For more information: www.cdc.gov/COVID19

Grading of Recommendations, 

Assessment, Development, and 

Evaluation (GRADE): 

Pfizer-BioNTech COVID-19 Vaccine 

ACIP COVID-19 Vaccines Work Group

Dr. Megan Wallace

12 May 2021
2

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

recommended for persons 12-15 years of age under an Emergency Use 

Authorization?

Policy Question
3

PICO Question

Population Persons aged 12-15 years

Intervention Pfizer-BioNTech COVID-19 vaccine BNT162b2 (30 μg, 2 

doses IM, 21 days apart)

Comparison No vaccine

Outcomes Symptomatic lab-confirmed COVID-19

Hospitalization due to COVID-19

Multisystem inflammatory syndrome in children (MIS-C) 

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

Asymptomatic SARS-CoV-2 infection

Serious Adverse Events

Reactogenicity
Outcomes – Pediatric vs. Adult Vaccines

4

Pediatric COVID-19 Vaccines Adult COVID-19 Vaccines

OutcomeImportancea Outcome Importancea

Benefits

Symptomatic lab-confirmed COVID-19 

(direct efficacy and immunobridging) Critical Symptomatic lab-confirmed COVID-19

Critical

Hospitalization due to COVID-19Important Hospitalization due to COVID-19Critical

Multisystem inflammatory syndrome 

in children (MIS-C) Important All-cause death Important

SARS-CoV-2 seroconversion Important SARS-CoV-2 seroconversion Important

Asymptomatic SARS-CoV-2 infection Important Asymptomatic SARS-CoV-2 infection Important

Harms

Serious adverse events 

(note: includes deaths) Critical Serious adverse events Critical

Reactogenicity Important Reactogenicity Important

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

5

OutcomeImportancea Description

Benefits

Symptomatic lab-confirmed 

COVID-19

Critical Current studies use PCR + specific symptoms; immunobridging

Hospitalization due to COVID19

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

groups for this outcome

Multisystem inflammatory 

syndrome in children (MIS-C) Important 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; no data available

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
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 BNT162b2 and 1) involved human subjects; 2) 

reported primary data; 3) included persons 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 (30 μg, 2 doses at 0 and 21 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.

6
Evidence Retrieval

7

Records identified through 

database searching

(n = 5378)

Records excluded

(n = 5341)

Records screened

(n = 5379)

Full-text articles assessed for 

eligibility

(n =38)

Full-text articles excluded, with reasons

(n =37)

32 Different vaccine

5 Different population

Articles included in evidence 

synthesis

(n =1)

Additional records identified 

through other sources

(n = 1)
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.

8

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. 9
Benefits
Outcome 1: Symptomatic Lab-confirmed COVID-19

Studies with Unvaccinated Comparator (n=1)

11

 Pfizer-BioNTech phase 2/3 randomized controlled trial (RCT) (unpublished, data

obtained from sponsor)

 Persons aged 12-15 years in United States

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

randomized within the predefined window and no other important protocol

deviations (data cut-off: March 13, 2021)
Pfizer/BioNTech phase 2/3 RCT Analysis Populations

Population Description N Person-years

Evaluable 

efficacy

All eligible randomized participants who 

received all vaccination(s) as randomized 

within the predefined window and had no 

other important protocol deviations as 

determined by the investigator, and who did 

not have evidence of prior SARS-CoV-2 

infection

Including persons with prior infection

1,983 

2,229

301

333

All-available 

efficacy

All randomized participants who received at 

least 1 vaccination.

