cdc.gov/coronavirus

Grading of Recommendations, 

Assessment, Development, 

and Evaluation (GRADE): 

Pfizer-BioNTech COVID-19 

Vaccine 

Dr. Julia Gargano

ACIP Meeting

August 30, 2021
2

 Should vaccination with Pfizer-BioNTech COVID-19 vaccine (2-doses, 

IM) be recommended for persons 16 years of age and older?

Policy Question
3

PICO Question

Population Persons aged ≥16 years

Intervention Pfizer-BioNTech COVID-19 vaccine BNT162b2 

(30 μg, 2 doses IM, 21 days apart)

Comparison No vaccine

Outcomes Symptomatic laboratory-confirmed COVID-19

Hospitalization due to COVID-19

Death due to COVID-19

Asymptomatic SARS-CoV-2 infection

Serious Adverse Events

Reactogenicity

PICO: Population, intervention, comparison, outcomes
Outcomes, Importance, and Data Sources

4

OutcomeImportancea Data sources

Benefits

Symptomatic laboratoryconfirmed COVID-19

Critical RCTs, observational studies of vaccine effectiveness 

Hospitalization due to COVID-19Critical RCTs, observational studies of vaccine effectiveness 

Death due to COVID-19 Important RCTs, observational studies of vaccine effectiveness 

Asymptomatic SARS-CoV-2 

infection Important Observational studies of vaccine effectiveness 

Harms

Serious adverse events (SAE)

(including myocarditis and 

anaphalaxis)

Critical RCTs for all SAEs, safety surveillance for specific SAEs

Reactogenicity Important RCTs

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

RCT: randomized controlled trial
Evidence Retrieval for Randomized Controlled Trials (RCTs)

 Data source: clinicaltrials.gov

 Inclusion: Relevant Phase 1, 2, or 3 randomized controlled trials of COVID-19 vaccine

– 1) involved human subjects 

– 2) reported primary data 

– 3) included adults (age ≥16 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 and timing being recommended (30 μg, 2 doses at 0 

and 21 days) 

 Additional resources: unpublished and other relevant data by consulting with vaccine 

manufacturers and subject matter experts

5
Evidence Retrieval for Vaccine Effectiveness (VE) Data

6

Articles were eligible for inclusion if published before 8/20/21. *Criteria included in the ongoing systematic review conducted by the International Vaccine Access Center and the World Health Organization 

(see https://view-hub.org/resources ). † Estimates of effectiveness against progression from infection disease are excluded §Studies were included with a lower proportion with confirmed vaccination status 

if there was sufficient cross-validation of vaccination status against confirmed information. ¶ Comparison group is not modelled or historical ** Vaccine effectiveness estimate includes confidence intervals if 

possible. Estimate accounts for confounding or statement that adjustment had no effect on estimate

 Inclusion Criteria for IVAC systematic review*

– Published or preprint study with adequate 

scientific details

– Includes group with and without infection or 

disease outcome

– Laboratory confirmed outcome†

– Vaccination status confirmed in ≥90%§

– Studies assess one vaccine or pooled mRNA 

vaccines

– Includes participants who did or did not receive a 

COVID-19 vaccine ¶

– Vaccine effectiveness estimate calculated 

comparing vaccinated to unvaccinated**

 Additional criteria for GRADE review

– Restricted to PICO-defined population, 

intervention, comparison, and outcomes

– Outcomes assessed 7 or 14 days after 2nd dose

– Only Pfizer-BioNTech vaccine 

(not mRNA vaccines as a group)

– Included studies of general population and 

special populations (e.g. elderly, pregnant 

persons, healthcare workers) 
Evidence Retrieval for Observational Safety Studies 

 Based on input from ACIP’s COVID-19 Vaccines Safety Technical (VaST) Work Group

 Data on safety signals identified by vaccine safety surveillance systems

 Data have been presented to ACIP

7
Evidence Retrieval

8

Records identified from 

WHO/IVAC literature review*

(n = 79)

Additional records identified through 

other sources**

(n = 7)

*See https://view-hub.org/resources

** clinicaltrials.gov, CDC vaccine safety surveillance systems, and other 

Records excluded from initial review

(n = 45)

2 different study design

28 different intervention

15 different outcome

Records screened

(n = 86)

Records assessed for 

eligibility

(n = 41) Full-text articles excluded

(n = 9)

1 no primary data

4 different intervention

4 different outcome

Records included in evidence 

synthesis (n = 32)

4 randomized trial records

2 safety surveillance systems

26 vaccine effectiveness studies
Observational Data (n = 28)

 28 records identified (one or more PICO outcomes)

 Assessed risk of bias using Newcastle-Ottawa Scale (9-point scale)

– For cohort studies: Selection of cohorts, Comparability of cohorts, 

Assessment of outcome

– For case-control or test-negative design studies: Selection of cases and 

controls, Comparability of cases and controls, Ascertainment of 

exposure

 Two reviewers assessed each study for each outcome

 Serious limitations identified by score <7

9
Pooling of VE Estimates

 For each outcome, assessed body of evidence for suitability for pooling

– Estimates subject to serious limitations excluded

– Most representative study selected if multiple studies in same population

 Meta-analyses conducted 

 Estimates evaluated for heterogeneity

– Examined I2

– Sensitivity analyses conducted to assess influence of study characteristics 

(e.g., special population vs. full population, preprint vs. peer-reviewed, 

standard/extended dosing interval, study design, circulating variants)

 Resulting pooled estimates summarize real-world data available at time of GRADE 

analysis

10
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 can 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% confidence intervals 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

Randomized Studies with Unvaccinated Comparator (n=1)

14

 Pfizer-BioNTech phase 2/3 randomized controlled trial (RCT)a,b

 Persons aged ≥16 years in United States, Brazil, Argentina, South Africa, Turkey, 

Germany

 Enrolled over 40,000 participants for approximately 12,000 person years of followup

 Data evaluated: all eligible randomized participants who received all vaccinations as 

randomized within the predefined window and no other important protocol 

deviations, up through unblinding date (data cut-off: March 13, 2021)

aPolack et al., New England Journal of Medicine; additional unpublished data obtained from authors

bThomas et al., preprint; additional unpublished data obtained from authors
Outcome 1: Symptomatic Laboratory-confirmed COVID-19

Studies with Unvaccinated Comparator (n=1)

15

Population Events/Vaccinea

(n/N)

