Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Updated COVID-19 vaccine (2024-2025 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 (2024-2025 Formulation) was presented to the Advisory Committee on Immunization Practices (ACIP) on June 27, 2024. 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 2024 – 2025 COVID-19 vaccines be recommended for use in persons ≥6 months of age?" To evaluate the certainty of evidence for anticipated benefits and harms for the 2024-2025 Formulation COVID-19 vaccine, the ACIP COVID-19 Vaccines Work Group (WG) assessed evidence from previous updated COVID-19 vaccines (i.e., bivalent or 2023 – 2024 Formulation) 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 specified a priori 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 harms identified a priori for both age groups were serious adverse events (SAEs) pre-specified by the ACIP COVID-19 Vaccines WG (i.e., myocarditis/pericarditis and anaphylaxis) (critical).

A 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 September 2, 2022, through May 10, 2024. The evidence from 13 vaccine effectiveness studies,234567891011121314 and 3 studies of a single vaccine safety surveillance system151617 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 for the outcomes of post-COVID conditions and MIS-C. Benefits for infants and children for hospitalization and death due to COVID-19 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 (VE) estimates from observational studies found that updated COVID-19 vaccines were associated with a lower risk of: medically-attended COVID-19 (ED/UC visits) (pooled VE: 43%; 95% confidence interval [CI]: 30%–54%; low certainty); hospitalization due to COVID-19 (pooled VE: 44%; 95% CI: 34%–53%; low certainty); and death due to COVID-19 (pooled VE: 23%, 95% CI: 8%–36%; low certainty). For infants and children, updated COVID-19 vaccines were associated with a lower risk of medically-attended COVID-19 (VE: 80%; 95% CI: 42%–96%; low certainty), and findings in adults and adolescents provided indirect evidence of benefits for prevention of hospitalization and death due to COVID-19 and were downgraded for serious concern for indirectness. The certainty assessment for both outcomes was very low.

In terms of harms, the available data from observational safety surveillance systems indicated that there was a rare risk of pre-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).

Introduction

On August 22, 2024, FDA approved the 2024-2025 Formulation COVID-19 vaccines by Moderna and Pfizer-BioNTech for use in persons aged ≥12 years1819 and authorized these vaccines for use in children aged 6 months−11 years under Emergency Use Authorization (EUA)2021. On August 30, 2024, FDA authorized 2024-2025 COVID-19 vaccine by Novavax for use in persons aged ≥12 years under EUA.22 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 (WG) 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 updated COVID-19 vaccines (i.e., bivalent or 2023–2024 Formulation), which were determined by the ACIP COVID-19 Vaccines WG to be the most directly applicable to the 2024–2025 COVID-19 vaccine due to their 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 COVID-19 vaccine (2024–2025 Formulation) be recommended for persons aged 6 months and older?" To evaluate the certainty of evidence for anticipated benefits and harms from the 2024–2025 Formulation COVID-19 vaccine, the ACIP COVID-19 Vaccines WG assessed evidence from previous updated COVID-19 vaccines (i.e., bivalent and 2023–2024 Formulation) 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 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 relevant observational studies through an ongoing systematic review conducted by the International Vaccine Access Center (IVAC).23 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 May 17, 2024. Outcomes were assessed starting at least 7 days after a dose of COVID-19 vaccine. We included bivalent or 2023-2024 COVID-19 vaccine effectiveness estimates, which could be combined vaccine effectiveness for multiple COVID-19 vaccines, or a single COVID-19 vaccine. We included studies of general populations and special populations. 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.

Vaccine effectiveness (VE) estimates and 95% confidence intervals (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 dose, all estimates were included in the pooled vaccine effectiveness estimate. When a single study provided estimates for overlapping populations at distinct time points, the estimate with most comprehensive population and follow-up time was selected for inclusion in the pooled estimate. The evidence certainty assessment for 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 June 27, 2024.

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 harms of interest were pre-specified serious adverse events (SAEs), (i.e., myocarditis/pericarditis and anaphylaxis).

After screening 313 publications yielded in the search, 293 were excluded from full-text review because they were in a different population (i.e., a different country n=211), studied a different outcome (i.e., symptomatic COVID-19, n=31) or a different study period (n=51). Of the 20 publications that were deemed eligible for full-text review, 2 were excluded because they had a different comparator and 2 were excluded because they had a different study period. The remaining 16 studies were included in the evidence synthesis and GRADE evidence assessment (Appendix 1). Data were reviewed from 13 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 the outcomes of prevention of hospitalization and death due to COVID-19 in infants and children. Benefits were indirectly inferred from adolescent and adult data.