2,260 507

12
Outcome 1: Symptomatic Lab-confirmed COVID-19

Studies with Unvaccinated Comparator (n=1)

13

Population Events/Vaccine 

(n/N)

Events/Placebo 

(n/N)

Vaccine efficacy 

(95% confidence interval)

Primary outcome

No evidence of prior infection, 

≥7 d post dose 2

0/1001a 16/972a 100.0%b

Secondary outcomes

± evidence of prior infection, 

≥7 d post dose 2

0/1109a 18/1094a 100.0%c

All available efficacy (± evidence 

of prior infection, post dose 1)

3/1120a 35/1119a 91.4% (72.2%, 97.4%)

a. Number of subjects at risk for the endpoint

b. With a standard continuity correction of 0.5 applied, the estimated VE (95% CI) is 97.1% (51.0%, 99.8%)

c. With a standard continuity correction of 0.5 applied, the estimated VE (95% CI) is 97.3% (55.8%, 99.8%)
Outcome 1: Symptomatic Lab-confirmed COVID-19

Studies with Unvaccinated Comparator (n=1)

14

Population Events/Vaccine 

(n/N)

Events/Placebo 

(n/N)

Vaccine efficacy 

(95% confidence interval)

Primary outcome

No evidence of prior infection, 

≥7 d post dose 2

0/1001a 16/972a 100.0%b

Secondary outcomes

± evidence of prior infection, 

≥7 d post dose 2

0/1109a 18/1094a 100.0%c

All available efficacy (± evidence 

of prior infection, post dose 1)

3/1120a 35/1119a 91.4% (72.2%, 97.4%)

a. Number of subjects at risk for the endpoint

b. With a standard continuity correction of 0.5 applied, the estimated VE (95% CI) is 97.1% (51.0%, 99.8%)

c. With a standard continuity correction of 0.5 applied, the estimated VE (95% CI) is 97.3% (55.8%, 99.8%)
Pfizer-BioNTech phase 2/3 RCT Immunogenicity Population

Population Description N

12-15 years Random sample of vaccine arm of the evaluable efficacy populationa,b 209

16-25 years Random sample of vaccine arm of the evaluable efficacy populationa,b 186

a. A random sample of 280 participants in each age group were selected, however 69 participants in the 

12-15 year group and 89 participants in the 16-25 year group were excluded due to participants not 

having at least 1 valid and determinate immunogenicity result after Dose 2, mostly as the result of 

testing laboratory supply limitation of the qualified viral lot. 

b. Some placebo participants were also randomly selected to maintain blinding of laboratory personnel. 

15
Outcome 1: Symptomatic Lab-confirmed COVID-19

Studies with Unvaccinated Comparator (n=1)

16

12-15 Years 16-25 Years

nc GMTd

(95% CI) nc GMTd(95% CI)

GMRe

(95% CI)

Met 

Noninferiority 

Objectivef

SARS-CoV-2 

neutralization assay –

NT50a,b

190

1239.5

(1095.5, 

1402.5)

170 705.1

(621.4, 800.2)

1.76

(1.47, 2.10) Yes

Abbreviations: NT50 = 50% neutralizing titer; GMT = geometric mean titer; GMR = geometric mean ratio; LLOQ = lower limit of quantitation

aAmong participants who had no serological or virological evidence (up to 1 month after receipt of the last dose) of past SARS-CoV-2 infection and had 

negative NAAT at any unscheduled visit up to one month after dose two.

bSampling time point was one month after dose two.

c

Number of subjects with valid and determinate assay results for the specified assay at the given dose and sampling time point.

dGMTs and 2-sided 95% CIs were calculated by exponentiating the mean logarithm of the titers and the corresponding CIs (based on the Student t 

distribution). Assay results below the LLOQ were set to 0.5 LLOQ

eGMRs and 2-sided 95% CIs were calculated by exponentiating the mean difference of the logarithms of the titers (Group 1 [12-15 years] – Group 2 [16-25 

years]) and the corresponding CI (based on the Student t distribution)

f

Noninferiority is declared if the lower bound of the 2-sided 95% CI for the GMR is greater than 0.67

Immunobridging: Summary of Geometric Mean Ratio
Outcome 1: Symptomatic Lab-confirmed COVID-19

Studies with Unvaccinated Comparator (n=1)

17

12-15 Years 16-25 Years

Nc nd (%)

(95% CIe) Nc nd (%)(95% CIe)

Differencef (%)

(95% CIg)

SARS-CoV-2 neutralization 

assay – NT50

a,b 143 140 (97.9)

