For more information: www.cdc.gov/COVID19

Grading of Recommendations, 

Assessment, Development, and 

Evaluation (GRADE): 

Moderna COVID-19 Vaccine 

ACIP COVID-19 Vaccines Work Group

Dr. Julia Gargano 

ACIP Meeting

19 December 2020
2

 Should vaccination with Moderna COVID-19 vaccine (2-doses, IM) be 

recommended for persons 18 years of age and older under an emergency 

use authorization?

Policy Question
3

PICO Question

Population Persons aged ≥18 years

Intervention Moderna COVID-19 vaccine mRNA-1273 (100 μg, 2 

doses IM, 28 days apart)

Comparison No COVID-19 vaccine

Outcomes Symptomatic laboratory-confirmed COVID-19

Hospitalization due to COVID-19

All-cause death

SARS-CoV-2 seroconversion to a non-spike protein

Asymptomatic SARS-CoV-2 infection

Serious adverse events

Reactogenicity grade ≥3
Outcomes

4

OutcomeImportancea Description

Benefits

Symptomatic laboratoryconfirmed COVID-19

Critical Primary outcome; current studies use PCR + specific symptoms

Hospitalization due to 

COVID-19

Critical Phase 3 trials not designed to detect statistical differences between treatment 

groups for this outcome

All-cause death Important Death from all causes; phase 3 trials not designed to detect statistical differences 

between treatment groups for this outcome

SARS-CoV-2 seroconversion Important Measured using antibodies to non-spike protein to differentiate seroconversion 

due to natural infection from immunogenicity to vaccine; no data available

Asymptomatic SARS-CoV-2 

infection Important Measured using serial PCR; data available from single time point

Harms

Serious adverse eventsCritical Evaluating balance of events between arms; also reporting on number deemed 

vaccine-related

Reactogenicity Important Evaluating grade ≥3 severity of systemic events and local reactions

aThree options: Critical; Important but not critical; Not important for decision making
Outcomes

5

OutcomeImportancea Description

Benefits

Symptomatic laboratoryconfirmed COVID-19

Critical Primary outcome; current studies use PCR + specific symptoms

Hospitalization due to 

COVID-19

Critical Phase 3 trials not designed to detect statistical differences between treatment 

groups for this outcome

All-cause death Important Death from all causes; phase 3 trials not designed to detect statistical differences 

between treatment groups for this outcome

SARS-CoV-2 seroconversion Important Measured using antibodies to non-spike protein to differentiate seroconversion 

due to natural infection from immunogenicity to vaccine; no data available

Asymptomatic SARS-CoV-2 

infection Important Measured using serial PCR; data available from single time point

Harms

Serious adverse eventsCritical Evaluating balance of events between arms; also reporting on number deemed 

vaccine-related

Reactogenicity Important Evaluating grade ≥3 severity of systemic events and local reactions

aThree options: Critical; Important but not critical; Not important for decision making
Outcomes

6

OutcomeImportancea Description

Benefits

Symptomatic laboratoryconfirmed COVID-19

Critical Primary outcome; current studies use PCR + specific symptoms

Hospitalization due to 

COVID-19

Critical Phase 3 trials not designed to detect statistical differences between treatment 

groups for this outcome

All-cause death Important Death from all causes; phase 3 trials not designed to detect statistical differences 

between treatment groups for this outcome

SARS-CoV-2 seroconversion Important Measured using antibodies to non-spike protein to differentiate seroconversion 

due to natural infection from immunogenicity to vaccine; no data available

Asymptomatic SARS-CoV-2 

infection Important Measured using serial PCR; data available from single time point

Harms

Serious adverse eventsCritical Evaluating balance of events between arms; also reporting on number deemed 

vaccine-related

Reactogenicity Important Evaluating grade ≥3 severity of systemic events and local reactions

aThree options: Critical; Important but not critical; Not important for decision making

Phase 3 trials not powered to 

evaluate differences in 

hospitalizations and deaths; 

interpret in light of findings for 

symptomatic COVID-19
Outcomes

7

OutcomeImportancea Description

Benefits

Symptomatic laboratoryconfirmed COVID-19

Critical Primary outcome; current studies use PCR + specific symptoms

Hospitalization due to 

COVID-19

Critical Phase 3 trials not designed to detect statistical differences between treatment 

groups for this outcome

All-cause death Important Death from all causes; phase 3 trials not designed to detect statistical differences 

between treatment groups for this outcome

SARS-CoV-2 seroconversion Important Measured using antibodies to non-spike protein to differentiate seroconversion 

due to natural infection from immunogenicity to vaccine; no data available

Asymptomatic SARS-CoV-2 

infection Important Measured using serial PCR; data available from single time point

