarditis among 197,554 males and 1 case among 268,412 females (rate per million doses in males was 15 [95% CI: 3 – 44] and in females was 4 [95% CI: 0 – 23]).  Among adults ages 18 – 29 years who received a monovalent booster dose of Moderna, there were 7 cases of myocarditis among 109,337 males and 1 case among 156,707 females (rate per million doses in males was 64 [95% CI: 26 – 132] and in females was 6 [95% CI: 0 – 36]). Among adults ages 30 – 39 years, there was 1 case of myocarditis among 149,468 males and 2 cases among 191,765 females (rate per million doses in males was 7 [95% CI: 0 – 37] and in females was 10 [95% CI: 1 – 38).
14. An analysis of data from VSD evaluated chart-reviewed cases of anaphylaxis among all vaccinated persons aged 12 and older. Based on events occurring in a 0 – 1-day risk interval after vaccination, the estimated incidence of confirmed anaphylaxis among adolescents and adults was 4.8 (95% CI: 3.2 – 6.9) per million doses of BNT162B2 and 5.1 (95% CI: 3.3 – 7.4) per million doses of mRNA-1273. There were fewer cases of anaphylaxis post dose 2 compared with dose 1.
15. Twelve studies were available for the body of evidence. Two small Phase I observational studies with no comparison group were not included in the GRADE analysis.
16. Very serious concern for indirectness was present. The available body of evidence did not include anyone who received an updated dose and excluded persons with prior COVID-19 infection, pregnant or breastfeeding women, and persons who were immunocompromised.
17. Absolute risk was calculated using the observed outcomes in the placebo arm during the available clinical trial follow-up. Absolute risk estimates should be interpreted in this context.

Table 4b: Grade Summary of Findings Table: Infants and Children Ages 6 Months to 11

CI: Confidence interval; RR: Risk ratio

Explanations 

1. The body of evidence includes preprints.
2. The body of evidence includes a manufacturer-funded study.
3. One study contained data only for Moderna mRNA COVID vaccine. This was deemed unlikely to lead to a substantial risk of bias in the magnitude of effect.
4. Serious concern for indirectness was present. The vast majority of the body of evidence contained data from adolescents and adults.
5. Pooled RR based on a fixed effects meta-analysis, using adjusted vaccine effectiveness estimates on a log scale. A fixed effects model was used for this analysis due to imprecise estimates of the between-studies variance.
6. Absolute risk was calculated using the observed risk among a single observational cohort in the available body of evidence. Absolute risk estimates should be interpreted in this context.
7. Six studies were available in the body of evidence. Two were excluded because the study population was already represented.
8. Although I² value was high (92.6%), no serious concern for inconsistency was present because all studies showed consistent magnitudes of effect at similar time points post bivalent dose.
9. Serious concern for indirectness was present. The vast majority of the body of evidence contained data from adolescents and adults. Measurement of outcomes differed by study (COVID-19 was not necessarily confirmed as the cause of hospitalizations), but this was deemed not serious.
10. The denominator from one cohort study was based on census population estimates.
11. Pooled RR based on a random effects meta-analysis, using adjusted vaccine effectiveness estimates on a log scale.
12. Serious concern for imprecision was present. The magnitude of effect and 95% CIs from the two studies in the body of evidence varied widely, possibly reflecting differences in study methods.
13. Serious concern for indirectness was present, as the body of evidence for myocarditis was only among children aged 5 – 11 receiving a monovalent booster and the body of evidence for anaphylaxis was among adults and adolescents aged 12 years and older receiving a primary series.
14. An analysis from Vaccine Safety Datalink (VSD) evaluated chart-reviewed cases of myocarditis occurring among children aged 5 – 11 years following a bivalent dose. Based on events occurring in a 7-day risk interval after vaccination vs. a comparison interval in vaccinated individuals, among children aged 5 – 11 years who received an updated dose of Pfizer-BioNTech, there were 0 cases of myocarditis among 50,415 males and 0 cases among 49,261 females (rate per million doses in men was 0 [95% CI: 0 – 59.4] and women was 0 [95% CI: 0-60.8])
15. A rapid cycle analysis of data from VSD evaluated chart-reviewed cases of anaphylaxis among all vaccinated persons aged 12 and older. Based on events occurring in a 0 – 1-day risk interval after vaccination, the estimated incidence of confirmed anaphylaxis among adolescents and adults 4.8 (95% CI: 3.2 – 6.9) per million doses of Pfizer and 5.1 (95% CI: 3.3 – 7.4) per million doses of Moderna. There were fewer cases of anaphylaxis post dose 2 compared with dose 1.
16. Very serious concern for indirectness was present. The available body of evidence did not include anyone who received an updated dose and excluded children who were immunocompromised. While children with a history of COVID-19 infection were included in the safety sets, the RCTs were conducted at a time of low seroprevalence.
17. Estimates only includes ages children ages 4/5 – 11 years due to differences in events and measurement of reactogenicity among children 6 months – 4/5 years. Among children 6 months – 4/5 years pooled reactogenicity was 1.58 (95% CI: 1.30 – 1.93).
18. Absolute risk was calculated using the observed outcomes in the placebo arm during the available clinical trial follow-up. Absolute risk estimates should be interpreted in this context.

Table 5. Summary of Evidence for Outcomes of Interest

Summary of Evidence for Outcomes of Interest– Adolescents and Adults (12 years and older)

Summary of Evidence for Outcomes of Interest – Infants and Children (6 months – 11 years)

Appendices

Appendix 1. Studies Included in the Review of Evidence

Observational Case-Control Studies

Safety Surveillance

^aPre-print
^bUpdated analysis from April 19, 2023 ACIP meeting “COVID-19 Vaccine Effectiveness Updates”.
^cErrata published on March 17, 2023
^dTotal population, cases, and controls reflect the population used in the meta-analysis.

Appendix 2. Databases and strategies used for systematic review

Appendix 3. Myocarditis and pericarditis rates 0 to 7 Days after mRNA COVID-19 monovalent and bivalent boosters among persons aged ≥5 years by age group, sex, and product