Seven observational vaccine effectiveness studies reported data on medically attended COVID-19 (ED/UC visits) (Table 3a); twelve reported data on hospitalization due to COVID-19 (Table 3b); four 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 VE estimates from the five observational studies demonstrated that the updated COVID-19 vaccine reduced medically-attended COVID-19 (ED/UC visits) (pooled VE: 43%, 95% CI: 30–54%; based on 5 studies)2341213 (1 study was excluded from the meta-analysis due to overlapping populations) among adults and adolescents. Among infants and children, one study demonstrated that the updated COVID-19 vaccine reduced medically-attended COVID-19 (ED/UC visits) (VE: 80%, 95% CI: 42–96%).8 The pooled VE against hospitalization due to COVID-19 was 44% (95% CI: 34–52%) based in 8 studies2345791012 (4 studies were excluded from the meta-analysis due to overlapping populations). The pooled vaccine effectiveness for prevention of death due to COVID-19 was 28% (95% CI: 8–36%), based on 3 studies2710 (1 study was excluded from the meta-analysis due to overlapping populations).

Observational data on serious adverse events were reviewed. One 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).1516 The rate of myocarditis and pericarditis per million doses varied by age group, gender, vaccine, and dose. For adolescents and adults, the highest incidence 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] per million doses). The highest incidence 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] per million doses), however due to low uptake of the bivalent booster, incidence 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. One 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 was conducted. Based on events occurring in a 0–1-day risk interval after vaccination, the estimated incidence rates 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.17 Due to low uptake, there were no data to inform harms of Novavax in VSD.

GRADE Summary

The initial GRADE evidence level was low for 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 there were no serious concerns in the certainty assessment (low certainty). Among infants and children, observational data 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). For hospitalization due to COVID-19 and death due to COVID-19 findings, observation findings indicated a reduction in risk, however both were downgraded for serious concern for indirectness and the certainty assessment was very low.

Observational data on pre-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).

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, low for prevention of death due to COVID-19, and low for pre-specified serious adverse events. The final certainty assessments for infants and children were low for prevention of medically attended COVID-19, very low for prevention of hospitalization due to COVID-19, very low for prevention of death due to COVID-19, and very low for pre-specified serious adverse events.

Tables

Table 1: Policy Question and PICO

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

Table 1: Policy Question and PICO
Policy question Should 2024 – 2025 COVID-19 vaccines be recommended for use in adolescents and adults aged ≥12 years?
Population Adolescents and adults aged ≥12 years
Intervention Updated COVID-19 vaccine (i.e., bivalent or 2023-2024 Formulation)
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)

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

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

Table 1b: Policy Question and PICO
Policy question Should 2024 – 2025 COVID-19 vaccines be recommended for use in infants and children aged 6 months to 11 years of age?
Population Infants and children aged 6 months – 11 years
Intervention Updated COVID-19 vaccine (i.e., bivalent or 2023-2024 Formulation)
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)

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

Table 2: Outcomes and Rankings

Table 2a: Outcomes and Rankings for Adolescents and Adults

Table 2a: Outcomes and Rankings
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

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

Table 2b: Outcomes and Rankings for Infants and Children

Table 2b: Outcomes and Rankings
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