Events/Placeboa

(n/N)

Vaccine efficacy 

(95% confidence interval)

Primary Outcomeb

Aged ≥16 years 77/19711 833/19741 91.1% (88.8%, 93.1%)

Aged 16–64 years 70/15519 709/15515 90.5% (87.9%, 92.7%) 

Aged ≥65 years 7/4192 124/4226 94.5% (88.3%, 97.8%)

Aged ≥75 yearsc 1/842 26/847 96.2% (76.9%, 99.9%)

At riskd 35/8954 395/8933 91.5% (88.0%, 94.2%)

Aged ≥65 years and at riskd 6/2322 71/2304 91.8% (81.4%, 97.1%)

a22,085 and 22080 persons were randomized to vaccine and placebo, respectively; 20,064 and 20,197 in each arm had no 

evidence of prior infection.

bCases diagnosed ≥7 days post dose 2 among persons without evidence of prior SARS-CoV-2 infection

c

FDA requested subgroup analysis

dIncludes persons with at least 1 comorbidity as assessed by Charlson Comorbidity Index, or obesity (BMI ≥ 30)
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% confidence interval)

Primary Outcomeb

Aged ≥16 years 77/19711 833/19741 91.1% (88.8%, 93.1%)

Aged 16–64 years 70/15519 709/15515 90.5% (87.9%, 92.7%) 

Aged ≥65 years 7/4192 124/4226 94.5% (88.3%, 97.8%)

Aged ≥75 yearsc 1/842 26/847 96.2% (76.9%, 99.9%)

At riskd 35/8954 395/8933 91.5% (88.0%, 94.2%)

Aged ≥65 years and at riskd 6/2322 71/2304 91.8% (81.4%, 97.1%)

a22,085 and 22080 persons were randomized to vaccine and placebo, respectively; 20,064 and 20,197 in each arm had no 

evidence of prior infection.

bCases diagnosed ≥7 days post dose 2 among persons without evidence of prior SARS-CoV-2 infection

c

FDA requested subgroup analysis

dIncludes persons with at least 1 comorbidity as assessed by Charlson Comorbidity Index, or obesity (BMI ≥ 30)
Outcome 1: Symptomatic Laboratory-confirmed COVID-19

Studies with Unvaccinated Comparator (n=1)

17

aAll analyses shown among persons without evidence of prior infection.

bPrimary efficacy endpoint, for comparison.

Population Events/Vaccin

e (n/N)

Events/Placebo 

(n/N)

Vaccine efficacy 

(95% confidence interval)

Vaccine efficacy by timinga

≥7 days after dose 2b 77/19711 833/19741 91.1% (88.8%, 93.1%)

1 to <11 days after dose 1 38/21385 46/21315 17.6% (-29.4%, 47.9%)

≥11 days after dose 1 to before dose 2 5/21282 52/21254 90.5% (76.3%, 97.0%)

≥7 days post dose 2 to <2 months 

after dose 2

11/19711 285/19741 96.2% (93.0%, 98.1%)

≥2 months post dose 2 to <4 months 

after dose 2

43/18908 425/18620 90.2% (86.6%, 93.0%)

≥4 months after dose 2 to unblinding 23/11951 123/11099 83.9% (74.7%, 90.1%)
Outcome 1: Symptomatic Laboratory-confirmed COVID-19

Studies with Unvaccinated Comparator (n=1)

18

Population Events/Vaccin

e (n/N)

Events/Placebo 

(n/N)

Vaccine efficacy 

(95% confidence interval)

Vaccine efficacy by timinga

≥7 days after dose 2b 77/19711 833/19741 91.1% (88.8%, 93.1%)

1 to <11 days after dose 1 38/21385 46/21315 17.6% (-29.4%, 47.9%)

≥11 days after dose 1 to before dose 2 5/21282 52/21254 90.5% (76.3%, 97.0%)

≥7 days post dose 2 to <2 months 

after dose 2

11/19711 285/19741 96.2% (93.0%, 98.1%)

≥2 months post dose 2 to <4 months 

after dose 2

43/18908 425/18620 90.2% (86.6%, 93.0%)

≥4 months after dose 2 to unblinding 23/11951 123/11099 83.9% (74.7%, 90.1%)

aAll analyses shown among persons without evidence of prior infection.

bPrimary efficacy endpoint, for comparison.
Outcome 1: Symptomatic Laboratory-confirmed COVID-19 

Observational Studies with Unvaccinated Comparator (n=17)

Overall

n=17

Peer-reviewed 

n=10

Pre-print

n=7

Design

- Case-control

- Cohort, prospective 

- Cohort, retrospective

- Test-negative

- Other

1

4

5

6

1

0

2

4

4

0

1

2

1

2

1

Location

- Europe

- Middle East

- North America

7

7

3

5

4

1

2

3

2

Most recent study period (2021) August May August

19
Location Study Population Method Time period 

(predominant 

variant)

Days 

after 

dose 2

n/N 

Vaccinated (or persontime)

n/N 

Unvaccinated (or 

person-time)

VE* 95% CI Included in 

pooled estimate?

(reason if no)

Canada 

(Ontario)

Chung, 

August 2021

General population 

≥16 years

Test-negative 12/14/20–4/19/21; 

(Alpha)

≥7 51/51,271 3,275/254,816 91 88–93 Yes

England Lopez Bernal, 

April 2021

Adults >80 years Test-negative 12/8/2020–

2/19/2021

7–13 28/8,988 201/15,718 79 68–86 No 

(same population as 

Whitaker preprint) ≥14 41/8,988 634/15,718 85 79–89 

Lopez Bernal 

August 2021

general population 

≥16 years

Test-negative 10/26/20 –5/16/21 

(Alpha and Delta)

≥14 Alpha: 143/23,993

Delta: 122/23,993

Alpha: 7,313/96,371

Delta: 4,043/96,371

Alpha: 93.7 

Delta: 88.0

91.6–95.3

85.3–90.1

Europe 

(8 countries)

Kissling, July 

2021

Symptomatic adults 

≥65 years 

Test-negative 12/10/20–5/31/21 

(Alpha)

≥14 14/519 512/2,857 87 74–93 Yes

Israel Haas, May 

2021

General population 

≥16 years

Retrospective 

cohort

1/24–4/3/21; 

(Alpha)

