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Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Moderna COVID-19 VaccineFDA Approved Biologics License Application						Print
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										Grading of Recommendations, Assessment, Development, and Evaluation
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			OverviewIntroductionMethodsResultsGRADE SummaryReferences
Overview
A Grading of Recommendations, Assessment, Development and Evaluation (GRADE) review of the evidence for benefits and harms for Moderna COVID-19 vaccine was presented to the Advisory Committee for Immunization Practices (ACIP) on February 4, 2022. GRADE evidence type indicates the certainty of estimates from the available body of evidence. Evidence certainty ranges from type 1 (high certainty) to type 4 (very low certainty) [1].
The policy question was, “Should vaccination with the Moderna COVID-19 vaccine (Spikevax, 2-dose primary series) be recommended for persons 18 years of age and older?” The potential benefits pre-specified by the ACIP COVID-19 Vaccines Work Group included prevention of symptomatic laboratory-confirmed COVID-19 (critical), hospitalization due to COVID-19 (critical), death due to COVID-19 (important), and asymptomatic SARS-CoV-2 infection (important). The two pre-specified harms were serious adverse events (SAEs) (including myocarditis and anaphylaxis) (critical) and reactogenicity (severe, grade ≥3) (important).
A systematic review of evidence on the benefits and harms of a two-dose regimen of Moderna COVID-19 vaccine among persons aged ≥18 years was conducted, based on data available as of December 10, 2021. The evidence from two Phase I open label trials [2, 3], one Phase II randomized controlled trial (RCT) [4], one Phase III RCT [5, 6], 26 vaccine effectiveness studies [7-32], and two vaccine safety surveillance systems [33, 34] were assessed using a modified GRADE approach [1]. Pooled efficacy and effectiveness estimates were calculated when multiple sources had data on an outcome.
In terms of benefits, the available data from RCTs demonstrated that, compared with placebo, vaccination was associated with a lower risk of symptomatic laboratory-confirmed COVID-19 (relative risk [RR] 0.07, 95% confidence interval [CI] 0.05–0.09; evidence type 1), hospitalization due to COVID-19 (RR 0.04; 95% CI 0.01–0.31; evidence type 2), death due to COVID-19 (RR 0.14, 95% CI 0.01–2.79; evidence type 3), and asymptomatic SARS-CoV-2 infection (RR 0.43; 95% CI 0.36–0.50; evidence type 1). The certainty of estimates regarding hospitalization and death due to COVID-19 was reduced due to imprecision.
The pooled vaccine effectiveness estimates from observational studies were consistent with these findings. Compared with no vaccination, vaccination with Moderna COVID-19 vaccine was associated with a decreased risk of symptomatic laboratory-confirmed COVID-19 (RR 0.11, 95% CI 0.06–0.18; evidence type 2), hospitalization (RR 0.05, 95% CI 0.04–0.07; evidence type 2), and death due to COVID-19 (RR 0.06, 95% CI 0.05–0.08; evidence type 2). The certainty of each of these estimates was increased for a strong association. Vaccination was also associated with a decreased risk of asymptomatic SARS-CoV-2 infection (RR 0.30, 95% CI 0.23–0.39; evidence type 4); the evidence certainty type was downgraded for inconsistency.
In terms of harms, the available data from RCTs indicated that serious adverse events were balanced between the vaccine and placebo arms (RR 0.92; 95% CI 0.78–1.08, evidence type 2), and 15 serious adverse events reported for 12 persons were judged to be related to vaccination among more than 15,000 persons vaccinated. The certainty of this estimate was reduced due to imprecision. Reactogenicity grade ≥3 was associated with vaccination (RR 5.03; 95% CI 4.65–5.45, evidence type 1). About 21% of vaccine recipients versus 5% of placebo recipients reported grade ≥3 reactions. Two rare but serious adverse events, anaphylaxis and myocarditis, have been associated with vaccination in post-authorization safety surveillance (see results section and Table 3e).
Introduction
On January 31, 2022, the U.S. Food and Drug Administration (FDA) approved the Biologics License Application (BLA) for Moderna COVID-19 Vaccine (Spikevax) for the prevention of COVID-19 in persons aged ≥18 years [35]. As part of the process employed by the Advisory Committee for Immunization Practices (ACIP), a systematic review and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) assessment of the evidence for Moderna COVID-19 vaccine was conducted and presented to ACIP [1]. There were no conflicts of interest reported by CDC and ACIP COVID-19 Vaccines Work Group members involved in the GRADE analysis.
ACIP adopted a modified GRADE approach in 2010 as the framework for evaluating the scientific evidence that informs recommendations for vaccine use. ACIP has made modifications to the GRADE approach by presenting assessed evidence as type 1, 2, 3, and 4, which corresponds to high, moderate, low, and very low certainty, whereas standard GRADE has high as level 4 and very low as level 1. 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 efficacy and safety of a two-dose regimen of Moderna COVID-19 vaccine among persons aged ≥18 years. Evidence of benefits and harms were reviewed based on the modified GRADE approach [1].
The policy question was, “Should vaccination with Moderna COVID-19 vaccine (Spikevax, 2-dose primary series) be recommended for persons 18 years of age and older?” (Table 1).
Methods
We conducted a systematic review of evidence on the benefits and harms of a two-dose regimen of Moderna 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 by the Work Group during Work Group calls and via online surveys where members were asked to rate and rank the importance of relevant outcomes.
We identified RCTs through clinicaltrials.gov. Relevant Phase I, II, or III RCTs of Moderna COVID-19 vaccine were included if they: 1) involved human subjects; 2) reported primary data; 3) included adults (aged ≥18 years) at risk for SARS-CoV-2 infection; 4) included data relevant to the efficacy and safety outcomes being measured; 5) included data for the dosage being recommended (100 μg, 2 doses at 0 and 28 days). We identified relevant observational studies through an ongoing systematic review conducted by the International Vaccine Access Center (IVAC) and the World Health Organization (WHO) [36]. Relevant observational studies, using case-control, test-negative, or cohort designs, were restricted to the defined population, intervention, comparison, and outcome outlined in the policy question. Outcomes were assessed starting at least 7 days after 2nd dose. We included only 2-dose Moderna vaccine effectiveness estimates, with combined mRNA vaccine effectiveness estimates excluded. We included studies of general populations and special populations. In addition, efforts were made to obtain unpublished and other relevant data by hand-searching reference lists, and consulting with vaccine manufacturers and subject matter experts. We included observational safety data from two vaccine safety surveillance systems based on input from ACIP’s COVID-19 Vaccines Safety Technical (VaST) Work Group: Vaccine Safety Datalink (VSD) and Vaccine Adverse Event Reporting System (VAERS). Characteristics of all included studies and surveillance systems are shown in Appendix 1 [2-33].