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

Table 3: Summary of Studies Reporting Outcomes of Interest

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

Table 3a: Summary of Studies Reporting Medically Attended COVID-19 (Emergency Department/Urgent Care Visits)
Authors last name, pub year Design, study population No. of patients vaccinated or No. of cases No. of patients unvaccinated or No. of controls Median days since updated dose Comparison Vaccine Effectiveness (95% CI) Study limitations (Risk of Bias)
Tseng a,b,c, 2023 [14] Observational (retrospective cohort-matched); General population ≥6 years immunocompetent & immunocompromised 855 cases/290,292 vaccinated 2,083 cases/580,584 unvaccinated 74 days BV compared to 2 doses OMV 55 (51 – 59) Not serious
Tenforde d, 2022 [13] Observational (test-negative design); General population ≥18 years immunocompetent 338 vaccinated cases/2,738 unvaccinated cases 4,359 vaccinated controls /20,361 unvaccinated controls 25 days BV mRNA compared to 2 doses OMV 50 (44 – 56) Not serious
Tartof b, 2022 [12] Observational (test-negative design); General population ≥18 years immunocompetent & immunocompromised 10,249 cases 53,317 controls 77 days Pfizer BV compared to at least two doses OMV 35 (30 – 40) Not serious
Ackerson b, 2024 [2] Observational (test-negative design); General population ≥18 years immunocompetent & immunocompromised BA.4/BA.5: 218 vaccinated cases /1,930 unvaccinated cases BA.4/BA.5: 1,190 vaccinated controls /5,254 unvaccinated controls Half of BA.4/BA.5 14-60 days Moderna BV compared to at least two OMV BA.4/BA.5: 58 (50 – 65) Not serious
XBB: 343 vaccinated cases /1,307 unvaccinated cases XBB: 1,113 vaccinated controls /3,837 unvaccinated controls Half of XBB 60- 180 days XBB: 26 (13 – 36) Not serious
DeCuir, 2024 [4] Observational (test-negative design); General population ≥18 years immunocompetent 1,297 vaccinated cases /17,229 unvaccinated cases 13,378 vaccinated controls /111,596 unvaccinated controls 44 days 2023-2024 dose compared to no updated dose 47 (44 – 50) Not serious
Caffrey a,b, 2024 [3] Observational (test-negative design); VA beneficiaries ≥18 years immunocompetent & immunocompromised Cases and controls: 61,976 76 days 2023-2024 dose Pfizer compared to no updated dose 39 (33 – 45) Not serious
Link-Gelles, 2023[8] Observational (test-negative design); General population 6 months – 5 years immunocompetent) 3 vaccinated cases/1,331 unvaccinated cases 315 vaccinated controls/29,133 unvaccinated controls 58 days BV compared to unvaccinated 80 (42 – 96) Not serious

CI: confidence interval; BV: bivalent; OMV: original monovalent

aPre-print article

bManufacturer-funded study

cStudy not included in the pooled estimate due to overlapping study population with another study captured in the systematic review.

dErrata published on March 17, 2023.