Harms

Serious adverse eventsCritical Evaluating balance of events between arms; also reporting on number deemed 

vaccine-related

Reactogenicity Important Evaluating grade ≥3 severity of systemic events and local reactions

aThree options: Critical; Important but not critical; Not important for decision making

Preliminary 

data
Outcomes

8

OutcomeImportancea Description

Benefits

Symptomatic laboratoryconfirmed COVID-19

Critical Primary outcome; current studies use PCR + specific symptoms

Hospitalization due to 

COVID-19

Critical Phase 3 trials not designed to detect statistical differences between treatment 

groups for this outcome

All-cause death Important Death from all causes; phase 3 trials not designed to detect statistical differences 

between treatment groups for this outcome

SARS-CoV-2 seroconversion Important Measured using antibodies to non-spike protein to differentiate seroconversion 

due to natural infection from immunogenicity to vaccine; no data available

Asymptomatic SARS-CoV-2 

infection Important Measured using serial PCR; data available from single time point

Harms

Serious adverse eventsCritical Evaluating balance of events between arms; also reporting on number deemed 

vaccine-related

Reactogenicity Important Evaluating grade ≥3 severity of systemic events and local reactions

aThree options: Critical; Important but not critical; Not important for decision making

No data available to 

evaluate antibodies; not 

included in evidence 

profile
Evidence Retrieval 

 Databases: Medline, Embase, and Cochrane Library, written in English, restricted to 2020

 Search terms: coronavirus, COVID-19, SARS-CoV-2, respiratory (symptom, disease, illness, 

condition), vaccine, immunization, trial, double blind, single blind, placebo, comparative 

study, phase 3, immunogenicity, efficacy, effective, adverse, evidence, and variations on 

these terms

 Inclusion: provided data on vaccination with mRNA-1273 and 1) involved human subjects; 2) 

reported primary data; 3) included adults (ages 18 and older) at risk for SARS-CoV-2 

infection; 4) included data relevant to the efficacy and safety outcomes being measured; and 

5) 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 hand-searching reference 

lists, and consulting with vaccine manufacturers, and subject matter experts

 Title and abstracts were screened independently by two separate reviewers.

9
Evidence Retrieval

10

Records identified through 

database searching

(n = 2822)

Records excluded

(n = 2805)

Records screened

(n = 2824)

Full-text articles assessed for 

eligibility

(n = 19)

Full-text articles excluded, with reasons

(n = 15)

15 different vaccine

Studies included in evidence 

synthesis

(n = 4)

Additional records identified 

through other sources

(n = 2)
GRADE Evidence Type

 Type 1 (high certainty): We are very confident that the true effect lies close 

to that of the estimate of the effect.

 Type 2 (moderate certainty): We are moderately confident in the effect 

estimate: The true effect is likely to be close to the estimate of the effect, 

but there is a possibility that it is substantially different.

 Type 3 (low certainty): Our confidence in the effect estimate is limited: The 

true effect may be substantially different from the estimate of the effect.

 Type 4 (very low certainty): We have very little confidence in the effect 

estimate: The true effect is likely to be substantially different from the 

estimate of effect.

11

NOTE: Evidence type is not measuring the quality of individual studies, but how much certainty we 

have in the estimates of effect across each outcome.
GRADE Criteria 

 Initial evidence type (certainty level) determined by study design

–

–

Initial evidence type 1 (high certainty): A body of evidence from randomized controlled trials

Initial evidence type 3 (low certainty): A body of evidence from observational studies

 Risk of bias: Can include failure to conceal allocation, failure to blind, loss to follow-up. Risk 

of bias may vary across outcomes.

 Inconsistency: Criteria for evaluating include similarity of point estimates, extent of overlap 

of confidence intervals, and statistical criteria including tests of heterogeneity and I2.

 Indirectness: Considers the generalizability of the evidence to the original PICO components 

(e.g., patients, intervention, comparison, or outcomes differ from those of interest1).

 Imprecision: Considers the fragility of the relative and absolute effect measures based on 

the interpretation of the 95% CIs and the optimal information size.

 Other considerations: Includes publication bias or indications of dose-response gradient, 

large or very large magnitude of effect, and opposing residual confounding.

