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Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Updated COVID-19 vaccine (2024-2025 Formulation)
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 [2-14], and 3 studies of a single vaccine safety surveillance system [15-17] 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 years [18, 19] and authorized these vaccines for use in children aged 6 months−11 years under Emergency Use Authorization (EUA) [20, 21]. 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) [2-4, 12, 13] (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 studies [2-5, 7, 9, 10, 12] (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 studies [2, 7, 10] (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) [15, 16]. 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.
References
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Table 1: Policy Question and PICO
Table 1a: Policy Question and PICO for Adolescents and Adults
| 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
| 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
| 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
| 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)
| 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
| 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
| 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)
| 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)
| № 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
- Six studies were available in the body of evidence. One was excluded because the study population was already represented.
- The body of evidence includes pre-prints.
- The body of evidence includes manufacturer-funded studies.
- 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.
- 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.
- Pooled VE based on a random effects meta-analysis, using adjusted vaccine effectiveness estimates on a log scale.
- Twelve studies were included in the body of evidence. Four were excluded because the study population was already represented.
- 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.
- 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.
- Measurement of outcomes differed by study (COVID-19 was not necessarily confirmed as the cause of hospitalizations), but this was deemed not serious.
- Four studies were included in the body of evidence. One was excluded because the study population was already represented.
- 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.
- 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.
- 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.
- 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).
- 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
| № 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
- Study population only included children aged 6 months – 5 years. This was deemed insufficient to downgrade for indirectness.
- Twelve studies were included in the body of evidence. Four were excluded because the study population was already represented.
- The body of evidence includes preprints.
- The body of evidence includes manufacturer-funded studies.
- 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.
- 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.
- 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.
- Serious concern for indirectness was present. Most 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.
- Pooled VE based on a random effects meta-analysis, using adjusted vaccine effectiveness estimates on a log scale.
- 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.
- 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.
- 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.
- 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]).
- 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)
| 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)
| 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
| 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 |
|
Government funding |
| Lin, 2023 [6] | Observational (Retrospective Cohort) | ≥12 years | 6,306,311 | 1,279,802 | 5,026,509 |
|
Government funding |
| Tseng a, 2023 [14] | Observational (Retrospective Cohort-matched) | ≥6 years | 870,876 | 290,292 | 580,584 |
|
Industry funding |
| Paritala a, 2023 [10] | Observational (Retrospective Cohort) | ≥12 years | 754,767 | 215,576 | 539,191 |
|
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 |
|
Government funding |
| Link-Gelles, 2022 [21] | Observational (Test-Negative Case Control) |
≥18 years | 28,872 | 13,358 | 15,514 |
|
Government funding |
| Tenforde c, 2022 [13] | Observational (Test-Negative Case Control) |
≥18 years | 27,796 | 4,697 | 23,099 |
|
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 |
|
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 |
|
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 |
|
Government funding |
| Caffrey a, 2024 [3] | Observational (Test-Negative Case Control) |
≥18 years | ED/UC: 61,976 Hospitalization: 24,206 |
- | - |
|
Industry funding |
| Link-Gelles, 2023 [8] | Observational (Test-Negative Case Control) |
6 months – 5 years | 30,464 | 1,331 | 29,133 |
|
Government funding |
| DeCuir a, 2024 [5] | Observational (Test-Negative Case Control) |
≥18 years | 9,674 | 4,075 | 5,599 |
|
Government funding |
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) |
|
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 |
|---|---|
| International Vaccine Access Center (IVAC) | Inclusion criteria for IVAC systematic review:
Additional criteria for GRADE review:
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:
|
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) |