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

Table 3b: Summary of Studies Reporting Hospitalization due to COVID-19
Authors last name, pub year Design, study population No. of patients vaccinated or No. of cases No. of patients unvaccinated or No. of controls Median days since updated dose Comparator Vaccine Effectiveness, % (95% CI) Study limitations (Risk of Bias)
Lin a, 2023 [7] Observational (retrospective cohort); General population ≥12 years immunocompetent & immunocompromised - - - BV compared to 2 dose OMV 59 (44 – 70) Not serious
Lin, 2023 [6] Observational (retrospective cohort); General population ≥12 years immunocompetent & immunocompromised 253 cases/1,279,802 vaccinated 1,955 cases/5,026,509 unvaccinated Maximum: 105 dases BV compared to 2 dose OMV 40 (26 – 51) Not serious
Tseng a,b,c, 2023 [14] Observational (retrospective cohort-matched); General population ≥6 years immunocompetent & immunocompromised 160 cases/290,292 vaccinated 646 cases/580,584 unvaccinated 74 days Moderna BV compared to 2 dose OMV 70 (64 – 75) Not serious
Paritala b, 2023 [10] Observational (retrospective cohort); General population ≥6 years immunocompetent & immunocompromised 371 cases/215,576 vaccinated 1,009 cases/539,191 vaccinated Maximum: 200 days BV compared to 1 fewer dose 22 (0 – 49) Not serious
Surie a,d, 2023 [11] Observational (test negative design); General population ≥65 years immunocompetent 61 vaccinated cases/844 unvaccinated cases 175 vaccinated cases/1,059 unvaccinated controls 34 days BV (7-59 days earlier) compared to 2 OMV 60 (45 – 71) Not serious
105 vaccinated cases/888 unvaccinated cases 183 vaccinated cases /1,067 unvaccinated controls 89 days BV (60-119 days earlier) compared to 2 OMV 35 (14 – 51)
73 vaccinated cases/856 unvaccinated cases 92 vaccinated controls /976 unvaccinated controls 141 days BV (120-176 days earlier) compared to 2 OMV 17 (-21 – 42)
Tenforde a,e, 2022 [13] Observational (test-negative design); General population ≥18 years immunocompetent 56 vaccinated cases/500 unvaccinated cases 444 vaccinated controls/4,933 unvaccinated controls 23 days BV compared to ≥ 2 doses OMV 48 (30 – 62) Not serious
Link-Gelles, 2023[9] Observational (test-negative design); General population ≥18 years immunocompetent 327 vaccinated cases/4,857 unvaccinated cases 1,791 vaccinated controls /15,514 unvaccinated controls 34 days BV (7-59 days earlier) compared to 2 OMV 62 (57 – 67) Not serious
486 vaccinated cases/5,191 unvaccinated cases 87 days BV (60-119 days earlier) compared to 2 OMV 47 (41 – 53)
315 vaccinated cases/3,310 unvaccinated cases 144 days BV (120-176 days earlier) compared to 2 OMV 24 (12 – 33)
Tartofc, 2023 [12] Observational (test-negative design); General population ≥18 years immunocompetent & immunocompromised 169 vaccinated cases /1457 unvaccinated cases 1905 vaccinated controls /11,101 unvaccinated controls 77 days Pfizer BV compared to ≥ 2 mRNA OMV 39 (28-49) Not serious
Ackersonc, 2024 [2] Observational (test-negative design); General population ≥18 years immunocompetent & immunocompromised BA.4/BA.5: 24 vaccinated cases/235 unvaccinated cases BA.4/BA.5: 196 vaccinated controls /581 unvaccinated controls Half of BA.4/BA.5 14-60 days Moderna BV vs ≥ 2 mRNA MV BA.4/BA.5: 67 (44 – 81) Not serious
XBB: 40 vaccinated cases /172 unvaccinated cases XBB: 209 vaccinated controls /427 unvaccinated controls Half of XBB 60-180 days XBB: 60 (37 – 75)
DeCuirb, 2024[5] Observational (test-negative design); General population ≥18 years immunocompetent 184 vaccinated cases /1995 unvaccinated cases 463 vaccinated controls /2843 unvaccinated controls 53 days BV mRNA (7-89 days after) vs 2 OMV 48 (36 – 57) Not serious
269 vaccinated cases /2080 unvaccinated cases 376 vaccinated controls /2756 unvaccinated controls 133 days BV mRNA (90-179 days after) vs 2 OMV 17 (-1 – 31)
DeCuir, 2024[4] Observational (test-negative design); General population ≥18 years immunocompetent 395 vaccinated cases /4589 unvaccinated cases 4199 vaccinated controls /32914 unvaccinated controls 42 days 2023-2024 dose vs no updated dose 52 (47 – 57) Not serious
94 vaccinated cases /1194 unvaccinated cases 353 vaccinated controls /2923 unvaccinated controls 47 days 43 (27 – 56)
Caffreyb,c, 2024 [3] Observational (test-negative design); VA beneficiaries ≥18 years immunocompetent & immunocompromised Cases and controls: 24206 76 days 2023-2024 Pfizer dose vs no updated dose 43 (34 – 51) Not serious

CI: confidence interval; BV: bivalent; OMV: original monovalent

aStudy not included in the pooled estimate due to overlapping study population with another study captured in the systematic review.

bPre-print article

cManufacturer-funded study

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

eErrata published on March 17, 2023.

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

Table 3c: Summary of Studies Reporting Death due to COVID-19
Authors last name, pub year Design, study population No. of patients vaccinated or No. of cases No. of patients unvaccinated or No. of controls Median days since updated dose Comparator Vaccine Efficacy/Effectiveness, % (95% CI) Study limitations (Risk of Bias)
Tseng a,b,c, 2023 [18] Observational (retrospective cohort-matched); General population ≥6 years immunocompetent & immunocompromised; United States 10 cases/290,292 vaccinated 59 cases/580,584 unvaccinated 74 days Moderna BV compared to 2 dose OMV 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 Maximum: 105 days BV compared to 2 dose OMV 44 (9 – 65) Not serious
Paritalaa, 2023 [10] Observational (retrospective cohort); General population ≥6 years immunocompetent & immunocompromised 59 cases /215,576 unvaccinated 167 cases /539,191 unvaccinated Maximum: 112 days BV compared to 1 fewer dose 18 (0-56) Not serious
Ackerson b, 2024 [2] Observational (test-negative design); General population ≥18 years immunocompetent & immunocompromised BA.4/BA.5: 2 vaccinated cases/15 unvaccinated cases BA.4/BA.5: 13 vaccinated controls /38 unvaccinated controls  Half of BA.4/BA.5 14-60 days Moderna BV compared to at least two OMV BA.4/BA.5: 53 (-84 – 97) Not serious
XBB: 4 vaccinated cases/ 10 unvaccinated cases XBB: 17 vaccinated controls /25 unvaccinated controls Half of XBB 60-180 days XBB: 32 (-84 – 94)

CI: confidence interval; BV: bivalent; OMV: original monovalent

aPre-print article

bManufacturer-funded study

cStudy not included in the pooled estimate due to overlapping study population with another study captured in the systematic review.