Guyatt GH, Oxman AD, Kunz R et al. GRADE guidelines: 8. Rating the quality of evidence--indirectness. J Clin Epidemiol. 2011. DOI:10.1016/j.jclinepi.2011.04.014. 12
Benefits
Outcome 1: Symptomatic Laboratory-confirmed COVID-19

Studies with Unvaccinated Comparator (n=1)

14

 Moderna phase 3 randomized controlled trial (RCT) (unpublished, data 

obtained from sponsor and FDA briefing documents)

 Persons aged ≥18 years in United States

 Data evaluated: primary scheduled analysis, data cut-off Nov 25, 2020

– Interim analyses cut-off Nov 11, 2020

NOTE: denominators shown for some analyses may differ from the totals shown here due to censoring or other exclusions applied.
Outcome 1: Symptomatic Laboratory-confirmed COVID-19

Studies with Unvaccinated Comparator (n=1)

15

 Full analysis set: 15,181 vaccine; 15,170 placebo

 Modified intention to treat (mITT) set: 14,550 vaccine, 14,559 placebo

–

–

No immunologic or virologic evidence of prior SARS-CoV-2 

infection

 Per-protocol set: 14,134 vaccine, 14,073 placebo

Subset of mITT who received planned doses per schedule, no 

major protocol deviations

NOTE: denominators shown for some analyses may differ from the totals shown here due to censoring or other exclusions applied.
Outcome 1: Symptomatic Laboratory-confirmed COVID-19

Studies with Unvaccinated Comparator (n=1)

16

Population Events/Vaccinea

(n/N)

Events/Placeboa

(n/N)

Vaccine efficacy 

(95% CI)

Primary Outcomeb

Aged ≥18 years 11/14134c 185/14073c 94.1% (89.3%, 96.8%)

Aged 18–64 years 7/10551 156/10521 95.6% (90.6%, 97.9%)

Aged ≥65 years 4/3583 29/3552 86.4% (61.4%, 95.5%)

Aged ≥75 years 0/630 7/688 100% (CI not calculated)

At riskd 4/3206 43/3167 90.9% (74.7%, 96.7%)

a15,208 and 15,210 persons were randomized to vaccine and placebo.

bCases diagnosed ≥14 days post dose 2 among persons without evidence of prior SARS-CoV-2 infection.

c Primary efficacy population (per protocol); includes a total of 3304.9 person-years of observation in vaccine group and 3273.7 person-years in placebo 

group.

d Symptomatic illness defined as at least one nasopharyngeal swab, nasal swab, or saliva sample (or respiratory sample, if hospitalized) positive for SARSCoV-2 by RT-PCR; and at least two symptoms: fever (≥ 38oC), chills, myalgia, headache, sore throat, new olfactory and taste disorder; or at least one 

symptom: cough, shortness of breath or difficulty breathing, or clinical or radiographical evidence of pneumonia.

eParticipants were considered to be at risk for severe COVID-19 illness if they had at least 1 of the following risk factors at screening: chronic lung 

disease, significant cardiac disease, body mass index ≥ 40 kg/m2, diabetes, liver disease, or controlled HIV infection. CI: confidence interval
Population Events/Vaccinea

(n/N)

Events/Placeboa

(n/N)

Vaccine efficacy 

(95% CI)

Primary Outcomeb

Aged ≥18 years 11/14134c 185/14073c 94.1% (89.3%, 96.8%)

Aged 18–64 years 7/10551 156/10521 95.6% (90.6%, 97.9%)

Aged ≥65 years 4/3583 29/3552 86.4% (61.4%, 95.5%)

Aged ≥75 years 0/630 7/688 100% (CI not calculated)

At riskd 4/3206 43/3167 90.9% (74.7%, 96.7%)

a15,208 and 15,210 persons were randomized to vaccine and placebo.

bCases diagnosed ≥14 days post dose 2 among persons without evidence of prior SARS-CoV-2 infection.

C Primary efficacy population (per protocol); includes a total of 3304.9 person-years of observation in vaccine group and 3273.7 

person-years in placebo group.

dParticipants were considered to be at risk for severe COVID-19 illness if they had at least 1 of the following risk factors at screening: 

chronic lung disease, significant cardiac disease, body mass index ≥ 40 kg/m2, diabetes, liver disease, or controlled HIV infection.

Outcome 1: Symptomatic Laboratory-confirmed COVID-19

Studies with Unvaccinated Comparator (n=1)

CI: confidence interval 17
Outcome 1: Symptomatic Laboratory-confirmed COVID-19

Studies with Unvaccinated Comparator (n=1)

18

Population Events/Vaccine 

(n/N)

Events/Placebo 

(n/N)

Vaccine efficacy 

(95% CI)

Primary outcome

No evidence of prior infection, 

≥14 days after dose 2

11/14134 185/14073 94.1% (89.3%, 96.8%)

Secondary outcomes

± evidence of prior infection, 

≥14 days after dose 2

12/15181 187/15170 93.6% (88.6%, 96.5%)

CDC definition of COVID-19, no 

evidence of prior infection, ≥14 

days after dose 2

11/14134 221/14073 95.1% (91.1%, 97.3%)

CI: confidence interval
Outcome 1: Symptomatic Laboratory-confirmed COVID-19

Studies with Unvaccinated Comparator (n=1)

19

Population Events/Vaccine 

(n/N)

Events/Placebo 

(n/N)

Vaccine efficacy 

(95% CI)

Secondary outcomes

Modified intention-to-treat set, 

dose 1 efficacy, post dose 1a

7/996 39/1079 80.2% (55.2%, 92.5%)

Full analysis set, post dose 1, ≥1 

doseb 21/15180 173/15170 87.9% (81.0%, 92.7%)

Full analysis set, post dose 1 and 

before dose 2b 14/15180 46/15170 69.5% (43.5%, 84.5%)

a. Modified intention to treat analysis excludes persons with evidence of prior infection. Interim analysis 

with Nov 11 cutoff to assess efficacy after one dose. Participants had a median of 28 days follow-up.

b. Full analysis set; interim analysis with Nov 11 cutoff.