≥7 1,692/201,882,183 p-d 39,065/120,076,136 p-d 97.0 96.7–97.2 Yes

Angel, May 

2021

Healthcare workers Retrospective 

cohort

12/20/20–2/25/21 

(Alpha)

>7 8/5,372 38/696 97 94–99 No 

(population 

subgroups of Haas) Dagan, April 

2021

General population 

≥16 years

Retrospective 

cohort

12/20/20–2/1/21 >7 2,389/596,618 3,607/596,618 94 87–98

Regev-Yochay, 

August 2021

Healthcare worders Prospective 

cohort

12/19/20 – 3/14/21 

(Alpha)

≥11 19/329,071 p-d 115/119,12 p-d 90 84–94

Italy Fabiani, April 

2021**

Healthcare worker Retrospective 

cohort

12/27/21–3/24/21 ≥7 2/ 216,098 p-d 13 / 77,073 p-d 93.7 50.8–99.2 Yes

Spain Martínez-Baz, 

May 2021 

Close contacts

≥18 years

Prospective 

cohort

Jan–April 2021 

(Alpha)

≥14 1/491 548/19,580 82 73–88 Yes

Outcome 1: Symptomatic Laboratory-confirmed COVID-19

Observational Studies with Unvaccinated Comparator, Peer-reviewed (n=10)

VE: vaccine effectiveness. CI: confidence intervals *Adjusted VE estimates used when available. See references for covariates. **Excluded from general population sensitivity analysis

20
Outcome 1: Symptomatic Laboratory-confirmed COVID-19

Observational Studies with Unvaccinated Comparator, Pre-print (n=7)

Location Study Population Method Time period 

(predominant 

variant)

Days 

after 

dose 2

n/N 

Vaccinated (or 

person-time)

n/N 

Unvaccinated 

(or persontime)

VE* 95% CI Included in pooled 

estimate?

(reason if no)

Canada 

(Ontario)

Nasreen General population

≥16 years 

(symptomatic)

Test-negative 12/14/20–

5/2/21 (Multiple)

≥7 Non-VOC: 18/28,705

Alpha: 92/36,832 

Beta/gamma: 

9/3,005 

Delta: 6/991 

6,914/351,540 Non-VOC: 93 

Alpha: 89 

Beta/gamma: 84

Delta: 87

88–96

86–91

69–92

64–95

No (same population 

as Chung)

Canada 

(Quebec)

Carazo** Healthcare workers Test-negative 1/17–6/5/21 

(Alpha)

≥7 20/2,813 1,954/18,663 92.2 87.8–95.1 Yes

England Whitaker General population 

with medicallyattended COVID-19

Prospective 

cohort

12/7/20–

6/13/21 

(Original, Alpha)

≥14 8/12,273.3 p-y 4,228/1,460,81

1.4 p-y

93.3 85.8–96.8 Yes

Israel Balicer Pregnant women Prospective 

cohort

12/20/21–

6/3/21 

(Original, Alpha)

≥7 67/10,861 144/10,861 97 91–100 No (population 

subgroup of Haas)

Kuwait Alali** Health care workers Retrospective 

cohort

12/24/20–

6/15/21

≥7 12 /90,015 p-d 114/ 90,367 p-d 94.5 89.4–97.2 Yes

Qatar Tang General population 

(any age)

Matched case 

control

12/21/20–

7/21/21 

(Delta only)

≥14 98/571 183/571 56.1 41.4–67.2 No (study 

limitations)

United 

Kingdom

Pouwels General population 

≥18 years 

Longitudinal 

household 

survey

12/1/20–8/1/21 

(Alpha, Delta)

≥14 Not reported Not reported Alpha-dominant 

period: 97 

Delta-dominant 

period: 84 

96–98

82–86

No (same population 

as Whitaker)

VE: vaccine effectiveness. CI: confidence intervals *Adjusted VE estimates used when available. See references for covariates. **Excluded from general population sensitivity analysis 21
0

1

2

3

4

5

6

7

8

9

10

0 10 20 30 40 50 60 70 80 90 100

Vaccine Effectiveness

Alali, Kuwait, Dec 2020–June 2021 

Carazo, Canada, Jan–June 2021 

Chung, Canada, Dec 2020–April 2021

Fabiani, Italy, Dec 2020–Mar 2021

Haas, Israel, Jan–Apr 2021 

Kissling, Europe, Dec 2020–May 2021 

Martinez-Baz, Spain, Jan–April 2021 

Whitaker, UK, Dec 2020–June 2021 

Pooled Estimate Pooled VE = 92.4% (87.5% to 95.3%)*

Outcome 1: Symptomatic Laboratory-confirmed COVID-19 

Observational Studies with Unvaccinated Comparator (n=8)

22 *Sensitivity analyses resulted in pooled estimates ranging from 90.4% to 93.5%
Evidence Table: Symptomatic Laboratory-confirmed COVID-19

23

Certainty assessment No of patients Effect

No of Certainty Importance

studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations

Pfizer BioNTech 

COVID-19 vaccine, 30 

mcg, 2 doses 21 days 

apart

No vaccine Relative

(95% CI)

1 RCT not 

seriousa

not serious not seriousb not serious none 77/19711 (0.4%) 833/19741 

(4.2%) 

RR 0.09

(0.07 to 0.12) 

Type 1 CRITICAL

8c Observationald not serious not seriouse not serious not serious strong association 85 cases 54603 controls 

1715/ exposed 43968/ 

unexposed d,f

RR 0.10

(0.05 to 0.16) g

Type 2 CRITICAL

CI: Confidence interval; RR: Risk ratio

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 immunocompromised. The population included in the RCT may 

not represent all persons aged >=16 years. 

c. 17 studies were available in the body of evidence. 8 were excluded because the study population was already represented, and 1 was excluded due to serious study limitations. 

d. The body of evidence includes preprints. 

e. Although I2 value was high (95.0%), no serious concern for inconsistency was judged because all studies showed a high degree of vaccine effectiveness, with point estimates ranging 

from 87% to 97%. In a sensitivity analysis including results from one study with study limitations identified that had a vaccine effectiveness estimate of 56%, the pooled RR was .10 

(95% CI .05, .18), and I2 was 98.1%. 

f. Data on numerators and denominators were not consistently reported in the available body of evidence. The n shown excludes events from studies that did not report the number 

of cases. The N is not included because studies variously provided person-time or number of persons. 