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

Table 3d: Summary of Studies Reporting Specified Serious Adverse Events (anaphylaxis and myocarditis/pericarditis)
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) [17] 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 [15, 16] (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 4 GRADE Summary of Findings Tables

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

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 Vaccine effectiveness (95% CI) Certainty Importance
Medically attended COVID-19 (emergency department/urgent care visit)
5a Observational studiesb,c not seriousd not serious not seriouse not serious None 27,478 cases/190,528 controls
61,976 cases and controls
VE 43 (30 to 54)f Low Critical
Hospitalization due to COVID-19
8g Observational studiesb,c not serioush not seriousi not serious not serious None 24,878 cases 166,023 controls
24,206 cases and controls
642/343,558 exposed 2,964/50,504,700 unexposedj
VE 44 (34 to 52)f Low Critical
Death due to COVID-19
3k Observational studiesb,c not seriousl not serious not serious not serious None 1,130/343,558 exposed 955/50,504,700 unexposed
35 cases/63 controls
VE 23 (8 to 36)m Low Important
Serious adverse events
2 Observational study not serious not serious not seriousn not serious None Footnote:o,p Low Critical

CI: Confidence interval; RR: Risk ratio

Explanations

  1. Six studies were available in the body of evidence. One was excluded because the study population was already represented.
  2. The body of evidence includes pre-prints.
  3. The body of evidence includes manufacturer-funded studies.
  4. Two studies contained data only for Pfizer mRNA COVID vaccine and one study contained data only for mRNA Moderna vaccine. This was deemed unlikely to lead to a substantial risk bias in the magnitude of effect.
  5. Although I2 value was high (90%), no serious concern for inconsistency was present because all studies showed consistent magnitudes of effect at similar time points post updated dose.
  6. Pooled VE based on a random effects meta-analysis, using adjusted vaccine effectiveness estimates on a log scale.
  7. Twelve studies were included in the body of evidence. Four were excluded because the study population was already represented.
  8. Two studies contained data only for Pfizer mRNA COVID vaccine and one study contained data only for mRNA Moderna vaccine. This was deemed unlikely to lead to a substantial risk bias in the magnitude of effect.
  9. Although I2 value was high (87%), no serious concern for inconsistency was present because all studies showed consistent magnitudes of effect at similar time points post bivalent dose.
  10. Measurement of outcomes differed by study (COVID-19 was not necessarily confirmed as the cause of hospitalizations), but this was deemed not serious.
  11. Four studies were included in the body of evidence. One was excluded because the study population was already represented.
  12. One study contained data only for Moderna COVID-19 vaccine. This was deemed unlikely to lead to a substantial risk bias in the magnitude of effect.
  13. Pooled VE based on a fixed effects meta-analysis, using adjusted vaccine effectiveness estimates on a log scale. Fixed effects model was used for this analysis due to imprecision of the between-studies variance estimate.
  14. 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.
  15. An analysis from Vaccine Safety Datalink (VSD) evaluated chart-reviewed cases of myocarditis occurring among persons aged 12 – 39 years following an original 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).
  16. 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.

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

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 Vaccine Effectiveness (95% CI) Certainty Importance
Medically attended COVID-19 (ED/UC visits)
1 Observational studies not serious not serious not seriousa not serious none 1,331 cases /29,133 controls VE 80
(42 to 96)
Low Critical
Hospitalization due to COVID-19
8b Observational studiesc,d not seriousf not seriousg serioush not serious none 24,878 cases 166,023 controls
24,206 cases and controls
642/343,558 exposed 2,964/50,504,700 unexposedi
VE 44 (34 to 52)j Very Low Critical
Death due to COVID-19
3k Observational studiesc,d not seriousk not serious serioush not serious none 1130/343,558 exposed 955/50,504,700 unexposed
35 cases/63 controls
VE 23 (8 to 36)l 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