CI: confidence interval
Outcome 1: Symptomatic Laboratory-confirmed COVID-19

Studies with Unvaccinated Comparator (n=1)

20

Population Events/Vaccine 

(n/N)

Events/Placebo 

(n/N)

Vaccine efficacy 

(95% CI)

Secondary outcomes

Modified intention-to-treat set, 

dose 1 efficacy, post dose 1a

7/996 39/1079 80.2% (55.2%, 92.5%)

Full analysis set, post dose 1, ≥1 

doseb 21/15180 173/15170 87.9% (81.0%, 92.7%)

Full analysis set, post dose 1 and 

before dose 2b 14/15180 46/15170 69.5% (43.5%, 84.5%)

a. Modified intention to treat analysis excludes persons with evidence of prior infection. Interim analysis 

with Nov 11 cutoff to assess efficacy after one dose. Participants had a median of 28 days follow-up.

b. Full analysis set; interim analysis with Nov 11 cutoff.

CI: confidence interval
Evidence Table: Symptomatic Laboratory-confirmed COVID-19

21

Certainty assessment No of patients Effect

Certainty Importanc

No of e

studies

Study 

design

Risk of 

bias Inconsistency Indirectness Imprecision

Other 

considerations

Moderna 

COVID-19 

vaccine

No vaccine Relative

(95% CI)

Vaccine efficacy against symptomatic COVID-19

1 RCT Not 

serious

a

Not serious Not serious 

b,c,d

Not 

serious

None 11/14134 

(0.1%)

185/14073 

(1.3%)

RR 0.06

(0.03 to 0.11)

Type 1 CRITICAL

CI: confidence interval; RR: relative risk

a. 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. 

b. 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 interim analysis using the full analysis set (persons who received at least 1 dose, with or without evidence of prior 

SARS-CoV-2 infection), there were 21 cases among 15180 persons in the vaccine arm and 173 cases among 15170 persons in the placebo arm (RR = 0.12 (0.07 to 

0.19)).

c. 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. 

d. Concern for indirectness was noted due to the short duration of observation in the available body of evidence. The vaccine efficacy observed at a median 2-

month follow-up may differ from the efficacy observed with ongoing follow-up. However, in consideration of the strength of association and precision observed, 

it is unlikely that the efficacy estimate for symptomatic COVID-19 would change substantially enough to fall below the FDA-defined efficacy threshold for an 

Emergency Use Authorization authorization (i.e. to <50% efficacy). 
Outcome 2: Hospitalization for COVID-19

Studies with Unvaccinated Comparator (n=1)

22

 Moderna Phase 3 randomized controlled trial (RCT) (unpublished, data obtained 

from sponsor)

 Data on severe COVID-19 per FDA guidance: COVID-19 case with ≥1 of following:

–

–

–

–

–

–

–

Clinical signs at rest indicative of severe systemic illness a

Respiratory failure a

Evidence of shock a

Significant acute renal, hepatic, or neurologic dysfunction

Admission to an intensive care unit

Death

 Hospitalizations among severe COVID-19 cases obtained b

One additional case, in vaccine recipient, adjudicated after data cutoff date, included 

a. Severe systemic illness: respiratory rate ≥30, heart rate ≥125, SpO2 ≤93% on room air at sea level or PaO2/FiO2<300 mm Hg; respiratory failure: needing 

high-flow oxygen, noninvasive ventilation, mechanical ventilation, ECMO; evidence of shock: SBP <90 mm Hg, DBP <60 mm Hg, requiring vasopressors.

b. Source: FDA VRBPAC briefing document, FDA VRBPAC presentation slides
Outcome 2: Hospitalization for COVID-19 

Studies with Unvaccinated Comparator (n=1)

23

Outcome Study/population Events/Vaccine 

(n/N)

Events/Placebo 

(n/N)

Vaccine efficacy 

(95% CI)

Secondary endpoint: 

Severe COVID-19, 

protocol definition a, b

No evidence of prior 

infection, ≥14 d post dose 2

1/14134 30/14073 97% (76%, 100%)

Severe COVID-19 & 

hospitalized b

No evidence of prior 

infection, ≥14 d post dose 2

1/14134 9/14073 89% (13%, 99%)

a. Severe COVID-19, defined by FDA guidance: clinical signs at rest indicative of severe systemic illness; 

respiratory failure; evidence of shock; significant acute renal, hepatic, or neurologic dysfunction; 

admission to an intensive care unit; or death 

b. There was one severe COVID-19 case in a vaccine recipient which occurred 2 months after dose 2, 

requiring hospitalization, that was not adjudicated by the data cutoff date.