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 comprises a series of questions structured into domains focusing on different aspects of trial design, conduct, and reporting. Based on question responses, judgement can be “low”, “moderate”, or “high” risk of bias. NOS is a 9-point scale which assesses study limitations related to participant selection and comparability, and assessment of outcome (cohort studies) or ascertainment of exposure (case-control studies). Studies with NOS scores <7 were considered to have serious study limitations.
From the RCT data, RR were calculated from numerators and denominators available in the body of evidence. Vaccine efficacy estimates were defined as 100% x (1-RR). Vaccine effectiveness estimates and 95% CIs were taken from the published/preprint studies, as defined by the authors using a variety of study designs and analytical approaches; adjusted estimates were used when available. When multiple studies were available, pooled estimates were calculated using random effects (>3 studies) or fixed effects (≤3 studies) meta-analysis (R meta package). When multiple studies provided estimates based on overlapping study populations, the study with the most comprehensive population and follow-up time was selected for inclusion in the pooled estimate. Because there was a relatively large body of evidence from vaccine effectiveness studies, with many available only in the preprint literature, an *a priori* decision was made to exclude studies judged to have serious study limitations from the main pooled estimate used for GRADE. Sensitivity analyses were performed to assess the influence of study characteristics (e.g., special populations vs. full population, preprint vs. peer-reviewed, standard vs. extended dosing interval, cohort vs. case-control/test-negative study design, study limitations, and circulating variants). The evidence certainty assessment for randomized and observational studies addressed risk of bias, inconsistency, indirectness, imprecision, and other characteristics. The GRADE assessment across the body of evidence for each outcome was presented in an evidence profile.
Results
The results of the GRADE assessment were presented to ACIP on February 4, 2022.
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 were prevention of symptomatic laboratory-confirmed COVID-19 and prevention of hospitalization due to COVID-19 (Table 2). Other important benefits included prevention of death due to COVID-19 and prevention of asymptomatic SARS-CoV-2 infection. The critical harm of interest was serious adverse events (SAEs), including myocarditis and anaphylaxis; reactogenicity grade ≥3 was deemed an important harm.
After screening 134 publications, 96 were excluded from full-text review because they were a different intervention (e.g., a different vaccine or a different dose, n=91), or a different outcome (e.g., any infection instead of symptomatic COVID-19 or asymptomatic infection, n=5). Of the 38 publications that were deemed eligible for full-text review, four were excluded because they assessed a different intervention, and one was excluded because it assessed a different outcome. The remaining 33 publications, which reported data on 31 studies or surveillance systems, were included in the evidence synthesis and GRADE evidence assessment (Appendix 1) [2-33]. Data were reviewed from five RCT publications, including two publications from the Phase I trial, one publication from a Phase II trial, and two publications from the Phase III trial [2-6]. Data were reviewed from 26 vaccine effectiveness studies. Two vaccine safety surveillance systems, VSD and VAERS, included data for SAEs [33, 34].
In the Phase III RCT, using data on all blinded follow-up (median follow up of 5 months), the Moderna COVID-19 vaccine reduced symptomatic laboratory-confirmed COVID-19 when compared to placebo (vaccine efficacy: 92.7%, 95% CI 90.4–94.4%) (Table 3a). For hospitalization due to COVID-19, 25 events occurred, 24 in the placebo group and one in the vaccine group. Vaccine efficacy against hospitalization due to COVID-19 was 95.9% (95% CI 69.5–99.4%) (Table 3b). Deaths due to COVID-19 were uncommon, zero in the vaccine group and three in the placebo group (vaccine efficacy: 100%) (Table 3c). Numbers of SAEs were comparable between the vaccine group and the placebo group across the two RCTs (Phase III: 268/15,184 (1.8%) vs. 292/15,164 (1.9%); Phase II: 0/200 (0.0%) vs. 0/200 (0.0%)); there were no cases of vaccine-associated enhanced disease or vaccine-related deaths (Table 3e). Grade ≥3 reactions generally were not uncommon and occurred more frequently in the vaccine than placebo groups (Table 3f).
Fourteen vaccine effectiveness studies reported data on symptomatic laboratory-confirmed COVID-19 (Table 3a), 19 reported data on hospitalization due to COVID-19 (Table 3b), five reported data on death due to COVID-19 (Table 3c), and three reported data on asymptomatic SARS-CoV-2 infection (Table 3d). The pooled vaccine effectiveness estimates from the observational studies demonstrated that the Moderna COVID-19 vaccine reduced symptomatic laboratory-confirmed COVID-19 when compared to no vaccination (pooled vaccine effectiveness: 89.2%, 95% CI 82.0–93.6%; based on 11 studies) [7, 10, 12, 13, 16, 19, 20, 22, 24, 28, 31]. The pooled vaccine effectiveness against hospitalization due to COVID-19 was 94.8% (95% CI 93.1–96.1%), based on 14 studies [8-10, 12, 16-20, 25-28, 31]. The pooled vaccine effectiveness for prevention of death due to COVID-19 was 93.8% (95% CI 91.5–95.4%), based on five studies [10, 17, 18, 25, 32]. The pooled vaccine effectiveness against asymptomatic SARS-CoV-2 infection was 69.8% (95% CI 60.9–76.7%), based on three studies [10, 12, 28].
Observational data on serious adverse events were reviewed. A rapid cycle analysis from VSD evaluated chart-reviewed cases of myocarditis and pericarditis occurring among persons aged 18–39 years following dose 2 of the Moderna COVID-19 vaccine (Table 3e) [34]. The rate of myocarditis and pericarditis was 33.0 cases per million doses in the 0–7-day risk interval. Data from VAERS showed an elevated ratio of observed to expected myocarditis cases in the 7-day interval following vaccination among females aged 18–29 years and among males aged 18–49 years, with higher observed/expected ratios in males than females [34]. A rapid cycle analysis of data from VSD evaluated chart-reviewed cases of anaphylaxis among all vaccinated persons aged ≥18 years. Based on events occurring in a 0–1 day risk interval after vaccination, the estimated incidence of confirmed anaphylaxis was 5.1 (95% CI 3.3–7.6) per million doses [33].