g. Pooled RR based on a random effects meta-analysis, using adjusted vaccine effectiveness estimates on a log scale. 
Outcome 2: Hospitalization for COVID-19

Randomized Studies with Unvaccinated Comparator (n=1)

24

 Pfizer/BioNTech phase 2/3 RCTa,b

 Severe COVID-19c: COVID-19 case with at least 1 of following:

– Clinical signs at rest indicative of severe systemic illness;d

– Respiratory failure;c

– Evidence of shock;c

– Significant acute renal, hepatic, or neurologic dysfunction;

– Admission to an intensive care unit; or

– Death

 Severe COVID-19 per CDC definition: hospitalization, admission to the ICU, 

intubation or mechanical ventilation, or death

a. Polack et al., New England Journal of Medicine; additional unpublished data obtained from authors

b. Thomas et al., preprint; additional unpublished data obtained from authors

c. Severe COVID-19 as defined in protocol using guidance from FDA.

d. 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.
Outcome 2: Hospitalization for COVID-19 

Studies with Unvaccinated Comparator, RCT (n=1)

25

Outcome Study/population Events/Vaccine 

(n/N)

Events/Placebo 

(n/N)

Vaccine efficacy 

(95% CI)

Secondary endpoint: 

Severe COVID-19, 

protocol definition a

No evidence of prior infection, 

≥7 d post dose 2

1/19,711 21/19,741 95.3% 

(71.0%, 99.9%)

Severe COVID-19 (CDC) 

& hospitalized

No evidence of prior infection, 

≥7 d post dose 2

0/19,687 31/19,708 100% (87.6%, 100%)

Severe COVID-19 (CDC) 

& hospitalized, includes 

confirmed and nonconfirmed COVID-19

No evidence of prior infection, 

after dose 1

2/21,909 59/21,908 96.6% (87.2%, 99.6%)

a. FDA definition of severe COVID-19: 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. CDC definition of severe COVID-19: hospitalization, admission to the ICU, intubation or mechanical ventilation, or death
Outcome 2: Hospitalization for COVID-19 

Observational Studies with Unvaccinated Comparator (n=13)

Overall

n=13

Peer-reviewed 

n=6

Pre-print

n=7

Design

- Case-control

- Cohort, prospective

- Cohort, retrospective

- Test-negative

1

3

7

2

1

1

4

0

0

2

3

2

Location

- Europe

- Middle East

- North America 

4

5

4

2

2

2

2

3

2

Most recent study period (2021) July July July 

26
Outcome 2: Hospitalization for COVID-19 

Observational Studies with Unvaccinated Comparator, Peer-reviewed (n=6)

Location Study Population Method Time period 

(predominant 

variant)

Days after 

dose 2

n/N 

vaccinated

n/N 

unvaccinated

VE* 95% CI Included in 

pooled 

estimate? 

(reason if no)

Israel Haas, 

May 2021

general 

population 

≥16 years

Retrospective 

cohort

1/24–4/3/21 

(Alpha)

≥7 596/201882183 p-d 5526/120076136 p-d 97.2 96.8– 97.5 Yes

Dagan, 

April 2021

General 

population 

≥16 years

Retrospective 

cohort

12/20/20–

2/1/21

>7 110/596,618 p-d 259/596,618 p-d 87 55–100 No (population 

subgroup of 

Haas)

Italy Flacco, 

June 2021

General 

population 

≥18 years

Retrospective 

cohort

1/2–5/21/21

(Original, Alpha)

≥14 NR/30,817 NR/174,023 99 96–100 Yes

Spain MartínezBaz, May 

2021 

Close contacts

≥18 years

Prospective 

cohort

Jan–April 2021 

(Alpha)

≥14 1/491 548/19,580 94 60–99 Yes

United 

States

Pawlowski, 

August 

2021 

Mayo Health 

system 

patients

Retrospective 

cohort

2/15– 4/20/21 

(Original, Alpha)

≥7 7 cases/1,915,615 

person-days 

60 cases /1,837,276 88.8 75.5–95.7 No (overlapping 

population with 

Puranik 

≥14 6 /1,671,628 p-d 49/1,599,076 p preprint) -d 88.3 72.6–95. 9

Tenforde, 

August 

2021

Hospitalized 

adults ≥18 

years

Case-control 3/11–5/5/21 

(Alpha)

≥14 95 /1,194 571/1,895 84.3 74.6– 90.3 Yes

VE: vaccine effectiveness. CI: confidence intervals *Adjusted VE estimates used when available. See references for covariates. **Excluded from general population sensitivity analysis 27
Outcome 2: Hospitalization for COVID-19 

Observational Studies with Unvaccinated Comparator, Pre-print (n=7)

Location Study Population Method Time period

(predominant 

variant)

Days 

after 

dose 

2

n/N 

vaccinated

n/N 

unvaccinate

d

VE* 95% CI Included in 

pooled 

estimate?

(reason if no)

Canada 

(Ontario)

Nasreen General 

population ≥16 

years 

(symptomatic)

Test-negative 12/14/20–5/2/21 

(Multiple)

≥7 Non-VOC: ≤5/6,327

Alpha: 26/6,896 

Beta/gamma: ≤5/780 

Delta: ≤5/165

6,910/

351,240

nonVOC: 96 

Alpha: 95 

Beta/Gamma: 95** 

Delta: -

82–99

92–97

81–99**

-

Yes

Denmark Emborg Groups prioritized 

for vaccination

Retrospective 

cohort

12/27/20–4/11/21

(Original, Alpha)

>7 24/37,429.7 p-y 1,014/152,17

1.4 p-y 

93 89–96 Yes

England Stowe General 

population

Test-negative 4/12–6/4/21 ≥14 Not reported Not 

reported

Alpha: 95

Delta: 96**

78–99 

86–99**

Yes 

Israel Balicer Pregnant women Prospective 

cohort

12/20/21–6/3/21 

(Original, Alpha)

≥7 11/10,861 25/10,861 89 43–100 No (population 

subgroups of 

Haas)

Goldberg General 

population ≥16 

years

Prospective 

cohort

12/20/20–3/20/21 ≥7 493/136.8M p-d 10057/288.5

M p-d

94.2 93.6–94.7

Saciuk active members of 

a large HMO ≥16 

years 

Retrospective 

cohort

1/18–4/25/21 ≥7 105/1,353,847 942/

1,162,033

94.4 93.2–95.5

United 

States

Puranik Adults ≥18 years 

with access to 

Mayo Health 

System (MN)