CI: Confidence interval; RR: Risk ratio

Explanations

  1. Study population only included children aged 6 months – 5 years. This was deemed insufficient to downgrade for indirectness.
  2. Twelve studies were included in the body of evidence. Four were excluded because the study population was already represented.
  3. The body of evidence includes preprints.
  4. The body of evidence includes manufacturer-funded studies.
  5. 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.
  6. Two studies contained data only for Pfizer mRNA COVID vaccine and one study contained data only for mRNA Moderna vaccine. This was deemed unlikely to lead to a substantial risk bias in the magnitude of effect.
  7. Although I2 value was high (87%), no serious concern for inconsistency was present because all studies showed consistent magnitudes of effect at similar time points post bivalent dose.
  8. Serious concern for indirectness was present. Most of the body of evidence contained data from adolescents and adults.
  9. Measurement of outcomes differed by study (COVID-19 was not necessarily confirmed as the cause of hospitalizations), but this was deemed not serious.
  10. Pooled VE based on a random effects meta-analysis, using adjusted vaccine effectiveness estimates on a log scale.
  11. One study contained data only for Moderna COVID-19 vaccine. This was deemed unlikely to lead to a substantial risk bias in the magnitude of effect.
  12. Pooled VE based on a fixed effects meta-analysis, using adjusted vaccine effectiveness estimates on a log scale. Fixed effects model was used for this analysis due to imprecision of the between-studies variance estimate.
  13. Serious concern for indirectness was present, as the body of evidence for myocarditis was only among children aged 5 – 11 receiving an original 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.

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– 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 Low
Post COVID Conditions Important - -
Specified serious adverse events (myocarditis and anaphylaxis) Critical Yes Low

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

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 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

Appendices

Appendix 1. Studies Included in the Review of Evidence

Observational Retrospective Cohort Studies

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 [7] Observational (Retrospective Cohort) ≥12 years 6,283,483 1,070,136 5,213,347
  • Hospitalization due to COVID-19
Government funding
Lin, 2023 [6] 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 a, 2023 [14] 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
Paritala a, 2023 [10] Observational (Retrospective Cohort) ≥12 years 754,767 215,576 539,191
  • Hospitalization due to COVID-19
  • Death due to COVID-19

Observational Case-Control Studies

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
Surieb, 2023 [11] 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 c, 2022 [13] Observational
(Test-Negative Case Control)
≥18 years 27,796 4,697 23,099
  • Medically attended COVID-19 (ED/UC)
Government funding
Tartof, 2022 [12] Observational
(Test-Negative Case Control)
≥18 years ED/UC: 63,566
Hospitalization: 12,556
ED/UC: 10,249
Hospitalization: 1,457
ED/UC: 53,317
Hospitalization: 11,101
  • Medically attended COVID-19 (ED/UC)
  • Hospitalization due to COVID-19
Industry funding
Ackerson,  2024 [2] Observational
(Test-Negative Case Control)
≥18 years ED/UC: 12,328
Hospitalization: 1,408
Death: 88
ED/UC: 3,237
Hospitalization: 407
Death: 25
ED/UC: 9,031
Hospitalization: 1,008
Death: 63
  • Medically attended COVID-19 (ED/UC)
  • Hospitalization due to COVID-19
  • Death due to COVID-19
Industry funding
DeCuir, 2024 [4] Observational
(Test-Negative Case Control)
≥18 years ED/UC: 128,825
Hospitalization: 41,620
ED/UC: 17,229
Hospitalization: 5,783
ED/UC: 111,596
Hospitalization: 35,837
  • Medically attended COVID-19 (ED/UC)
  • Hospitalization due to COVID-19
Government funding
Caffrey a, 2024 [3] Observational
(Test-Negative Case Control)
≥18 years ED/UC: 61,976
Hospitalization: 24,206
- -
  • Medically attended COVID-19 (ED/UC)
  • Hospitalization due to COVID-19
Industry funding
Link-Gelles, 2023 [8] Observational
(Test-Negative Case Control)
6 months – 5 years 30,464 1,331 29,133
  • Medically attended COVID-19 (ED/UC)
Government funding
DeCuir a, 2024 [5] Observational
(Test-Negative Case Control)
≥18 years 9,674 4,075 5,599
  • Hospitalization due to COVID-19
Government funding

Safety Surveillance

Safety Surveillance
Name of system Study design Age group Total population N
vaccinated
N
unvaccinated
Outcomes Funding source
Vaccine Safety Datalink (VSD) [15-17] 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

Appendix 2. Databases and strategies used for systematic review
Database Strategy
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 May 17, 2024
  • Vaccines with updated formulation (i.e., 2023-2024 Formulation or bivalent)
  • Included studies of general population and special populations (e.g., elderly, pregnant persons, healthcare workers)

Detailed methods, including search terms: https://view-hub.org/sites/default/files/2022-09/COVID19_VE_Lit_Review_Methods.pdf

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

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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