GRADE Summary
The initial GRADE evidence level was type 1 (high) for randomized controlled trials and type 3 (low) for the observational data (Table 4). In terms of benefits, the RCT data indicated that the vaccine reduces the risk of symptomatic laboratory-confirmed COVID-19, and no serious concerns impacting certainty were identified for this outcome (type 1, high). Observational data for symptomatic laboratory-confirmed COVID-19 indicated a similar risk reduction with vaccination, and the certainty was upgraded one point for a strong association (type 2, moderate). The certainty of the evidence from one RCT for hospitalization due to COVID-19 was downgraded one point for serious concern of imprecision (type 2, moderate). Observational data for hospitalization due to COVID-19 indicated a similar risk reduction with vaccination, and the certainty was upgraded one point for a strong association (type 2, moderate). The certainty of the evidence for death due to COVID-19 was downgraded two points for very serious concern of imprecision (type 3, low). Observational data for death due to COVID-19 concurred with a strong risk reduction with vaccination, and the certainty was upgraded one point for a strong association (type 2, moderate). RCT data indicated that the vaccine reduces the risk for asymptomatic SARS-CoV-2 infection, and no serious concerns impacting certainty were identified for this outcome (type 1, high). Observational data for asymptomatic SARS-CoV-2 infection indicated a similar risk reduction with vaccination, and the certainty was downgraded one point for serious concern of inconsistency (type 4, very low). The certainty of evidence for serious adverse events was downgraded one point for serious concern of imprecision (type 2, moderate). Observational data on specific serious adverse events (i.e., myocarditis among persons aged 18–39 years and anaphylaxis among persons aged 12 years and older) demonstrated these events were rare (evidence type 3, low). No serious concerns impacted the certainty of estimates of reactogenicity from RCTs (type 1, high).
The summary of evidence types is shown in Table 5. The final evidence types were type 1 for symptomatic laboratory-confirmed COVID-19, type 2 for hospitalization due to COVID-19 and death due to COVID-19, type 1 for asymptomatic SARS-CoV-2 infection, type 2 for serious adverse events, and type 1 for reactogenicity.
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Table 1: Policy Question and PICO
Policy question:
Should vaccination with Moderna COVID-19 vaccine (Spikevax, 2-dose, primary series) be recommended for persons 18 years of age and older?Population
Persons aged ≥18 yearsIntervention
Moderna COVID-19 vaccine mRNA-1273 (100 μg, 2 doses IM, 28 days apart)Comparison
No vaccineOutcomes
Symptomatic laboratory-confirmed COVID-19
Hospitalization due to COVID-19
Death due to COVID-19
Asymptomatic SARS-CoV-2 infection
Serious Adverse Events (SAEs) (including myocarditis and anaphylaxis)
Reactogenicity (proportion with grade 3 or worse reactions)**Abbreviations**: IM: intramuscular; PICO: population, intervention, comparison, outcomes.Table 2: Outcomes and Rankings
Table 2: Outcomes and Rankings
Outcome
Importancea
Included in evidence profileSymptomatic laboratory-confirmed COVID-19
Critical
YesHospitalization due to COVID-19
Critical
YesDeath due to COVID-19
Important
YesAsymptomatic SARS-CoV-2 infection
Important
YesSerious Adverse Events (SAEs) (including myocarditis and anaphylaxis)
Critical
YesReactogenicity (proportion with grade 3 or worse reactions)
Important
Yes
aThree options: 1. Critical; 2. Important but not critical; 3. Not important for decision makingTable 3a: Summary of Studies Reporting Symptomatic Laboratory-confirmed COVID-19
Table 3a: Summary of Studies Reporting Symptomatic Laboratory-confirmed 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**
Comparator
**Vaccine Efficacy/Effectiveness (95% CI)**
Study limitations (Risk of Bias)Baden 2020, El Sahly 2021a,b [5, 6]
Phase III RCT; Age ≥18 years
55 cases/14,287 vaccine recipients
744 cases/14,164 placebo recipients
Placebo
92.7 (90.4–94.4)
Not seriousAndrews, 2021c [7]
Observational (test-negative design); General population ≥18 years; England
24,328 vaccinated/361,470 cases
100,606 vaccinated/570,293 controls
No vaccine
94.8 (94.4–95.2)d
Not seriousBruxvoort, 2021 [10]
Observational (prospective cohort); General population ≥18 years; United States
254 cases/352,878 vaccinated
1,078 cases/352,878 unvaccinated
No vaccine
88.3 (86.5–89.9)d
Not seriousCarazo, 2021 [11]
Observational (test-negative design); Healthcare workers; Canada
0 vaccinated/2,813 cases
126 vaccinated/18,663 controls
No vaccine
100e
Not seriousChemaitelly, 2021 [12]
Observational (test-negative design); General population ≥18 years; Qatar
1 vaccinated/32,527 cases
72 vaccinated/32,527 controls
No vaccine
98.6 (92.0–100)d
Not seriousChin, 2021 [13]
Observational (retrospective cohort); Incarcerated population; United States
4 cases/459 vaccinated
23 cases/329 unvaccinated
No vaccine
84.2 (56.4–94.3)d
Not seriousChung, 2021 [14]
Observational (test-negative design); General population ≥18 years; Canada
6 vaccinated/51,226 cases
542 vaccinated /252,083 controls
No vaccine
94 (86–97)f
Not seriousGrannis, 2021 [16]
Observational (test negative design); General population ≥18 years; United States
98 vaccinated/3,243 cases
2,558 vaccinated/10,285 controls
No vaccine
92 (89–93)d
Not seriousMartinez-Baz, 2021 [19]
Observational (prospective cohort); General population ≥18 years; Spain
46 cases/1,127 vaccinated
3,278 cases/14,348 unvaccinated
No vaccine
85 (80–89)d
Not seriousNasreen, 2021 c [20]
Observational (test negative design); General population ≥18 years; Canada
28 vaccinated/1,859 cases
9,893 vaccinated/ 450,284 controls
No vaccine
94 (86–97)d
Not seriousNordström, 2021 c [22]
Observational (retrospective cohort); General population ≥18 years; Sweden
1.0 case /100,000 person days among vaccinated
2.6 cases/100,000 person days among unvaccinated
No vaccine
71 (56–81)d
Not seriousNordström, 2021 [21]
Observational (retrospective cohort); General population ≥18 years; Sweden
1.3 cases/100,000 person days among vaccinated
13.5 cases/100,000 person days among unvaccinated
No vaccine
87 (84–88)f
Not seriousPilishvili, 2021 [24]
Observational (test negative design); Healthcare workers; United States
18 vaccinated/1,472 cases
190 vaccinated/3,420 controls
No vaccine
96.3 (91.3–98.4)d
Not seriousTang, 2021 [28]
Observational (test-negative design); General population ≥18 years; Qatar
75 vaccinated/1,356 cases
821 vaccinated/5,573 controls
No vaccine
73.9 (65.9–79.9)d
Not seriousThompson , 2021 [31]
Observational (test negative design); General population ≥50 years; United States
49 vaccinated/2,896 cases
2,427 vaccinated /11,392 controls
No vaccine
92 (89–94)f
Not seriousaAssessed using a primary outcome of the RCT, defined as SARS-CoV-2 RT-PCR-positive symptomatic illness, in seronegative adults, ≥14 days post second dose.  Seronegative status was not a criterion for inclusion of observational studies.
