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

About

CDC vaccine recommendations are developed using an explicit evidence-based method based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.

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,23 10 Phase I, II, II/III, or III randomized controlled trials (RCTs),456789101112131415 6 vaccine effectiveness studies,161718192021 and 3 studies of a single vaccine safety surveillance system222324 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 years2526 and issued an Emergency Use Authorization (EUA)2728 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).1618 The pooled vaccine effectiveness against hospitalization due to COVID-19 was 48% (95% CI: 30–61%), based on 8 estimates from 4 studies17182021 (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.1820

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).2324 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 adults23456789 and 4 among infants and children101112131415 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.

Tables

Table 1: Policy Question and PICO

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

Policy question
Should vaccination with an updated COVID-19 vaccine (2023-2024 Formulation, monovalent with XBB.1.5 component) be recommended for adolescents and adults aged ≥12 years?
Population
Adolescents and adults aged ≥12 years
Intervention
Updated COVID-19 vaccine (i.e., bivalent with ancestral and BA.4/5 components)
Comparison
No updated vaccine
Outcomes
Medically attended COVID-19 (emergency department/urgent care visits)
Hospitalization due to COVID-19
Death due to COVID-19
Post-COVID Conditions
Specified serious adverse events (myocarditis/pericarditis and anaphylaxis)
Reactogenicity (grade ≥3)

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

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

Policy question
Should vaccination with an updated COVID-19 vaccine (2023-2024 Formulation, monovalent with XBB.1.5 component) be recommended for infants and children aged 6 months – 11 years?
Population
Infants and children aged 6 months – 11 years
Intervention
Updated COVID-19 vaccine (i.e., bivalent with ancestral and BA.4/5 components)
Comparison
No updated vaccine
Outcomes
Medically attended COVID-19 (emergency department/urgent care visits)
Hospitalization due to COVID-19
Death due to COVID-19
Post-COVID Conditions
MIS-C
Specified serious adverse events (myocarditis/pericarditis and anaphylaxis)
Reactogenicity (grade ≥3)

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

Table 2: Outcomes and Rankings

Table 2a: Outcomes and Rankings for Adolescents and Adults

Outcome Importancea Included in evidence profile
Medically attended COVID-19 (emergency department/urgent care visits) Critical Yes
Hospitalization due to COVID-19 Critical Yes
Death due to COVID-19 Important Yes
Post-COVID Conditions Important No
Specified serious adverse events (myocarditis/pericarditis and anaphylaxis) Critical Yes
Reactogenicity (grade ≥3) Important Yes

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

Table 2b: Outcomes and Rankings for Infants and Children

Outcome Importancea Included in evidence profile
Medically attended COVID-19 (emergency department/urgent care visits) Critical Yes
Hospitalization due to COVID-19 Critical Yes
Death due to COVID-19 Important Yes
Post-COVID Conditions Important No
MIS-C Important No
Specified serious adverse events (myocarditis/pericarditis and anaphylaxis) Critical Yes
Reactogenicity (grade ≥3) Important Yes

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)

References in this table:1618

Authors last name, pub year Design, study population No. of patients vaccinated or No. of cases No. of patients unvaccinated or No. of controls Days after bivalent booster Comparator Vaccine Effectiveness (95% CI) Study limitations (Risk of Bias)
Tseng, 2023a [18] Observational (retrospective cohort-matched); General population ≥6 years immunocompetent & immunocompromised; United States 855 cases/290,292 vaccinated 2,083 cases/580,584 unvaccinated ≥14 days ≥ 2 doses, monovalent 55 (51 – 59) Not serious
Tenforde, 2022b [16] Observational (test-negative design); General population ≥18 years immunocompetent; United States 338 vaccinated/4,697 cases 2738 vaccinated/23,099 controls ≥7 days ≥ 2 doses, monovalent 50 (44 – 56) Not serious

aPre-print article

bErrata published on March 17, 2023.