Matched 

retrospective 

cohort

Jan–July 2021

(Alpha, Delta)

≥14 11 /2,333,145 p-d 82/

2,532,948 

p-d 

85 73–93 Yes

VE: vaccine effectiveness. CI: confidence intervals *Adjusted VE estimates used when available. See references for covariates. **Used for pooled analysis 28
0

1

2

3

4

5

6

7

8

9

10

0 10 20 30 40 50 60 70 80 90 100

Vaccine Effectiveness

Outcome 2: Hospitalization for COVID-19 

Observational Studies with Unvaccinated Comparator (n=8)

Emborg, Denmark, Dec 2020–Apr 2021 

Flacco, Italy, Jan–May 2021 

Haas, Israel, Jan–Apr 2021 

Martinez-Baz, Spain, Jan–Apr 2021 

Nasreen, Canada, Dec 2020–May 2021

Puranik, USA, Jan–July 2021 

Stowe, UK, Apr–June 2021 

Tenforde, USA, Mar–May 2021 

Pooled Estimate Pooled VE = 94.3% (87.9% to 97.3%)*

*Sensitivity analyses resulted in pooled estimates ranging from 89.4% to 95.7% 29
Evidence Table: Hospitalization for COVID-19 

30

Certainty assessment No of patients Effect

No of Certainty Importance

studies Study 

design Risk of bias Inconsistency Indirectness Imprecision

Other 

considerations

Pfizer BioNTech 

COVID-19 

vaccine, 30 mcg, 

2 doses 21 days 

apart

No vaccine Relative

(95% CI)

Vaccine efficacy against hospitalization due to COVID-19 

1 RCT not seriousa,b not serious not seriousc seriousd none 0/19,687 (0.0%) 31/19,708 

(0.2%) 

RR 0.02

(0.00–0.26)e

Type 2 CRITICAL

8f Obsg not serious not serioush not seriousi not serious strong 

association 

95 cases 1359 controls 

632/ exposed 

7170/ unexposedg,j

RR 0.06

(0.03–0.12) k 

Type 2 CRITICAL

― 0.2%

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. Risk of bias was considered due to concern about misclassification of outcome. Hospitalization due to COVID-19 is not specified in the study protocol, and the data shown include only persons who met the protocol definition of 

COVID-19 using an approved assay or confirmation in a central laboratory; it was unclear if constructing a non-protocol measure may have resulted in bias. Data on all hospitalizations due to COVID-19 diagnosed by any assay after 

dose 1 were also obtained and reviewed. Two hospitalizations due to COVID-19 occurred among 21909 persons in the vaccine arm and 59 occurred among 21908 persons in the placebo arm (RR = 0.03, 95% CI 0.01, 0.10); the 

similar efficacy diminished concerns regarding risk of bias.

c. The RCT excluded persons with prior COVID-19 diagnosis, pregnant or breastfeeding women, and persons who were immunocompromised. The population included in the RCT may not represent all persons aged >=16 years.

d. Serious concerns of imprecision due to fragility in the estimate was present because there were only 31 events observed from a single RCT.

e. RR calculated using a standard continuity correction of 0.5.

f. 13 studies were available in the body of evidence. 5 were excluded because the study population was already represented.

g. The body of evidence includes preprints.

h. Although I2 value was high (91.7%), no serious concern for inconsistency was judged because all studies showed a high degree of vaccine effectiveness, with point estimates ranging from 84% to 99%.

i. 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. 

j. Data on numerators and denominators were not consistently reported in the available body of evidence. The n shown excludes events from studies that did not report the number of cases. The N is not included because studies 

variously provided person-time or number of persons.

k. Pooled RR based on a random effects meta-analysis, using adjusted vaccine effectiveness estimates on a log scale. CI: Confidence interval; RR: Risk ratio
Outcome 3: Death due to COVID-19

Studies with Unvaccinated Comparator (n=1)

31

 Pfizer/BioNTech phase 2/3 randomized controlled trial (RCT)a

 Data evaluated: any COVID-19 death in eligible randomized trial 

participants, irrespective of the confirmation of the COVID-19 diagnosis by 

trial protocol (data cut-off: March 13, 2021)

a. Polack et al., New England Journal of Medicine; additional unpublished data obtained from authors

b. Thomas et al., preprint; additional unpublished data obtained from authors
Outcome 3: Death due to COVID-19

Studies with Unvaccinated Comparator, RCT (n=1)

32

Study/population Events/Vaccine 

(n/N)

Events/Placebo 

(n/N)

VE

(95% confidence interval)

Persons aged ≥16 years 1/19687 6/19708 83% (-39%, 98%)

Persons aged ≥16 years, 

COVID-19 case confirmed 

using a protocol-approved 

assay or centrally confirmed

0/19687 3/19708 100%
Outcome 3: Death due to COVID-19

Observational Studies with Unvaccinated Comparator (n=6)

33

Overall

n=6

Peer-reviewed 

n=2

Pre-print

n=4

Design

- Case-control 

- Cohort, prospective

- Cohort, retrospective

- Test-negative

0

1

5

0

0

0

2

0

0

1

3

0

Location

- Europe

- Middle East

- North America 

2

3

1

1

1

0

1

2

1

Most recent study period (2021) July May July 
Locationc Study Population Method Time period 

(predominant 

variant)

Days 

after 

dose 2

n/N 

vaccinated

n/N 

unvaccinated

VE* 95% CI Included in 

pooled estimate? 