bAdditional data provided by sponsor
cPreprint
dVaccine effectiveness estimate included in main pooled analysis used for GRADE.
e Vaccine effectiveness estimate not included in main pooled analysis used for GRADE because a confidence interval for the effect estimate was not provided.
f Vaccine effectiveness estimate not included in main pooled analysis used for GRADE because study population overlapped with another study that was included.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
Comparator
Vaccine Efficacy/Effectiveness, % (95% CI)
Study limitations (Risk of Bias)Baden 2020, El Sahly 2021a [5, 6]
Phase III RCT, Age ≥18 years
1 hospitalization/14,287 vaccine recipients
24 hospitalizations/14,164 placebo recipients
Placebo
95.9 (69.5–99.4)
Not seriousAndrews, 2021b [7]
Observational (test negative design); General population ≥18 years; United Kingdom
0 vaccinated/Not reported
6,363 vaccinated/Not reported
No vaccine
100c
Not seriousBajema, 2021 [8]
Observational (test negative design); Hospitalized VA; United States
11 vaccinated/388 cases
136 vaccinated/787 controls
No vaccine
91.6 (83.5–95.7)d
Not seriousBruxvoort, 2021 [9]
Observational (test negative design); General population ≥18 years; United States
5 vaccinated/141 cases
365 vaccinated/705 controls
No vaccine
97.5 (92.7–99.2)d
Not seriousBruxvoort, 2021  [10]
Observational (prospective cohort); General population ≥18 years; United States
13 hospitalizations /352,878 vaccinated
182 hospitalizations/352,878 unvaccinated
No vaccine
95.8 (92.5–97.6)d
Not seriousChemaitelly, 2021 [12]
Observational (test-negative design); General population ≥18 years; Qatar
1 vaccinated/3,394 cases
23 vaccinated/3,394 controls
No vaccine
95.7 (73.4–99.9)d
Not seriousEmbi, 2021 [15]
Observational (test negative design); General population ≥18 years; United States
357 vaccinated/10,210 cases
11,984 vaccinated/41,791 controls
No vaccine
93 (92–94)e
Not seriousGrannis, 2021 [16]
Observational (test negative design); General population ≥18 years; United States
70 vaccinated/1,386 cases
2,905 vaccinated/8,549 controls
No vaccine
95 (92–97)d
Not seriousIrizarry, 2021a [17]
Observational (retrospective cohort); General population ≥18 years; United States
Not reported
Not reported
No vaccine
90 (84–94)d
Not seriousLin, 2022 [18]
Observational (retrospective cohort); General population ≥18 years; United States
Not reported
Not reported
No vaccine
94.9 (92.4–96.6)d
Not seriousMartinez-Baz, 2021 [19]
Observational (prospective cohort); General population ≥18 years; Spain
1 hospitalization/1,127 vaccinated
216 hospitalizations/14,348 unvaccinated
No vaccine
98 (82–100)d
Not seriousNasreen, 2021a [20]
Observational (test negative design); General population ≥18 years; Canada
Not reported
Not reported
No vaccine
98 (93–100)d
Not seriousPawlowski, 2021 [23]
Observational (retrospective cohort); ≥18 years with access to Mayo Health system (MN); United States
5 hospitalizations/15,985 vaccinated
52 hospitalizations/15,896 unvaccinated
No vaccine
90.6 (76.5–97.1)e
Not seriousPuranika , 2021 [25]
Observational (retrospective cohort); ≥18 years with access to Mayo Health system (MN); United States
6 hospitalizations /2,215,483 person-days among vaccinated
82 hospitalizations/2,532,948 person-days among unvaccinated
No vaccine
91.6 (81–97)d
Not seriousSelf, 2021 [26]
Observational (test negative design); Hospitalized adults ≥18 years; United States
54 vaccinated/1,517 cases
422 vaccinated/1,321 controls
No vaccine
93 (91–95)d
Not seriousSkowronskia, 2021 [27]
Observational (test negative design); General population ≥18 years; Canada (British Columbia and Quebec)
British Columbia: 38 vaccinated/1403 cases
Quebec: 24 vaccinated/726 cases
British Columbia: 41,889 vaccinated/118,510 controls
Quebec: 109,861 vaccinated/322,779 controls
No vaccine
British Columbia: 97 (96–98)d
Quebec: 97 (95–98)d
Not seriousTang, 2021 [28]
Observational (test-negative design); General population ≥18 years; Qatar
1 vaccinated/104 cases
71 vaccinated/376 controls
No vaccine
96.1 (71.6–99.5)d
Not seriousTenforde, November 2021 [30]
Observational (test negative design); Hospitalized adults ≥18 years; United States
32 vaccinated/1,701 cases
103 vaccinated/1,247 controls
No vaccine
85 (77–91)e
Not seriousTenforde, August 2021 [29]
Observational (test negative design); Hospitalized adults ≥18 years; United States
17 vaccinated/473 cases
93 vaccinated/366 controls
No vaccine
90.1 (82.3–94.5)e
Not seriousThompson, 2021 [31]
Observational (test negative design); General population ≥50 years; United States
95 vaccinated/3,790 cases
6,279 vaccinated/22,990 controls
No vaccine
91 (89–93)d
Not seriousaAdditional data provided by study sponsor. Hospitalization due to COVID-19 was a post-hoc analysis.
bPreprint
cVaccine effectiveness estimate not included in main pooled analysis used for GRADE because a confidence interval for the effect estimate was not provided.
dVaccine effectiveness estimate included in main pooled analysis used for GRADE.
e Vaccine effectiveness estimate not included in main pooled analysis used for GRADE because study population overlapped with another study that was included.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**
**No. of patients unvaccinated**
Comparator
**Vaccine Efficacy/Effectiveness, % (95% CI)**
Study limitations (Risk of Bias)Baden 2020, El Sahly 2021a [5, 6]
Phase III RCT, Age ≥18 years
0 deaths/14,287 vaccine recipients
3 deaths/14,164 placebo recipients
Placebo
100
Not seriousBruxvoort, 2021 [10]
Observational (prospective cohort); General population ≥18 years; United States
1 death/352,878 vaccinated
25 deaths/352,878 unvaccinated
No vaccine
97.9 (84.5–99.7)b
Not seriousIrizarry, 2021c [17]
Observational (retrospective cohort); General population ≥18 years; United States
Not reported
Not reported
No vaccine
93 (81–97)b
Not seriousLin, 2021 [18]
Observational (retrospective cohort); General population ≥18 years; United States
Not reported
Not reported
No vaccine
93.7 (90.2–95.9)b
Not seriousPuranik, 2021a [25]
Observational (retrospective cohort); ≥18 years with access to Mayo Health system (MN); United States
0 deaths/2,215,773 person-days among vaccinated
4 deaths/2,537,030 person-days among unvaccinated
No vaccine
100 (-70–100)b
Not seriousVoko, 2021 [32]
Observational (retrospective cohort); General population ≥18 years; Hungary
0.31 deaths/100,000 person-days​ among vaccinated
1.80 deaths/100,000 person-days among unvaccinated
No vaccine
93.6 (90.5–95.7)b
Not seriousa Additional data provided by study sponsor
bVaccine effectiveness estimate included in main pooled analysis used for GRADE.