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

References in this table:161718192021

Authors last name, pub year Design, study population No. of patients vaccinated or No. of cases No. of patients unvaccinated or No. of controls Days after bivalent booster Comparator Vaccine Efficacy/Effectiveness, % (95% CI) Study limitations (Risk of Bias)
Lin, 2023a [19] Observational (retrospective cohort); General population ≥12 years immunocompetent & immunocompromised; United States 57 cases/1,070,136 vaccinated 954 cases/5,213,347 unvaccinated ≥14 days ≥ 2 doses, monovalent 59 (44 – 70) Not serious
Lin, 2023 [20] Observational (retrospective cohort); General population ≥12 years immunocompetent & immunocompromised; United States  379 cases/1,279,802 vaccinated 1,829 cases/5,026,509 unvaccinated ≥14 days ≥ 2 doses, monovalent 40 (26 – 51) Not serious
Tseng, 2023b[18] Observational (retrospective cohort-matched); General population ≥6 years immunocompetent & immunocompromised; United States 160 cases/290,292 vaccinated 646 cases/580,584 unvaccinated ≥14 days ≥ 2 doses, monovalent 70 (64 – 75) Not serious
Surie, 2023c [17] Observational (test negative design); General population ≥65 years immunocompetent; United States 61 vaccinated/844 cases 175 vaccinated/1,059 controls 7 – 59 days ≥2 doses, monovalent 60 (45 – 71) Not serious
105 vaccinated/888 cases 183 vaccinated /1,067 controls 60 – 119 days 35 (14 – 51)
73 vaccinated /856 cases 92 vaccinated /976 controls 120 – 179 days 17 (-21 – 42)
Tenforde, 2022 a, d [16] Observational (test-negative design); General population ≥18 years immunocompetent; United States 54 vaccinated /884 cases 444 vaccinated /4549 controls ≥7 days ≥ 2 doses, monovalent 48 (30 – 62) Not serious
Link-Gelles, 2023e[21] Observational (test-negative design); General population ≥18 years immunocompetent; United States 327 vaccinated/4857 cases 1791 vaccinated /15514 controls 7 – 59 days Unvaccinated 62 (57 – 67) Not serious
486 vaccinated /5191 cases 60 – 119 days 47 (41 – 53)
315 vaccinated/3310 cases 120 – 179 days 24 (12 – 33)

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

References in this table:1820

Authors last name, pub year Design, study population No. of patients vaccinated or No. of cases No. of patients unvaccinated or No. of controls Days after bivalent booster Comparator Vaccine Efficacy/Effectiveness, % (95% CI) Study limitations (Risk of Bias)
Tseng, 2023a[18] Observational (retrospective cohort-matched); General population ≥6 years immunocompetent & immunocompromised; United States 10 cases/290,292 vaccinated 59 cases/580,584 unvaccinated ≥14 days ≥ 2 doses, monovalent 82 (63 – 91) Not serious
Lin, 2023 [20] Observational (retrospective cohort); General population ≥12 years immunocompetent & immunocompromised; United States 79 cases/1,279,802 vaccinated 788 cases/5,026,509 unvaccinated ≥14 days ≥ 2 doses, monovalent 44 (9 – 65) Not serious

a Preprint article

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

References in this table:222324

Authors last name, pub year Age or other characteristics of importance n/N (%) intervention n/N (%) comparison Comparator RR (95% CI) Study limitations (Risk or Bias)
Klein (Anaphylaxis) [22] Age ≥12 years Rate per million following a first or second dose of an original monovalent primary series in a 0 – 1 day risk interval:
Pfizer: 4.8 (95% CI 3.2 – 6.9)
Moderna: 5.1 (95% CI: 3.3 – 7.4)
Not serious
Goddard, Kleina [23, 24] (Myocarditis/pericarditis)b 5–39 years Rate per million following an original monovalent booster and a bivalent booster series in a 0 – 7 day risk interval are in Appendix 3 Not serious

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 Reactogenicitya

References in this table:23456789101112131415

Authors last name, pub year Age or other characteristic of importance n/N (%) intervention n/N (%) comparison Comparator RR (95% CI) Study limitations (Risk of Bias)
Anderson, 2020 [2] b Phase I open label study, persons aged >55 years 1/20 (5.0) c
Jackson, 2020 [3] b Phase I open label study, persons aged 18-55 years 1/15 (6.7) c
Chu, 2021 [4] b Phase II RCT, persons aged ≥18 years 32/200 (16.0) 6/200 (3.0) Placebo 5.3 (2.3, 12.5) Not serious
Baden 2020, El Sahly 2021 [5, 6] b Phase III RCT, persons aged ≥18 years 3,243/15,179 (21.4) 679/15,159 (4.5) Placebo 5.0 (4.7, 5.5) Not serious
Moderna, 2021 [10] Phase II/III RCT, persons aged 12-17 years 629/2485 (25.3) 60/1240 (4.8) Placebo 5.2 (4.1, 6.8) Not serious
Walsh 2020 [7] b Phase I RCT, persons aged ≥ 16 years 3/24 (8.3) 0/6 (0) Placebo 2.0 (0.1, 33.6) Not serious
Polack, 2020
Thomas 2021 [8, 9] b
Phase II/III RCT, persons aged ≥ 16 years 520/4,924 (10.6) 111/4,915 (2.3) Placebo 4.7(3.8, 5.7) Not serious
Pfizer, 2021 [15] Phase II/III RCT, persons aged 12-15 years 121/1,131 (10.7) 22/1,129 (1.9) Placebo 5.5 (3.5, 8.6) Not serious
Moderna, 2022 [11] Phase II/III RCT, persons aged 6-11 years 514/3,006 (17.1) 33/994 (3.3%) Placebo 5.2 (3.6, 7.3) Not serious
Moderna, 2022 [12] Phase II/III RCT, persons aged 6 months-5 years 366/4,774 (7.7) 65/1,582 (4.1) Placebo 1.9 (1.4, 2.4) Not Serious
Pfizer, 2021 [14] Phase II/III RCT, persons aged 5-11 years 41/1,517 (2.7) 8/750 (1.1) Placebo 2.5 (1.2, 5.4) Not serious
Pfizer, 2022 [13] Phase II/III RCT, persons aged 6 months-4 years 129/3,010 (4.3) 54/1,510 (3.6) Placebo 1.2 (0.9, 1.6) Not serious