CI: Confidence interval
Evidence Table: Hospitalization for COVID-19 

24

Certainty assessment No of patients Effect

Certainty Importan

ce

No of 

studies Study 

design Risk of bias Inconsistency Indirectness Imprecision

Other 

considerations

Moderna 

COVID-19 

vaccine

No 

vaccine

Relative

(95% CI)

Vaccine efficacy against hospitalization due to COVID-19 

1 RCT Not 

serious 

a

Not serious Serious 

b,c,d

Not serious None 1/14134 

(0.0%)

e

9/14073 

(0.2%)

0.11 

(0.01, 

0.87)

Type 2 CRITICAL

a. 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. 

b. 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. 

c. The effects noted are from a per protocol analysis with outcomes assessed at least 14 days post dose 2, among persons who received 2 doses, and had no 

evidence of prior SARS-CoV-2 infection. 

d. Serious concern for indirectness was noted due to the short duration of follow-up in the available body of evidence. Severe COVID-19 cases leading to 

hospitalization may not have had time to occur in a median 2-month follow-up. Additionally, hospitalization was ascertained on a subset of cases meeting a 

protocol-specified definition of severe COVID-19; hospitalization due to COVID-19 was not ascertained for all COVID-19 cases, and it is possible that 

hospitalizations for COVID-19 occurred in cases not meeting the specific severe COVID-19 criteria.

e. Includes one hospitalized case in the vaccine arm that had not yet been adjudicated by the data cutoff date. 

CI: confidence interval; RR: relative risk
Outcome 3: All-cause Death

Studies with Unvaccinated Comparator (n=1)

25

 Moderna Phase 3 randomized controlled trial (RCT) (unpublished, data 

obtained from sponsor)
Outcome 3: All-cause Death

Studies with Unvaccinated Comparator (n=1)

26

Outcomea Study/population Events/Vaccine 

(n/N)b

Events/Placebo 

(n/N)

Relative Riskc

(95% CI)

All-cause death Persons aged ≥18 

years

6/15184 7/15165 0.86 (0.29, 2.55)

COVID-19 related 

deaths

Persons aged ≥18 

years

0/14134 1/14073

a. Deaths in study participants as of December 3, 2020.

b. Six participants in mRNA-1273 group: 

• 78 yo: cardio-respiratory arrest 21 days after dose 1

• 62 yo: completed suicide 21 days after dose 1

• 77 yo: myocardial infarction 45 days after dose 2

• 72 yo: multisystem organ failure 59 days after dose 2

• 70 yo: death not otherwise specified; found deceased at home 57 day after dose 2

• 56 yo: head injury; found deceased at home 37 days after dose 1

c. Estimate and confidence interval were calculated based on number of participants.

CI: Confidence interval; YO: Year old
Evidence Table: All-cause Death

27

a. Serious concern for indirectness was noted due to the short duration of follow-up in the available body of evidence. The vaccine 

efficacy over a practical time frame for a vaccination program may differ from the short-term efficacy observed in the clinical trial. 

b. Deaths due to COVID-19 may not have had time to occur during the follow-up period.

c. 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.

d. Imprecision assessed based on the width of the 95% confidence interval. This outcome may be imprecise due to small number of 

events reported during the observation period.

e. Death from all causes was considered a descriptive outcome in the clinical trial data. The sponsor provided counts of total deaths but 

appropriate denominators for analysis to evaluate benefits for this outcome are not clear. While the number of events is accurate, lack of 

an agreed upon denominator may introduce some fragility in the estimate.

Certainty assessment No of patients Effect

No of Certainty Importance

studie

s

Study 

design Risk of bias Inconsistency Indirectness Imprecision Other 

considerations

Moderna 

COVID-19 

vaccine

No vaccine Relative

(95% CI)

Vaccine efficacy against death, all cause

1 RCT Not 

serious 

Not 

serious

Serious 

a,b,c

Very 

serious 

d,e

None 6/15184

(0.0%)

7/15165

(0.0%)

RR 0.86

(0.29 to 2.55)

Type 4 IMPORTANT

CI: confidence interval; RR: relative risk
Outcome 4: Asymptomatic SARS-CoV-2 Infection

Studies with Unvaccinated Comparator (n=1)

28

 Moderna Phase 3 randomized controlled trial (RCT) (unpublished, data 

obtained from sponsor)