(reason if no)

Peer-reviewed

Israel Haas, May 2021 General 

population ≥16 

years

Retrospective 

cohort

1/24 –4/3/21 

(Alpha)

≥7 138/20188218

3 p-d

715/120076136

p-d

96.7 96.0–97.3 Yes

Italy Flacco, June 2021 General 

population ≥18 

years

Retrospective 

cohort

1/2–5/21/21 

(Original, Alpha)

≥14 NR/30,817 NR/174,023 98 87–100 Yes

Pre-print 

Denmark Emborg Groups prioritized 

for vaccination

Retrospective 

cohort

12/27/20–

4/11/21 

(Original, Alpha)

>7 25/

37631.7 p-y 

445/

153,179.6 p-y

Overall: 

94

90–96 Yes

Israel Goldberg General 

population ≥16 

years

Prospective 

cohort

12/20/20–

3/20/21

≥7 136/136.8M pd

1749/288.5 p-d 93.7 92.5–94.7 No 

(population 

subgroups of 

Saciuk active members of Haas)

a large HMO ≥16 

years 

Retrospective 

cohort

1/18–4/25/21 ≥7 33/1,354,444 131/1,166,487 84.0 76.6–89.1

United States Puranik Adults ≥18 years 

with access to 

Mayo Health 

System (MN)

Matched 

retrospective 

cohort

Jan–July 2021

(Alpha, Delta)

≥14 0 /2,333,860 pd4 /2,537,030 p-d 100 -60–100 Yes

Outcome 3: Death due to COVID-19

Observational Studies with Unvaccinated Comparator (n=6)

VE: vaccine effectiveness. CI: confidence intervals *Adjusted VE estimates used when available. See references for covariates. 34
0

1

2

3

4

5

6

0 10 20 30 40 50 60 70 80 90 100

Vaccine Effectiveness

Outcome 3: Death due to COVID-19

Observational Studies with Unvaccinated Comparator (n=4)

Emborg, Denmark, Dec 2020–Apr 2021 

Flacco, Italy, Jan–May 2021 

Haas, Israel, Jan–Apr 2021 

Puranik, USA, Jan–July 2021

Pooled Estimate Pooled VE = 96.1% (91.5% to 98.2%)*

*Sensitivity analyses resulted in pooled estimates ranging from 95.6% to 96.8% 35
Evidence Table: Death Due to COVID-19

36

a. Risk of bias was considered due to possible misclassification of outcomes. One death in a vaccine recipient and 3 deaths among placebo recipients were in persons who had been diagnosed with COVID-19 based on local 

clinical nucleic acid amplification tests that were not protocol approved; these diagnoses were not confirmed by the central study laboratory and were not counted in the efficacy estimates for symptomatic laboratoryconfirmed COVID-19 or hospitalization due to COVID-19. In an analysis using only protocol approved or central laboratory confirmed cases resulting in death, with a standard continuity correction applied, the relative 

risk was 0.14 (95% CI 0.01, 2.77). 

b. The RCT excluded persons with prior COVID-19 diagnosis, pregnant or breastfeeding women, and persons who were immunocompromised. The population included in the RCT may not represent all persons aged >=16 

years. 

c. 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. 

d. Calculated risk among placebo arm in available body of evidence from RCT was 0.03%, but it appears lower here due to rounding. 

e. 6 studies were available in the body of evidence. 2 were excluded because the study population was already represented. 

f. The body of evidence includes preprints.

g. The relative risk shown is from a pooled analysis of 4 cohort studies conducted in different populations. I2 was 48.8%. 

h. Definitions varied by study. Indirectness was considered given COVID-19 was not necessarily confirmed as the cause of deaths, but this was not deemed not serious. 

i. Data on numerators and denominators were not consistently reported in the available body of evidence. The n shown excludes events from studies that did not report the number of cases. The N is not included 

because the type of denominator varied across studies (e.g., person-time or number of persons). 

j. Pooled RR based on a random effects meta-analysis, using adjusted vaccine effectiveness estimates on a log scale. 

Certainty assessment No of patients Effect

Certainty

No of Importance

studies

Study 

design

Risk of 

bias Inconsistency Indirectness Imprecision Other considerations Intervention comparison Relative(95% CI)

1 RCT not seriousa not serious not seriousb seriousc none 1/19687 (0.0%) 6/19708 (0.0%)d RR 0.17

(0.02 to 1.39) 

Type 2 IMPORTANT

4e observationalf not serious not seriousg not serioush not serious strong association 163/ exposed 

1164/ 

unexposedi

0.0% RR 0.03

(0.02 to .07)j

Type 2 IMPORTANT
Outcome 4: Asymptomatic SARS-CoV-2 Infection

Randomized Studies with Unvaccinated Comparator (n=0)

37

 No RCT studies provided data on this outcome
38

Overall

n=5

Peer-reviewed 

n=3

Pre-print

n=2

Design

- Case-control

- Cohort, prospective

- Cohort, retrospective

- Test-negative 

- Other

1

1

2

0

1

0

1

2

0

0

1

0

0

0

1

Location

- Europe

- Middle East

- North America 

1

4

0

0

3

0

1

1

0

Most recent study period (2021) August April August

Outcome 4: Asymptomatic SARS-CoV-2 Infection

Studies with Unvaccinated Comparator (n=5)
Outcome 4: Asymptomatic SARS-CoV-2 Infection

Studies with Unvaccinated Comparator (n=5)

Location Study Population Method Time period 

(predominant 

variant)

Days after 

dose 2

n/N 

Vaccinated (or 

person-time)

n/N 

Unvaccinated 

(or person-time)

VE* 95% CI Included in pooled 

estimate? (reason if 

no)

Peer-reviewed

Israel Haas, May 

2021

general 

population ≥16 

years

Retrospective 

cohort

1/24–4/3/21 

(Alpha)

≥7 3632/201882183 

p-d

49138/12007613

6 p-d

91.5 90.7–92.2 Yes

Angel, May 

2021

Healthcare 

workers

Retrospective 

cohort

12/20/20–2/25/21 

(Alpha)

>7 19/5372 17/696 86 69–93 No 

(population 

subgroups of Haas) Regev-Yochay, 

August 2021

Healthcare 

worders

Prospective 

cohort

12/19/20 – 3/14/21 

(Alpha)

≥11 12/1300 

exposure events

48/1441 

exposure events

72 48–86

Pre-print

Qatar Tang General 

population (any 

age)

Matched case 

control

12/21/20–7/21/21 

(Delta only)

≥14 73 

vaccinated/757 

cases

108 

vaccinated/757 

controls

35.9 11.1–53.9 No 

(study limitations)

United 

Kingdom

Pouwels General 

population 18–

64 years

Longitudinal 

household 

survey

12/1/20–8/1/21 

(Delta)

≥14 NR NR Deltadominant 

period: 74

69–78 Yes

VE: vaccine effectiveness. CI: confidence intervals *Adjusted VE estimates used when available. See references for covariates. 39
Outcome 5: Asymptomatic SARS-CoV-2 infection

Observational Studies with Unvaccinated Comparator (n=2)

0

1

2

3

4

0 10 20 30 40 50 60 70 80 90 100

Vaccine Effectiveness

Haas, Israel, Jan–Apr 2021

Pouwels, UK, May–July 2021 

Pooled Estimate Pooled VE = 89.3% (88.4% to 90.1%)*

*Including a 3rd study that did not meet inclusion criteria, the pooled VE was 88.1% (87.2%, 89.0%) 40
Evidence Table: Asymptomatic SARS-CoV-2 Infection

41

a. 5 studies were available in the body of evidence. 2 were excluded because the study population was already represented, and one study was 

excluded due to study limitations.

b. The body of evidence includes preprints.

c. Serious concern for inconsistency was present (I2 = 98.1%). The magnitude of the relative risks from the two 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. In a 

sensitivity analysis including results from one study with study limitations identified that had a vaccine effectiveness estimate of 35.9%, the pooled 

RR was 0.12 (95% CI 0.11, 0.13), and I2 was 99.1%. 

d. 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.