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)

№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations № of patients Intervention № of patients Comparison Effect Relative (95% CI) Effect Absolute (95% CI) Certainty Importance
Medically attended COVID-19 (emergency department/urgent care visit)
2 Observational studiesa,b not seriousc not serious not serious not serious none 338/4,697 cases; 2,738/23,099 controls
855/290,292 exposed; 2,083/580,584 unexposeda,b
RR 0.5
(0.4 to 0.5)d
186 fewer per 100,000
(from 196 fewer to 175 fewer)e
Low Critical
Hospitalization due to COVID-19
4f Observational studiesa,b not seriousc not seriousg not serioush not serious none 1,367/15,946 cases; 12,241/18,616 controls
557/1,570,094 exposed;
2,475/5,607,093 unexposeda,b,i
RR 0.5
(0.4 to 0.7)j
53 fewer per 100,000
(from 67 fewer to 33 fewer)e
Low Critical
Death due to COVID-19
2 Observational studiesa,b not seriousc seriousk not serious not serious none 89/1,570,094 exposed
847/5,607,098 unexposeda,b,i
RR 0.4
(0.3 to 0.6)d
6 fewer per 100,000
(from 8 fewer to 4 fewer)e
Very Low Important
Serious adverse events
2 Observational study not serious not serious not seriousl not serious none Footnote:m,n Low Critical
Reactogenicity, grade >=3
10o Randomized controlled trial not serious not serious very seriousp not serious none 4,556/23,943 (19.0%) 878/22,649 (3.9%) RR 4.8 (4.5 to 5.2) 14,847 more per 100,000 (from 13,568 more to 16,204 more)q Low Important

CI: Confidence interval; RR: Risk ratio

Explanations

a. The body of evidence includes preprints.
b. The body of evidence includes a manufacturer-funded study.
c. 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.
d. 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.
e. 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.
f. Six studies were available in the body of evidence. Two were excluded because the study population was already represented.
g. 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.
h. Measurement of outcomes differed by study (COVID-19 was not necessarily confirmed as the cause of hospitalizations), but this was deemed not serious.
i. The denominator from one cohort study was based on census population estimates.
j. Pooled RR based on a random effects meta-analysis, using adjusted vaccine effectiveness estimates on a log scale.
k. 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.
l. 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.
m. 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).
n. 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.
o. 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.
p. 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.
q. 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

№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations № of patients Intervention № of patients Comparison Effect Relative
(95% CI)
Effect Absolute
(95% CI)
Certainty Importance
Medically attended COVID-19 (ED/UC visits)
2 Observational studiesa,b not seriousc not serious seriousd not serious none 338/4,697 cases; 2,738/23,099 controls
855/290,292 exposed 2,083/580,584 unexposeda,b
RR 0.5
(0.4 to 0.5)e
186 fewer per 100,000
(from 196 fewer to 175 fewer)f
Very Low Critical
Hospitalization due to COVID-19
4g Observational studiesa,b not seriousc not serioush seriousi not serious none 1,367/15,946 cases; 12,241/18,616 controls
557/1,570,094 exposed;
2,475/5,607,093 unexposeda,b,j
RR 0.5
(0.4 to 0.7)k
53 fewer per 100,000
(from 67 fewer to 33 fewer)f
Very Low Critical
Death due to COVID-19
2 Observational studiesa,b not seriousc seriousl seriousd not serious none 89/1,570,094 exposed; 847/5,607,098 unexposeda,b,j RR 0.4
(0.3 to 0.6)e
6 fewer per 100,000
(from 8 fewer to 4 fewer)f
Very Low Important
Specified serious adverse events (anaphylaxis and myocarditis/pericarditis)
1 Observational studies not serious not serious seriousm not serious none Footnoten,o Very Low Critical
Reactogenicity, grade ≥3
2 Randomized controlled trial not serious not serious very seriousp,q not serious None 555/4,523 (12.3%) 41/1,744 (2.4%) RR 4.7k (3.4 to 6.4) 8,675 more per 100,000 (from 5,713 more to 12,718 more)r Low Important