c PreprintTable 3d: Summary of Studies Reporting Asymptomatic SARS-CoV-2 infection (assessed bAB levels against SARS-CoV-2)
Table 3d: Summary of Studies Reporting Asymptomatic SARS-CoV-2 infection (assessed bAB levels against SARS-CoV-2)
Authors last name, pub year
Design, study population
No. of patients vaccinated or No. of cases
No. of patients unvaccinated or No. of controls
Comparator
Vaccine Efficacy/Effectiveness, % (95% CI)
Study limitations (Risk of Bias)Baden 2020, El Sahly 2021a [5, 6]
Phase III RCT, Age ≥18 years
214 cases/14,287 vaccinated
498 cases/14,164 unvaccinated
Placebo
57.4 (50.1–63.6)
Not seriousBruxvoort, 2021 [10]
Observational (prospective cohort); General population ≥18 years; United States
35 cases/352,878 vaccinated
66 cases/352,878 unvaccinated
No vaccine
72.7 (57.6–82.4)b
Not seriousChemaitelly, 2021 [12]
Observational (test-negative design); General population ≥18 years; Qatar
8 vaccinated/37,776 cases
107 vaccinated/37,776 controls
No vaccine
92.5 (84.8–96.9)b
Not seriousTang, 2021 [28]
Observational (test-negative design); General population ≥18 years; Qatar
53 vaccinated/528 cases
368 vaccinated/2,323 controls
No vaccine
53.6 (33.4–67.6)b
Not serious
aAdditional data provided by study sponsor
bVaccine effectiveness estimate included in main pooled analysis used for GRADE.Table 3e: Summary of Studies Reporting Serious Adverse Eventsa
Table 3e: Summary of Studies Reporting Serious Adverse Events
Authors last name, pub year
Age or other characteristics of importance
n/N (%) intervention
n/N (%) comparison
Comparator
RR (95% CI)
Study limitations (Risk of Bias)Anderson, 2020a [2]
Phase I open label study, persons aged >55 years
1/20
–
–
–
bJackson, 2020a [3]
Phase I open label study, persons aged 18-55 years
1/15
–
–
–
bChu, 2021a [4]
Phase II RCT, Adults ≥18 years
0/200
0/200
Placebo
0
Not SeriousBaden 2020, El Sahly 2021a [5, 6]
Phase III RCT, Adults ≥18 years
268/15,184c
292/15,164
Placebo
0.92 (0.78, 1.08)
Not SeriousVAERS (Myocarditis)d [34]
Age ≥18 years
Observed cases by age (years) and sex per 1,000,000 second dosesfFemales
Age 18–24: 5.5
Age 25–29: 5.8
Age 30–39: 0.6
Age 40–49: 1.6
Age 50–64: 0.4
Age ≥ 65: 0.5Males
Age 18–24: 40.0
Age 25–29: 18.3
Age 30–39: 8.4
Age 40–49: 3.5
Age 50–64: 0.9
Age ≥ 65: 0.6
Expected cases per 1,000,000 second doses overallf
0.2 – 2.2
Expected numbers occurring in population
Elevated ratio of observed to expected cases among females aged 18–29 years and males 18–49 years.
SeriousVSD (Anaphylaxis)e [33]
Age ≥18 years
5.1/1,000,000 doses



Not seriousVSD (Myocarditis)f [34]
18–39 years
33.0/1,000,000 second doses



Not serious
aAdditional data provided by sponsor
bRisk of bias was not formally assessed for these small studies with no comparator; these were not included in the quantitative estimate used for GRADE.
c15 serious adverse events reported in 12 participants were deemed by blinded investigators to be related to vaccination. These included: B-cell small lymphocytic lymphoma, Basedow’s disease, autonomic nervous system imbalance, cerebrovascular accident, multiple sclerosis, pericardial effusion, pericarditis, pleural effusion, nausea, vomiting, alopecia areata, angioedema, rheumatoid arthritis, and two reports of facial swelling.
dRisk evaluated in a 7-day interval following vaccination
eRisk evaluated in a 0–1 day risk interval after vaccination
fRisk evaluated in a 7-day interval following dose 2Table 3f: Summary of Studies Reporting Reactogenicitya
Table 3f: Summary of Studies Reporting Reactogenicity
Authors last name, pub year
Age or other characteristic of importance
n/N (%) intervention
n/N (%) comparison
Comparator
RR (95% CI)
Study limitations (Risk of Bias)Anderson, 2020 [2] b
Phase I open label study, persons aged >55 years
1/20 (5.0)
–
–
–
cJackson, 2020 [3] b
Phase I open label study, persons aged 18-55 years
1/15 (6.7)
–
–
–
cChu, 2021 [4] b
Phase II RCT, persons aged ≥18 years
32/200 (16.0)
6/200 (3.0)
Placebo
5.33 (2.28, 12.47)
Not seriousBaden 2020, El Sahly 2021 [5, 6] b
Phase III RCT, persons aged ≥18 years
3,243/15,179 (21.4)
679/15,159 (4.5)
Placebo
5.03 (4.65, 5.45)
Not seriousaGrade 3 or worse. Grade 3 local reactions include pain at injection site or axillary swelling/tenderness that prevents daily activity, redness > 10 cm, and swelling > 10 cm. Grade 3 systemic events include fever >38.9°C to 40.0°C; vomiting that requires intravenous hydration; and headache, fatigue/tiredness, new or worsened muscle pain, or new or worsened joint pain that prevents daily routine activity.
bAdditional data provided by sponsor.