Certainty assessment No of patients Effect

No of Certainty Importance

studies Study design Risk of 

bias Inconsistency Indirectness Imprecision Other considerations

Pfizer 

BioNTech 

COVID-19 

vaccine, 30 

mcg, 2 doses 

21 days apart

no vaccine Relative

(95% CI)

2a observational 

studiesb

not 

serious

seriousc not serious not serious none 3,632/ 

exposed 

49138/ 

unexposed

4.2% RR 0.11

(0.10–0.12) d

Type 4 IMPORTANT

CI: Confidence interval; RR: Risk ratio
Harms
Outcome 5: Serious Adverse Events

Studies with Unvaccinated Comparator (n=2)

43

 Pfizer-BioNTech phase 2/3 RCTa,b

 Pfizer-BioNTech phase 1 RCTc

a. Polack et al., New England Journal of Medicine; additional unpublished data obtained from authors

b. Thomas et al., preprint; additional unpublished data obtained from authors

c. Walsh et al., New England Journal of Medicine; additional unpublished data obtained from authors
Pfizer-BioNTech Phase 1 RCT*

44

 Population: healthy adults aged 18–55 or 65–85 years, United States

 Data evaluated: 

– 18–55 years: 12 received 2 doses of 30 μg of BNT162b2, 3 placebo

– 65–85 years: 12 received 2 doses of 30 μg of BNT162b2, 3 placebo

 Primary outcomes: safety 

– Local and systemic reactions: active surveillance through prompted electronic 

diary for 7 days following each dose

– Adverse events: passive surveillance (unprompted reporting), clinical 

laboratory assessments 1–2 and 7 days after each dose

*Unpublished data and Walsh EE, Frenck RW, Falsey AR et al. Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates. NEJM. 2020. DOI: 10.1056/NEJMoa2027906.
Outcome 5: Serious Adverse Events

Studies with Unvaccinated Comparator, Randomized (n=2)

45

Study/populationa Events/Vaccine 

(n/N)b

% SAE

Vaccine

Events/Placebo

(n/N)

% SAE

Placebo

Associated 

with 

vaccinationc

Walsh, 2020 1/24 4.2 0/6 0 0

Polack, 2020, 

Thomas, 2021

268/21926 1.2 268/21921 1.2 2

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

b. One SAE of neuritis was reported from the phase 1 trial that had not been identified at the time of the Walsh publication. This SAE 

was deemed unassociated to vaccination. In the phase 3 trial, there was a potential clinical imbalance of appendicitis, with 8 events in 

the vaccine group and 4 in the placebo group. One report of pericarditis was identified in the vaccine group, 28 days after dose 2. This 

SAE was deemed unassociated with vaccination.

c. Four serious adverse events were deemed by blinded investigators to be related to vaccination. These included: shoulder injury 

related to vaccine administration, ventricular arrhythmia, lymphadenopathy, and lower back pain and bilateral lower extremity pain 

with radicular paresthesia. Through further investigation by the FDA, only two were classified as related to vaccination: shoulder injury 

and lymphadenopathy.
Serious Adverse Events (Myocarditis)

 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

46

n/N Rate per 1 million 

person-years

Adjusted rate ratio 

(95% CI)

7-day risk interval after BNT-162b2 dose 2, 

persons 18–39 years

9/24,432 368 9.1 (2.1–48.6)

Comparison interval in vaccinated 

individuals

3/62,481 48 REF
Serious Adverse Events (Myocarditis)

 Data from the national Vaccine Adverse Event Reporting System (VAERS)a showed an 

elevated ratio of observed to expected myocarditis casesb in the 7-day interval 

following vaccination among females in age groups 16–24 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 Pfizer vaccination is consistent with that 

observed in VSD.

47

a As of August 18, 2021

b Counts among persons aged 16–29 years were verified by provider interview or medical record review to meet the 

case definition; counts in older age groups were identified by computer search for standardized codes assigned to 

reports and have not been verified to meet case definition.
Serious Adverse Events (Anaphalaxis)

 A rapid cycle analysis of data from VSD evaluated chart-reviewed cases 

of anaphalaxis among all vaccinated persons aged 12 years and older. 

Based on events occurring in a 0–1 day risk interval after vaccination, the 

estimated incidence of confirmed anaphalaxis was 5.0 (95% CI 3.5–6.9) 

per million doses. 

 The absolute reporting rate to VAERS was 4.7 per million doses 

administered.

48
Evidence Table: Serious Adverse Events

49

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 immunocompromised. The population included in the RCT may 

not represent all persons aged ≥16 years. 

c. Serious concern for imprecision was present. The confidence interval indicates that both reduced and increased risk of serious adverse events are possible. 

d. Pooled RR based on a fixed effects meta-analysis. Fixed effects model was used for this analysis due to imprecise estimates of the between-studies variance.

Certainty assessment No of patients Effect

Certainty Importance

No of 

studies

Study 

design

Risk of 

bias Inconsistency Indirectness Imprecision Other considerations Intervention Comparison Relative(95% CI)

2 RCT not 

seriousa

not serious not seriousb seriousc None 269/21950 

(1.2%) 

268/21927 (1.2%) RR 1.00

(0.85 to 1.18) d

Type 2 CRITICAL
Evidence Table: Serious Adverse Events (Myocarditis and Anaphalaxis)

50

a. For the outcomes of myocarditis and anaphalaxis evaluated in Vaccine Safety Datalink, data are shown for the age groups 18-39 and ≥12 years, respectively, therefore these were not completely 

generalizable to the age groups of all persons aged >=16 years as defined in the PICO question. This was deemed not serious.

b. Counts among persons aged 16–29 years were verified by provider interview or medical record review to meet the case definition; counts in older age groups were identified by computer search for 

standardized codes assigned to reports and have not been verified to meet the case definition.