CI: Confidence interval; RR: Risk ratio

Explanations

a. The body of evidence includes preprints.
b. The body of evidence includes a manufacturer-funded study.
c. 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.
d. Serious concern for indirectness was present. The vast majority of the body of evidence contained data from adolescents and adults.
e. 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.
f. 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.
g. Six studies were available in the body of evidence. Two were excluded because the study population was already represented.
h. 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.
i. 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.
j. The denominator from one cohort study was based on census population estimates.
k. Pooled RR based on a random effects meta-analysis, using adjusted vaccine effectiveness estimates on a log scale.
l. 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.
m. 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.
n. 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])
o. 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.
p. 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.
q. 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).
r. 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)

Outcome Importance Included in profile Certainty
Medically attended COVID-19 (emergency department/urgent care visit) Critical Yes Low
Hospitalization due to COVID-19 Critical Yes Low
Death due to COVID-19 Important Yes Very Low
Post COVID Conditions Important
Specified serious adverse events (myocarditis and anaphylaxis) Critical Yes Low
Reactogenicity (≥ grade 3) Important Yes Low

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

Outcome Importance Included in profile Certainty
Medically attended COVID-19 (emergency department/urgent care visit) Critical Yes Very low
Hospitalization due to COVID-19 Critical Yes Very low
Death due to COVID-19 Important Yes Very Low
Post COVID Conditions Important
MIS-C Important
Specified serious adverse events (myocarditis and anaphylaxis) Critical Yes Very low
Reactogenicity (≥ grade 3) Important Yes Low

Appendices

Appendix 1. Studies Included in the Review of Evidence

Last name first author, Publication year Study design Age group Total population N Intervention N comparison Outcomes Funding source
Anderson, 2020 [2] Phase I open label study >55 years 40 20 0
  • Reactogenicity
Government and Industry funded
Jackson, 2020a [3] Phase I open label study 18-55 years 45 15 0
  • Reactogenicity
Government and Industry funded
Chu, 2021a [4] Phase II RCT ≥18 years 600 200 200
  • Reactogenicity
Industry funded
Baden 2020, El Sahly 2021a,b [5, 6] Phase III RCT ≥18 years 30,415 14,287 14,164
  • Reactogenicity
Industry funded
Walsh, 2020 [7] Phase I RCT 18-55, 65-85 years 195 12 3
  • Reactogenicity
Industry funded
Polack 2020; Thomas, 2021a; [8, 9]b Phase II/III RCT ≥16 years 43,548 19,711 19,741
  • Reactogenicity
Industry funded
Moderna, 2021 [10] Phase II/III RCT Persons aged 12-17 years 3725 2486 1240
  • Reactogenicity
Industry funded
Pfizer, 2021 [15] Phase II/III RCT Persons aged 12-15 years 2260 1131 1129
  • Reactogenicity
Industry funded
Moderna, 2022 [11] Phase II/III RCT Persons aged 6–11 years 4002 3007 995
  • Reactogenicity
Industry funded
Moderna, 2022 [12] Phase II/III RCT Persons aged 6 months-5 years 6,388 4,791 1,597
  • Reactogenicity
Industry funded
Pfizer, 2021 [14] Phase II/III RCT Children aged 5─11 years 4,647 3,109 1,538
  • Reactogenicity
Industry funded
Pfizer, 2022 [13] Phase II/III RCT Persons aged 6 months-4 years 4,526 3,013 1,513
  • Reactogenicity
Industry funded

Observational Retrospective Cohort Studies

Last name first author, Publication year Study design Age group Total population N Intervention N comparison Outcomes Funding source
Lin, 2023 [19] Observational (Retrospective Cohort) ≥12 years 6,283,483 1,070,136 5,213,347
  • Hospitalization due to COVID-19
Government funding
Lin, 2023 [20] Observational (Retrospective Cohort) ≥12 years 6,306,311 1,279,802 5,026,509
  • Hospitalization due to COVID-19
  • Death due to COVID-19
Government funding
Tseng, 2023a [18] Observational (Retrospective Cohort-matched) ≥6 years 870,876 290,292 580,584
  • Medically attended COVID-19 (ED/UC)
  • Hospitalization due to COVID-19
  • Death due to COVID-19
Industry funding