cRisk of bias was not formally assessed for these small studies with no comparator; these were not included in the quantitative estimate used for GRADE.Table 4. Grade Summary of Findings Table
Table 4. Grade Summary of Findings Table
Certainty assessment
No of patients Vaccinated
No of patients Unvaccinated
Effect Relative
(95% CI)
Effect Absolute
(95% CI)
Certainty
ImportanceNo of studies
Study design
Risk of bias
Inconsistency
Indirectness
Imprecision
Other considerations**Symptomatic laboratory-confirmed COVID-19**1
Randomized studies
not seriousa
not serious
not seriousb,c
not serious
none
55/14287 (0.4%)
744/14164 (5.3%)
**RR 0.07**
(0.05–0.09)
**4,885 fewer per 100,000**
(from 4,990 fewer to 4,780 fewer)d
Type 1
CRITICAL11e
Nonrandomized studiesf
not serious
not seriousg
not serioush
not serious
strong association
f,i
f,i
**RR 0.11**
(0.06–0.18)j
**4,717 fewer per 100,000**
(from 4,982 fewer to 4,346 fewer)d
Type 2
CRITICAL**Hospitalization for COVID-19**1
Randomized studies
not seriousa,k
not serious
not seriousc
seriousl
none
1/14287 (0.0%)
24/14164 (0.2%)
**RR 0.04**
(0.01 to 0.31)
**163 fewer per 100,000**
(from 168 fewer to 117 fewer)d
Type 2
CRITICAL15m
Nonrandomized studiesf
not serious
not seriousn
not seriouso
not serious
strong association
f,p
f,p
**RR 0.05**
(0.04 to 0.07)j
**190 fewer per 100,000**
(from 192 fewer to 186 fewer)d
Type 2
CRITICAL**Death due to COVID-19**1
Randomized studies
not seriousa
not serious
not seriousc
very seriousq
none
0/14287 (0.0%)
3/14164 (0.0%)
**RR 0.14**
(0.01 to 2.79)r
**18 fewer per 100,000**
(from 21 fewer to 38 more)d
Type 3
IMPORTANT5s
Nonrandomized studiese
not serious
not serioust
not seriousu
not serious
strong association
f,v
f,v
**RR 0.06**
(0.05 to 0.08)j
**19 fewer per 100,000**
(from 19 fewer to 18 fewer)d
Type 2
IMPORTANT**Asymptomatic SARS-CoV-2 infection, assessed with PCR**1
Randomized studies
not seriousa
not serious
not seriousc
not serious
none
214/14287 (1.5%)
498/14164 (3.5%)
**RR 0.43**
(0.36 to 0.50)
**2,004 fewer per 100,000**
(from 2,250 fewer to 1,758 fewer)d
Type 1
IMPORTANT3s
Nonrandomized studiesf
not serious
seriousw
not serious
not serious
none
f,x
f,x
**RR 0.30**
(0.23 to 0.39)y
**2,450 fewer per 100,000**
(from 2,695 fewer to 2,135 fewer)d
Type 4
IMPORTANT**Serious adverse events**2z
Randomized studies
not seriousa
not serious
not seriousc
seriousaa
none
268/15384 (1.7%)
292/15364 (1.9%)
**RR 0.92**
(0.78 to 1.08)ab
**152 fewer per 100,000**
(from 418 fewer to 152 more)d
Type 2
CRITICAL2w
Nonrandomized studies
not serious
not serious
not seriousac
not serious
none


See narrativead,ae,af

Type 3
CRITICAL**Reactogenicity, grade >=3**2ah
Randomized studies
not serious
not serious
not seriousc
not serious
none
3275/15379 (21.3%)
685/15359 (4.5%)
**RR 5.03**
(4.65 to 5.45)ab
**17,974 more per 100,000**
(from 16,279 more to 19,847 more)d
Type 1
IMPORTANT0
Nonrandomized studies
**CI:** Confidence interval; **RR:** Risk ratio
*Explanations*
Risk of bias related to blinding of participants and personnel was present. Although participants and study staff were blinded to intervention assignments, they may have inferred receipt of vaccine or placebo based on reactogenicity. This was deemed unlikely to overestimate efficacy or underestimate risk of serious adverse events, therefore the risk of bias was rated as not serious.
The effects noted are from a per protocol analysis with outcomes assessed at least 14 days post dose 2 among persons who received two doses and had no evidence of prior SARS-CoV-2 infection. In an analysis using the full analysis set (persons with or without evidence of prior SARS-CoV-2 infection), there were 58 cases among 15180 persons in the vaccine arm and 754 cases among 15166 persons in the placebo arm (RR = 0.08 (0.06 to 0.10)).
The RCT excluded persons with prior COVID-19 diagnosis, pregnant or breastfeeding women, and persons who were in an immunosuppressive or immunodeficient state, had asplenia or recurrent severe infections (HIV-positive participants on stable antiretroviral therapy were not excluded). The population included in the RCT may not represent all persons aged >=18 years.
Absolute risk was calculated using the observed risk among placebo recipients in the available body of evidence from randomized controlled trials. Absolute risk estimates should be interpreted in this context.
14 studies were available in the body of evidence. 2 were excluded because the study population was already represented, and 1 was excluded because the confidence interval for the effect estimate was provided.
The body of evidence includes preprints.
Although I2 value was high (96.6%), no serious concern for inconsistency was judged because all studies showed a high degree of vaccine effectiveness, with point estimates ranging from 79% to 92%.
Two included studies measured COVID-19 vaccine effectiveness against laboratory-confirmed COVID-19–associated emergency department and urgent care clinic encounters and hospitalizations. In a sensitivity analysis excluding these studies the pooled RR was 0.11 (95% CI: 0.06, 0.22).
Data on numerators and denominators were not consistently reported in the available body of evidence. Seven test negative studies contributed 404,823 cases and 1,083,774 controls. In addition to the test negative study data, four cohort studies contributed data to the pooled estimate.
Pooled RR based on a random effects meta-analysis, using adjusted vaccine effectiveness estimates on a log scale.
Hospitalization due to COVID-19 was not a protocol defined outcome and was provided in a post-hoc analysis, which may be subject to bias. However, severe COVID-19, defined per FDA guidance, was a protocol defined outcome. There were 2 severe COVID-19 cases among 14164 persons in the vaccine arm and 106 severe COVID-19 cases among 14287 persons in the placebo arm (RR = 0.02 (0.00 to 0.08)). Due to the similarity of these estimates, we deemed the risk of bias as not serious.
Serious concerns of imprecision due to fragility in the estimate was present because there were only 25 events observed from a single RCT.
19 studies were available in the body of evidence. Four were excluded because the study population was already represented, and one was excluded because no confidence interval for the effect estimate was provided. One included study provided two VE estimates from distinct study locations.
Although I2 value was high (77.6%), no serious concern for inconsistency was judged because all studies showed a high degree of vaccine effectiveness, with point estimates ranging from 93% to 97%.
Definitions varied by study. Indirectness was considered given COVID-19 was not necessarily confirmed as the cause of hospitalizations, but this was deemed not serious.
Data on numerators and denominators were not consistently reported in the available body of evidence. Ten test negative studies contributed 9,059 cases and 457,807 controls. In addition to the test negative study data, five cohort studies contributed data to the pooled estimate.
Very serious concern for imprecision was present due to the small number of events that were observed. In addition to a 95% confidence interval crossing the line of no effect, there was concern for fragility in the estimate due to the small number of events.
RR calculated using a standard continuity correction of 0.5.
All available studies in the body of evidence were included in the pooled estimate.