 Data evaluated: descriptive results of asymptomatic infections between 

dose 1 & dose 2 among participants without evidence of prior infection

–

–

Nasopharyngeal swab for PCR testing day of dose 1 & dose 2

No documented COVID-19 symptoms between dose 1 & dose 2

 Use of PCR at time of dose 2 to assess asymptomatic infection was not a pre-defined 

protocol objective
Outcome 4: Asymptomatic SARS-CoV-2 Infection

Studies with Unvaccinated Comparator (n=1)

29

Outcome Study/population Events/Vaccine 

(n/N)

Events/Placebo 

(n/N)

Relative Risk

(95% CI)

PCR-positive for 

SARS-CoV-2 at dose 

2, no COVID-19 

symptoms between 

doses 1 and 2

Persons aged ≥18 

years, no evidence 

of prior SARS-CoV-2 

infection at dose 1

14/14134 38/14073 0.37 (0.20, 0.68)

a

a. FDA presentation on December 17, 2020 based on interim analysis included asymptomatic infection 

detected among 12/13934 in vaccination arm and 37/13883 in placebo arm based on interim 

analysis; RR 0.32 (0.17, 0.62).

CI: Confidence interval
Evidence Table: Asymptomatic SARS-CoV-2 Infection

30

a.Serious concern for risk of bias due to selective outcome reporting was present. Evaluation of asymptomatic infection 

from SARS-CoV-2 PCR testing done at dose 2 was not a pre-defined protocol objective. Due to the limited COVID-19 

symptom data provided, it is unknown whether persons classified as asymptomatic experienced COVID-19 symptoms 

after dose 2 and were truly presymptomatic.

b.Very serious concern for indirectness was present. The intended outcome was asymptomatic infection assessed with 

serial PCR testing for SARS-CoV-2, to include follow-up after completion of the full vaccination schedule. Data are 

presented from an analysis of participants with SARS-CoV-2 positive PCR test results from nasopharyngeal swabs 

collected on the day of the second vaccine dose, among persons who were seronegative at baseline and did not report 

COVID-19 symptoms after dose 1. The available evidence are indirect because they represent 1) SARS-CoV-2 testing at a 

single point in time, 2) assessment after one dose, and 3) short follow-up period.

Certainty assessment No of patients Effect

No of Certainty Importance

studie

s

Study 

design Risk of bias Inconsistency Indirectness Imprecision Other 

considerations

Moderna 

COVID-19 

vaccine

No vaccine Relative

(95% CI)

Vaccine efficacy against asymptomatic SARS-CoV-2 infection

1 RCT serious a not 

serious

very 

serious b

not 

serious

none 14/14134 

(0.1%)

38/14073 

(0.3%)

RR 0.37

(0.20 to 

0.68)

Type 

4

IMPORT

-ANT

CI: confidence interval; RR: relative risk
Harms
Outcome 6: Serious Adverse Events

32

Studies with Unvaccinated Comparator (n=2) 

 Moderna phase 3 randomized controlled trial (RCT) (unpublished, data obtained 

from sponsor)

 Moderna phase 2 randomized controlled trial (RCT) (unpublished, data obtained 

from sponsor)

Studies without Unvaccinated Comparator (n=2)

 Moderna Phase 1 dose-escalation, open-label trial (Jackson, 2020)

 Moderna Phase 1 dose-escalation, open-label trial (Anderson, 2020)
Moderna Phase 3 Randomized Controlled Trial 

33

 Unpublished, data obtained from sponsor and FDA briefing documents

 Persons aged ≥18 years in United States

 Data evaluated: final scheduled analysis, data cut-off Nov 25, 2020

–

–

–

–

Interim analyses cut-off Nov 11, 2020

 Safety set: 15,185 vaccine; 15,166 placebo

All randomized participants who received at least one dose

Contributed any solicited adverse reaction data

Analyzed according to intervention actually received

NOTE: denominators shown for some analyses may differ from the totals shown here due to censoring or other exclusions applied
Moderna Phase 2 Randomized Controlled Trial

 Moderna phase 2 dose-confirmation randomized controlled trial (RCT) (unpublished, data 

obtained from sponsor)

 Population: healthy adults aged ≥18 years, United States

 Data evaluated:

–

–

–

–

–

200 persons received 2 doses of 100 μg of mRNA-1273

200 persons received 2 doses of placebo

 Primary outcomes: Safety

Local and systemic reactions: collected using memory aid 7 days following each dose

Adverse events (AE): unsolicited AEs during 28 day follow up period

Serious AEs for duration of study period
Moderna Phase 1 Open Label Trial (Jackson, 2020)

35

 Population: healthy adults aged 18-55 years, United States

 Data evaluated: 