Observational Case-Control Studies

Last name
first author, Publication year
Study design Age, central tendency or range Total populationd N
casesd
N
controlsd
Outcomes Funding source
Surie, 2023b [17] Observational
(Test-Negative Case Control)
≥18 years 5,690 2,588 3,102
  • Hospitalization due to COVID-19
Government funding
Link-Gelles, 2022 [21] Observational
(Test-Negative Case Control)
≥18 years 28,872 13,358 15,514
  • Hospitalization due to COVID-19
Government funding
Tenforde, 2022c [16] Observational
(Test-Negative Case Control)
≥18 years 27,796 4,697 23,099
  • Medically attended COVID-19 (ED/UC)
Government funding

Safety Surveillance

Name of system Study design Age group Total population N
vaccinated
N
unvaccinated
Outcomes Funding source
Vaccine Safety Datalink (VSD) [22-24] Cohort ≥12 years (anaphylaxis);
5–39 years (myocarditis)
  • Serious Adverse Events
Government funding

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

Database
Strategy
clinicaltrials.gov
Inclusion:Relevant Phase I, II, II/III, or III randomized controlled trials of COVID-19 vaccine
  • Involved human subjects
  • Reported primary data
  • Included data on reactogenicity
Additional resources: Unpublished and other relevant data by consulting with vaccine manufacturers and subject matter experts
International Vaccine Access Center (IVAC)
Inclusion criteria for IVAC systematic review:
  • Published or preprint study with adequate scientific details
  • Includes groups with and without infection or disease outcome
  • Laboratory confirmed outcome
  • Vaccination status confirmed in ≥90%
  • Studies assess one vaccine or pooled mRNA vaccines
  • Includes participants who did or did not receive a COVID-19 vaccine
  • Vaccine effectiveness estimates include confidence intervals if possible
Additional criteria for GRADE review:
  • Restricted to PICO-defined population, intervention, comparison, and outcomes
  • Studies set in the United States
  • Majority of study period between September 2, 2022 and April 19, 2023
  • Vaccines with updated formulation (i.e., bivalent)
  • Included studies of general population and special populations (e.g., elderly, pregnant persons, healthcare workers)
Safety Surveillance Systems
Evidence Retrieval for Observational Safety Studies:
  • Based on input from ACIP’s COVID-19 Vaccine Safety Technical (VaST) Work Group
  • Data on safety signals identified by vaccine surveillance systems
  • Data have been presented to ACIP

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

Monovalent Booster Dose Bivalent Booster Dose
Age group (years) Cases/Doses Administered Incidence Rate/Million Doses (95% CI) Cases/Doses Administered Incidence Rate/Million Doses (95% CI)
Pfizer
Male
5 – 11 0/50415 0.0 (0.0-59.4)
12 – 17 0/55,649 0.0 (0.0 – 53.8)
12 – 15 5/81,613 61.3 (19.9 – 143.0)
16 – 17 9/47,874 188.0 (86.0 – 356.9)
18 – 29 7/166,973 41.9 (16.9 – 86.4) 1/60,338 16.6 (0.4 – 92.3)
30 – 39 3/197,554 15.2 (3.1 – 44.4) 0/97,171 0.0 (0.0 – 30.8)
Female
5 – 11 0/49,261 0.0 (0.0-60.8)
12 – 17 0/57,776 0.0 (0.0 – 51.9)
12 – 15 0/84,114 0.0 (0.0 – 35.6)
16 – 17 2/55,004 36.4 (4.4 – 131.3)
18 – 29 1/240,226 4.2 (0.1 – 23.2) 0/95,162 0.0 (0.0 – 31.5)
30 – 39 1/268,412 3.7 (0.1 – 20.8) 0/133,305 0.0 (0.0 – 22.5)
Moderna
Male
18 – 29 7/109,337 64.0 (25.7 – 131.9) 0/22,247 0.0 (0.0 – 134.7)
30 – 39 1/149,468 6.7 (0.2 – 37.3) 1/41,820 23.9 (0.6 – 133.2)
Female
18 – 29 1/156,707 6.4 (0.2 – 35.6) 0/35,393 0.0 (0.0 – 84.6)
30 – 39 2/191,765 10.4 (1.3 – 37.7) 0/55,816 0.0 (0.0 – 53.7)

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