The relative risk shown is from a pooled analysis of 5 cohort studies conducted in different populations. I2 was 0%.
Definitions varied by study. Indirectness was considered given COVID-19 was not necessarily confirmed as the cause of deaths, but this was deemed not serious.
Data on numerators and denominators were not consistently reported in the available body of evidence. The n is not included because studies reported rates and did not report the number of cases. The N is not included because studies variously provided person-time.
Serious concern for inconsistency was present (I2= 90.3%). The magnitude of the relative risks from the three studies in the body of evidence varied widely, possibly reflecting different prevalence of circulating SARS-CoV-2 variants at the time of data collection or differences in study design.
Data on numerators and denominators were not consistently reported in the available body of evidence. Two test negative studies contributed 38,304 cases and 40,099 controls. In addition to the test negative study data, one cohort study contributed data to the pooled estimate.
Pooled RR 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 imprecise estimates of the between-studies variance.
Two small Phase 1 observational studies with no comparison group were not included in the GRADE analysis. In a total of 35 vaccinated persons, 0 serious adverse events were observed.
Serious concern for imprecision was present. The confidence interval indicates that both reduced and increased risk of serious adverse events are possible.
Pooled RR based on a fixed effects meta-analysis. Fixed effects model was appropriate for this analysis because these RCTs used the same protocol and were conducted in similar populations.
For the outcome of myocarditis evaluated in Vaccine Safety Datalink, data are shown for the age groups 18-39, therefore these were not completely generalizable to the age groups of all persons aged >=18 years as defined in the PICO question. This was deemed not serious.
A rapid cycle analysis from Vaccine Safety Datalink (VSD) evaluated chart-reviewed cases of myocarditis occurring among persons aged 18–39 years following dose 2. Based on events occurring in a 7-day risk interval after vaccination vs. a comparison interval in vaccinated individuals, the adjusted rate ratio was 18.75 (95% CI 6.73–64.94). The excess cases of myocarditis in the risk interval were 31.2 per million doses.
Data from the national Vaccine Adverse Event Reporting System (VAERS) showed an elevated ratio of observed to expected myocarditis cases in the 7-day interval following vaccination among females in age groups 18-29 years, and among males in age groups 16-49 years, with higher observed/expected ratios in males than females. Although VAERS data are subject to the limitations of a passive surveillance system, the elevated risk of myocarditis following Moderna vaccination is consistent with that observed in VSD.
A rapid cycle analysis of data from VSD evaluated chart-reviewed cases of anaphalaxis among all vaccinated persons aged 18 years and older. Based on events occurring in a 0–1 day risk interval after vaccination, the estimated incidence of confirmed anaphalaxis was 5.1 (95% CI 3.3–7.6) per million doses.Table 5: Summary of Evidence for Outcomes of Interest
Table 5: Summary of Evidence for Outcomes of Interest
Outcome
Importance
Included in evidence profile
CertaintySymptomatic laboratory-confirmed COVID-19
Critical
Yes
Type 1 (high)Hospitalization due to COVID-19
Critical
Yes
Type 2 (moderate)Death due to COVID-19
Important
Yes
Type 2 (moderate)Asymptomatic SARS-CoV-2 infection
Important
Yes
Type 4 (very low)Serious Adverse Events (SAEs) (including myocarditis and anaphylaxis)
Critical
Yes
Type 2 (moderate)Reactogenicity (proportion with grade 3 or worse reactions)
Important
Yes
Type 1 (high)Appendix 1. Studies Included in the Review of Evidence
Randomized Controlled Trial
Randomized Controlled Trial
Last name first author, Publication year
Study design
Country (or more detail, if needed)
Age, central tendency or range
Total population
N vaccinated
N unvaccinated
Outcomes
Funding sourceBaden 2020, El Sahly 2021a,b [5, 6]
RCT
United States
≥18 years
30,415
14,287
14,164
Symptomatic COVID-19 (PCR confirmed)c
Hospitalization due to COVID-19
Death due to COVID-19
Asymptomatic infection
Serious Adverse Events
Reactogenicityd
Industry fundingAnderson, 2020a [2]
RCT
United States
>55 years
40
20
0
Serious Adverse Events
Reactogenicityd
Industry fundingJackson, 2020a [3]
RCT
United States
18-55 years
45
15
0
Serious Adverse Events
Reactogenicityd
Industry fundingChu, 2021a [4]
RCT
United States
≥18 years
600
200
200
Serious Adverse Events
Reactogenicityd
Industry funding
Observational Cohort Studies
Observational Cohort Studies
Last name first author, Publication year
Study design
Country (or more detail, if needed)
Age, central tendency or range
Total population
N vaccinated
N unvaccinated
Outcomes
Funding sourceBruxvoort, 2021 [10]
Observational (Prospective Cohort)
United States
≥18 years
705,756
352,878
352,878
Symptomatic COVID-19 (PCR confirmed)c
Hospitalization due to COVID-19
Death due to COVID-19
Asymptomatic infection
Industry fundingChin, 2021 [13]
Observational (Retrospective Cohort)
United States, Incarcerated population
≥18 years
3,221
459
329
Symptomatic COVID-19 (PCR confirmed)c
University/Academic & Government fundingIrizarry, 2021a [17]
Observational (Retrospective Cohort)
United States
≥18 years
NRe
NRe
NRe
Hospitalization due to COVID-19
Death due to COVID-19
Government fundingLin, 2021 [18]
Observational (Retrospective Cohort)
United States
≥18 years
NRe
NRe
NRe
Hospitalization due to COVID-19
Death due to COVID-19
University/Academic & Government fundingMartinez-Baz, 2021 [19]
Observational (Prospective Cohort)
Spain
≥18 years
30,240
1,127 contacts
14,348 contacts
Symptomatic laboratory-confirmed COVID-19c
Hospitalization due to COVID-19
Government funding & Other (Horizon 2020 program of the European Commission)Nordström, 2021 [21]
Observational (Retrospective Cohort)
Sweden
≥18 years
721,787
312
889
Symptomatic laboratory-confirmed COVID-19c
None declaredNordström, 2021a [22]
Observational (Retrospective Cohort)
Sweden
≥18 years
1,684,958
NRe
NRe
Symptomatic laboratory-confirmed COVID-19c
None declaredPawlowski, 2021 [23]
Observational (Retrospective Cohort)
United States
≥18 years
136,532
NRe
NRe
Hospitalization due to COVID-19
Other (nference; data analysis organization)Puranika,  [25]
Observational (Retrospective Cohort)
United States
≥18 years
179,546
NRe
NRe