–

–

–

–

15 received 2 doses of 100 μg of mRNA-1273

 Primary outcomes: Safety 

Local and systemic reactions: collected using memory aid 7 days following each dose

Adverse events (AE): unsolicited AEs during 28 day follow up period

Serious AEs for duration of study period

Jackson LA, Anderson EJ, Rouphael NG et al. An mRNA Vaccine against SARS-CoV-2. NEJM. 2020. DOI: 10.1056/NEJMoa2022483.
Moderna Phase 1 Open Label Trial (Anderson, 2020)

36

 Population: healthy adults aged >55 years, United States

 Data evaluated: 

–

–

–

–

–

Aged 56-70 years: 10 received 2 doses of 100 μg of mRNA-1273

Aged ≥71 years: 10 received 2 doses of 100 μg of mRNA-1273

 Primary outcomes: Safety 

Local and systemic reactions: collected using memory aid 7 days following each dose

Adverse events (AE): unsolicited AEs during 28 day follow up period

Serious AEs for duration of study period

Anderson EJ, Rouphael NG, Widge AT et al. Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults. NEJM. 2020. DOI: 10.1056/NEJMoa2028436.
Outcome 6: Serious Adverse Events (SAE)

Studies with Unvaccinated Comparator (n=2)

37

Study/populationa Events/Vaccine 

(n/N)

% SAE

Vaccine

Events/Placebo

(n/N)

% SAE

Placebo

Associated 

with 

vaccination

Anderson, 2020 0/20 0 - - 0

Jackson, 2020 0/15 0 - - 0

Moderna, phase 2, 

unpublished

0/200 0 0/200 0 0

Moderna, phase 3, 

unpublishedb

147/15185 1.0 153/15166 1.0 3c

a. Included all participants who received at least 1 dose of vaccine.

b. Proportion of participants who reported at least one SAE from dose 1 to primary analysis cutoff date (Nov 25).

c. Seven serious adverse events were deemed by blinded investigators to be related to vaccination. These included: intractable nausea/vomiting; facial 

swelling (two reports); rheumatoid arthritis; dyspnea with exertion and peripheral edema; autonomic dysfunction; and B-cell lymphocytic lymphoma. 

Through further investigation by the FDA, only three were classified as related to vaccination: one report of intractable nausea/vomiting and two reports 

of facial swelling. The FDA concluded that the possibility that the vaccine contributed to the SAE reports of rheumatoid arthritis, dyspnea and peripheral 

edema, and autonomic dysfunction cannot be excluded. The FDA concluded that B-cell lymphocytic lymphoma was not related to vaccination.
Evidence Table: Serious Adverse Events

38

a. Risk of bias related to blinding of participants was present. Although participants and study staff were blinded to intervention 

assignments, they may have inferred receipt of vaccine or placebo based on reactogenicity. Some reactogenicity outcomes may also

have been reported as serious adverse events, and experiences of reactions immediately after vaccination could have influenced 

recall or reporting of subsequent serious adverse events. This was rated as not serious. 

b. 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. 

c. Serious concern of indirectness was noted. The body of evidence does not provide certainty that rare serious adverse events 

were captured due to the short duration of follow-up and the sample size. 

Certainty assessment No of patients Effect

Certainty Importance

No of 

studies

Study 

design

Risk of 

bias Inconsistency Indirectness Imprecision Other considerations

Moderna 

COVID-19 

vaccine

No vaccine Relative

(95% CI)

Serious adverse events

2 RCT Not 

serious

a

Not serious Serious 

b,c

Not 

serious 

None 147/15385 

(1.0%)

153/15366 

(1.0%)

RR 0.96

(0.77 to 1.20)

Type 2 CRITICAL

CI: confidence interval; RR: relative risk
Outcome 7: Reactogenicity, Severe (Grade ≥3)a

39

Studies with Unvaccinated Comparator (n=2)

 Moderna phase 3 randomized controlled trial (RCT) (unpublished, data 

obtained from sponsor)

 Moderna phase 2 randomized controlled trial (RCT) (unpublished, data 

obtained from sponsor)

Studies without Unvaccinated Comparator (n=2)

 Moderna Phase 1 dose-escalation, open-label trial (Jackson, 2020)

 Moderna Phase 1 dose-escalation, open-label trial (Anderson, 2020)

aGrade 3: prevents daily routine activity. Grade 4: requires emergency room visit or hospitalization. 
Outcome 7: Reactogenicity, Severe (Grade ≥3)

Definitions

40

 Both trials solicited events through electronic diaries for 7 days following each dose

 Local reactions (pain at injection site, redness, swelling, axillary swelling/tenderness)

–

–

–

–

Grade 3: pain at injection site or axillary swelling/tenderness that prevents daily activity or use of 

prescription pain reliever; redness > 10 cm; and swelling > 10 cm 

Grade 4: emergency room visit or hospitalization for severe pain at the injection site or axillary 

swelling/tenderness, necrosis (redness and swelling categories) or exfoliative dermatitis (redness 

category only).