Certainty assessment No of patients Effect

No of Certainty Importance

studies

Study 

design

Risk of 

bias Inconsistency Indirectness Imprecision

Other 

considerati

ons

Intervention Comparison Relative

(95% CI)

2 Obs not 

serious

not serious not serious a not serious None • A rapid cycle analysis from Vaccine Safety Datalink (VSD) evaluated chartreviewed 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 9.1 (95% CI 2.1–48.6). The rates of myocarditis were 368 per 1 

million person-years (9/24432) in the 0–7 day risk interval and 48 per 1 million 

person-years (3/62481) in vaccinated comparators.

• Data from the national Vaccine Adverse Event Reporting System (VAERS) 

showed an elevated ratio of observed to expected myocarditis casesb in the 7-

day interval following vaccination among females in age groups 16-24 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 Pfizer 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 12 years and older. Based on 

events occurring in a 0–1 day risk interval after vaccination, the estimated 

incidence of confirmed anaphalaxis was 5.0 (95% CI 3.5–6.9) per million doses. 

The absolute reporting rate to VAERS was 4.7 per million doses administered.

Type 3 CRITICAL
Outcome 6: Reactogenicity, Severe (Grade ≥3)

Studies with Unvaccinated Comparator (n=2)

51

 Pfizer-BioNTech phase 2/3 RCTa,b

 Pfizer-BioNTech phase 1 randomized RCTc

a. Polack et al., New England Journal of Medicine; additional unpublished data obtained from authors

b. Thomas et al., preprint; additional unpublished data obtained from authors

c. Walsh et al., New England Journal of Medicine; additional unpublished data obtained from authors
Outcome 6: Reactogenicity, Severe (Grade ≥3)

Definitions

52

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

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

– Grade 3: pain at injection site that prevents daily activity; redness > 10 cm; and swelling > 10 cm 

– Grade 4: emergency room visit or hospitalization for severe pain at the injection site, necrosis 

(redness and swelling categories) or exfoliative dermatitis (redness category only).

 Systemic events (fever, vomiting, diarrhea, headache, fatigue, chills, new or worsened 

muscle pain, new or worsened joint pain)

– Grade 3: fever >38.9°C to 40.0°C , vomiting that requires IV hydration; diarrhea of ≥6 loose stools 

in 24 hours; severe fatigue, severe headache, severe muscle pain, or severe 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 6: Reactogenicity, Severe (Grade ≥3)

Studies with Unvaccinated Comparator (n=2)

53

Study/population Events/Vaccine 

(n/N)

% Vaccine Events/Placebo

(n/N)

% Placebo

Walsh, 2020a 3/24 8.3 0/6 0.0

Polack, 2020, 

Thomas, 2021a 520/4924 10.6 111/4915 2.3

a. Additional data provided by sponsor
Evidence Table: Reactogenicity, Severe (Grade ≥3)

54

a. The RCT excluded persons with prior COVID-19 diagnosis, pregnant or breastfeeding women, and persons who were immunocompromised. The population included in the RCT may not 

represent all persons aged >=16 years.

b. Pooled RR based on a fixed effects meta-analysis. Fixed effects model was used for this analysis due to imprecise estimates of the between-studies variance.

Certainty assessment No of patients Effect

No of Certainty Importance

studies Study 

design Risk of bias Inconsistency Indirectness Imprecision

Other 

considerations Intervention Comparison Relative

(95% CI)

Reactogenicity, severe (grade ≥3) 

2 RCT not serious not serious not seriousa not serious none 531/4,948 

(10.7%) 

111/4,921 

(2.3%) 

RR 4.69

(3.83–5.73) b

Type 1 IMPORTANT 

CI: Confidence interval; RR: Risk ratio
Summary of GRADE

55

OutcomeImportance Design

(# of studies)

FindingsEvidence

type

Benefits

Symptomatic 

laboratory-confirmed 

COVID-19

Critical RCT (1)

OBS (9)

Pfizer-BioNTech COVID-19 vaccine is effective in preventing symptomatic 

COVID-19

1

Hospitalization due to 

COVID-19

Critical RCT (1)

OBS (8)

Pfizer-BioNTech COVID-19 vaccine prevents COVID-19-resulting in 

hospitalization 2

Death due to COVID-19 Important RCT (1)

OBS (4) Pfizer-BioNTech COVID-19 vaccine prevents death due to COVID-19 2

Asymptomatic SARSCoV-2 infection Important OBS (2) Two cohort studies show benefit of vaccination for preventing 

asymptomatic infections, but magnitude inconsistent 4

Harms

Serious adverse eventsCritical RCT (2)

In the RCT, SAEs were balanced between vaccine and placebo arms. In 

post-authorization safety monitoring, myocarditis and anaphylaxis were 

rare but more common following vaccination

2

Reactogenicity Important RCT (2)

Severe reactions within 7 days were more common in vaccinated; any 

grade ≥3 reaction was reported by 10.7% of vaccinated vs. 2.3% of 

placebo group

1

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

 Policy question: focuses on recommendation following licensure of Pfizer-BioNTech COVID-19 

vaccine that has been in use for several months under an emergency use authorization

 Benefits: Supported by body of evidence from RCTs and observational studies

– RCT evidence demonstrated efficacy against the 2 critical outcomes: symptomatic 

disease and hospitalization

– Direct evidence of efficacy for hospitalization and deaths limited from RCTs; body of 

evidence from observational studies demonstrates effectiveness

– Few data from observational studies available to assess prevention of asymptomatic 

infection

 Harms: 

– Grade 3 reactions were more common in vaccine than placebo recipients

– Serious adverse events occurred at a similar frequency in vaccine and placebo groups

– Two specific, rare SAEs have been associated with vaccination through safety surveillance

56
Acknowledgements  Megan Wallace  Jennifer Collins  Heidi Moline  Monica Godfrey  Ian Plumb  Hannah Rosenblum  Kathleen Dooling  Sara Oliver  Karen Broder  Naomi Tepper  Rebecca Morgan  Doug Campos-Outcalt  VTF ACIP WG Team  ACIP COVID-19 Vaccines Work Group 57
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