Hospitalization due to COVID-19
Death due to COVID-19
NReVoko, 2021 [32]
Observational (Retrospective Cohort)
Hungary
≥18 years
3,740,066
24
10,956
Death due to COVID-19
None declared
Observational Case-Control Studies
Observational Case-Control Studies
Last name first author, Publication year
Study design
Country (or more detail, if needed)
Age, central tendency or range
Total population
N vaccinated
N unvaccinated
Outcomes
Funding sourceAndrews, 2021a [7]
Observational
(Test-Negative Case Control)
England
≥18 years
1,475,391
361,470
570,293
Symptomatic laboratory-confirmed COVID-19c
Hospitalization due to COVID-19
Government fundingBajema, 2021 [8]
Observational
(Test-Negative Case Control)
United States
≥18 years
1,175
388
787
Hospitalization due to COVID-19
Government fundingBruxvoort, 2021 [9]
Observational
(Test-Negative Case Control)
United States
≥18 years
8,153
141
705
Hospitalization due to COVID-19
Industry fundingCarazo, 2021a [11]
Observational
(Test-Negative Case Control)
Canada
18–74 years
58,476
2,813
18,663
Symptomatic laboratory-confirmed COVID-19c
Other (Ministere de la sante’ et des services sociaux du Quebec)Chemaitelly, 2021 [12]
Observational
(Test-Negative Case Control)
Qatar
≥18 years
NRe
32,527
32,527
Symptomatic laboratory-confirmed COVID-19c
Hospitalization due to COVID-19
Asymptomatic infection
NReChung, 2021 [14]
Observational
(Test-Negative Case Control)
Canada
≥18 years
324,033
51,226
252,083
Symptomatic laboratory-confirmed COVID-19c
University/Academic & Government fundingEmbi, 2021 [15]
Observational
(Test-Negative Case Control)
United States
≥18 years
89,217
10,210
41,791
Hospitalization due to COVID-19
Government fundingGrannis, 2021 [16]
Observational
(Test-Negative Case Control)
United States
≥18 years
14,636
3,243
10,285
Symptomatic laboratory-confirmed COVID-19c
Hospitalization due to COVID-19
Government fundingNasreena, [20]
Observational (Test-Negative Case Control)
Canada
≥18 years
682,071
1,859
450,284
Symptomatic laboratory-confirmed COVID-19c
Hospitalization due to COVID-19
Government fundingPilishvili, 2021 [24]
Observational (Test-Negative Case Control)
United States
≥18 years
109,865
1,472
3,420
Symptomatic laboratory-confirmed COVID-19c
Government fundingSelf, 2021 [26]
Observational (Test-Negative Case Control)
United States
≥18 years
3,689
1,517
1,321
Hospitalization due to COVID-19
NReSkowronskia, 2021 [27]
Observational (Test-Negative Case Control)
British Columbia, Canada
≥18 years
380,532
1,403
118,510
Hospitalization due to COVID-19
Government fundingSkowronskia, 2021 [27]
Observational (Test-Negative Case Control)
Quebec, Canada
≥18 years
854,915
726
322,779
Hospitalization due to COVID-19
Government fundingTang, 2021 [28]
Observational (Test-Negative Case Control)
Qatar
≥18 years
39,156
1,356
5,573
Symptomatic laboratory-confirmed COVID-19c
Hospitalization due to COVID-19
Asymptomatic infection
NReTenforde,  August 2021 [29]
Observational (Test-Negative Case Control)
United States
≥18 years
1,210
473
366
Hospitalization due to COVID-19
Government fundingTenforde, November 2021 [30]
Observational (Test-Negative Case Control)
United States
≥18 years
4,513
1,701
1,247
Hospitalization due to COVID-19
Government fundingThompson, 2021 [31]
Observational (Test-Negative Case Control)
United States
≥50 years
41,552
3,790
22,990
Symptomatic laboratory-confirmed COVID-19c
Hospitalization due to COVID-19
Government funding
Safety Surveillance
Safety Surveillance
Name of system
Study design
Country (or more detail, if needed)
Age, central tendency or range
Total population
N vaccinated
N unvaccinated
Outcomes
Funding sourceVaccine Adverse Event Reporting System (VAERS) [32,33]
Passive surveillance
United States
≥18 years (anaphylaxis);
18–49 years (myocarditis)



Serious Adverse Events
Government fundingVaccine Safety Datalink (VSD) [34]
Cohort
United States
≥12 years (anaphylaxis);
18–39 years (myocarditis)



Serious Adverse Events
Government funding
aPre-print
bAdditional data provided by sponsor
cThis was a primary outcome of the RCT, defined as SARS-CoV-2 RT-PCR-positive symptomatic illness, in seronegative persons aged ≥18 years, ≥7 days post second dose. In a secondary analysis among seronegative and seropositive persons, the efficacy was Grade 3 or worse.
dGrade 3 local reactions include pain at injection site that prevents daily activity, redness > 10 cm, and swelling > 10 cm. Grade 3 systemic events include vomiting that requires IV hydration, diarrhea of 6 or more loose stools in 24 hours, or headache, fatigue/tiredness, chills, new or worsened muscle pain, or new or worsened joint pain that prevent daily routine activity.
eNot reportedAppendix 2. Databases and strategies used for systematic review
Appendix 2. Databases and strategies used for systematic review
Database
Strategy**clinicaltrials.gov**
**Inclusion**: Relevant Phase 1, 2, or 3 randomized controlled trials of Moderna COVID-19 vaccine
Involved human subjects
Reported primary data
Included adults (aged ≥18 years) at risk for SARS-CoV-2 infection
Included data relevant to the efficacy and safety outcomes being measured
Included data for the dosage and timing being recommended (100 μg, 2 doses at 0 and 28 days)**Additional resources**: Unpublished and other relevant data by consulting with vaccine manufacturers and subject matter experts**International Vaccine Access Center (IVAC)**
**Inclusion criteria for IVAC systematic review:**
Published or preprint study with adequate scientific details
Includes groups with and without infection or disease outcome
Laboratory confirmed outcome
Vaccination status confirmed in ≥90%
Studies assess one vaccine or pooled mRNA vaccines
Includes participants who did or did not receive a COVID-19 vaccineVaccine effectiveness estimate calculated comparing vaccinated to unvaccinated****Additional criteria for GRADE review:**
Restricted to PICO-defined population, intervention, comparison, and outcomes
Outcomes assess 7 or 14 days after 2nd dose
Only Moderna vaccine (not mRNA vaccines as a group)
Included studies of general population and special populations (e.g., elderly, pregnant persons, healthcare workers)**Safety Surveillance Systems**
**Evidence Retrieval for Observational Safety Studies:**
Based on input from ACIP’s COVID-19 Vaccine Safety Technical (VaST) Work Group
Data on safety signals identified by vaccine surveillance systems
Data have been presented to ACIPTop of Page
							
					
							Last Reviewed:  March 15, 2022						Source: 	National Center for Immunization and Respiratory Diseases
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