 Systemic events (fever, nausea/vomiting, headache, fatigue, chills, muscle pain, joint pain)

Grade 3: fever >38.9°C to 40.0°C , vomiting that requires IV hydration; fatigue, headache, chills 

muscle pain, or joint pain that prevents daily activity.

Grade 4: fever >40.0°C, fatigue, headache, muscle pain, joint pain, diarrhea, or vomiting that 

require emergency room visit or hospitalization.
Outcome 7: Reactogenicity, Severe (Grade ≥3)a,b

Studies with and without unvaccinated comparator (n=4)

41

Study/population Events/Vaccine 

(n/N)

% Vaccine Events/Placebo

(n/N)

% Placebo

Anderson, 2020 1/20 5.0 - -

Jackson, 2020 1/15 6.7 - -

Moderna, phase 2, 

unpublished

32/200 16.0 6/200 3.0

Moderna, phase 3, 

unpublished c

3276/15176 21.6 665/15162 4.4

a. Grade 3: prevents daily routine activity or requires use of a pain reliever. Grade 4: requires emergency room visit or 

hospitalization. There were 26 grade 4 systemic adverse reactions, 17 in vaccine group and 7 in placebo group.

b. Includes local and systemic events, grade ≥3.

c. Based on interim analysis, data cutoff Nov. 11, 2020.

Note: GRADE was conducted considering pooled phase 2 and 3 data.
Evidence Table: Reactogenicity, Severe (Grade ≥3)

42

a. 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. 

Certainty assessment No of patients Effect

Certainty Importance

No 

of 

stu

dies

Study 

design Risk of bias Inconsistency Indirectness Imprecision

Other 

considerations

Moderna 

COVID-19 

vaccine

No vaccine Relative

(95% CI)

Reactogenicity, severe (grade ≥3) 

2 RCT not 

serious 

not serious not 

serious 

a

not 

serious 

none 3308/15376

(21.5%) 

671/15362

(4.4%) 

RR 4.93

(4.55 to 5.34) 

Type 1 IMPORTANT 

CI: confidence interval; RR: relative risk
Summary of GRADE

43

OutcomeImportance Design

(# of studies)

FindingsEvidence

type

Benefits

Symptomatic laboratoryconfirmed COVID-19

Critical RCT (1) Moderna COVID-19 vaccine prevents symptomatic COVID-191

Hospitalization due to 

COVID-19

Critical RCT (1) Moderna COVID-19 vaccine prevents COVID-19-resulting in 

hospitalization 2

All-cause death Important RCT (1) Moderna COVID-19 vaccine may or may not prevent death; certainty is 

very low because this is a rare outcome 4

SARS-CoV-2 

seroconversion Important No studies Data not yet available from any studies ND

Asymptomatic SARS-CoV-2 

infection Important RCT (1) Preliminary data consistent with a lower incidence of asymptomatic SARSCoV-2 infection among vaccinated compared with placebo 4

Harms

Serious adverse events

Critical RCT (2) SAEs were balanced between vaccine and placebo arms. 3 SAEs were 

judged by FDA to be related to vaccination 2

Reactogenicity Important RCT (2) Severe reactions were almost 5 times more common in vaccinated vs. 

placebo; any grade ≥3 reaction was reported by 21.5% of vaccinated 1

Evidence type: 1=high; 2=moderate; 3=low; 4=very low; ND, no data
Conclusion

 Policy question: focuses on recommendation during an EUA

 Benefits: Phase 3 trial is ongoing, and effect estimates may change with additional 

follow-up 

–

–

–

Unlikely that efficacy estimate for symptomatic COVID-19 would change 

substantially enough in the months following vaccination to fall below the FDAdefined efficacy threshold for EUA (i.e., to <50% efficacy) 

Direct evidence of efficacy for hospitalization and deaths limited; from efficacy 

against disease, we infer that vaccination would reduce hospitalizations and 

deaths

Preliminary data were consistent with effect of prevention of asymptomatic 

infection

 Harms: Grade 3 reactions not uncommon in vaccinated persons; serious adverse 

events occurred at a similar frequency in vaccine and placebo groups 
Acknowledgements

 Katie Curran

 Megan Wallace

 Kathleen Dooling

 Mona Marin

 Sara Oliver

 Karen Broder

 Rebecca Morgan

 Doug Campos-Outcalt 

 VTF ACIP WG Team
For more information, contact CDC

1-800-CDC-INFO (232-4636)

TTY: 1-888-232-6348 www.cdc.gov

The findings and conclusions in this report are those of the authors and do not necessarily represent the 

official position of the Centers for Disease Control and Prevention.

Thank you