(94.0, 99.6) 124 124 (100.0)(97.1, 100.0)

-2.1

(-6.0, 0.9)

Abbreviations: NT50 = 50% neutralizing titer; LLOQ = lower limit of quantitation

aAmong participants who had no serological or virological evidence (up to 1 month after receipt of the last dose) of past SARS-CoV2 infection and had negative NAAT at any unscheduled visit up to one month after dose two.

bSampling time point was one month after dose two.

c

Number of subjects with valid and determinate assay results for the specified assay both before vaccination and at the given dose 

and sampling time point. These values are the denominator for the percentage calculations.

dNumber of subjects with a ≥4-fold rise in titer from before vaccination for the given assay at the given dose and sampling time 

point.

eExact 2-sided CI based on the Clopper and Pearson method

f

Difference in proportions, expressed as a percentage (12-15 years – 16-25 years).

g2-sided CI, based on the Miettinen and Nurminen method for the difference in proportions, expressed as a percentage.

Immunogenicity: Summary of Seroresponse (≥4-Fold Rise in Antibody Titer)
Evidence Table: Symptomatic Lab-confirmed COVID-19

18

Certainty assessment No of patients Effect

Certainty Importanc

No of e

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 symptomatic COVID-19

1 RCT Not 

serious

a

Not serious Not serious 

b,c,d

Not 

serious

None 0/1001 

(0.0%)

16/972 

(1.6%)

RR 0.03

(0.00 to 0.49) 

e

Type 1 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 effects noted are from an analysis of the evaluable efficacy population with outcomes assessed at least 7 days post dose 2 among persons who received two doses 

and had no evidence of prior SARS-CoV-2 infection. In the all-available efficacy population (persons who received at least 1 dose, with or without evidence of prior SARSCoV-2 infection), there were 3 cases reported among 1,131 persons who received the vaccine, and 35 cases among 1,129 persons who received the placebo, for a relative 

risk of 0.09 (95% CI: 0.03 to 0.28).

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 12-15 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 followup 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 licensure under an Emergency Use 

Authorization (e.g. to <50% efficacy).

e. Relative risk calculated using the standard continuity correction of 0.5.
Harms
Outcome 6: Serious Adverse Events

Studies with Unvaccinated Comparator (n=1)

20

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

data obtained from sponsor)
Outcome 6: Serious Adverse Eventsa

Studies with Unvaccinated Comparator (n=1)

21

Study/populationb Events/Vaccine 

(n/N)c

% SAE

Vaccine

Events/Placebo

(n/N)

% SAE

Placebo

Associated 

with 

vaccination

Pfizer/BioNTech, 

unpublished

5/1131 0.4 2/1129 0.2 0

a. Serious adverse event (SAE) is defined as any untoward medical occurrence that, results in death, is life 

threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent 

disability/incapacity, or is a congenital anomaly/birth defect

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

c. Data cutoff of March 13, 2021
Evidence Table: Serious Adverse Events

22

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 12-15 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. 

d. Very serious concern for imprecision was noted based on the 95% confidence interval crossing the line of no effect. The width of the 

confidence interval contains estimates for which different policy decisions might be considered. This outcome may be imprecise due to the 

small number of events during the observation period.

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)

Serious adverse events

2 RCT Not 

serious

a

Not serious Serious

b,c

Very 

Seriousd

None 5/1131 

(0.4%)

2/1129 (0.2%) RR 2.50

(0.49 to 12.84)

Type 4 CRITICAL
Outcome 7: Reactogenicity, Severe (Grade ≥3)

Studies with Unvaccinated Comparator (n=1)

23

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

data obtained from sponsor)
Outcome 7: Reactogenicity, Severe (Grade ≥3)

Definitions

24

 Phase 2/3 trial 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 7: Reactogenicitya, Severe (Grade ≥3)

Studies with Unvaccinated Comparator (n=1)

25

Study/population Events/Vaccine 

(n/N)

% Vaccine Events/Placebo

(n/N)

% Placebo

Pfizer/BioNTech, 

unpublished 121/1131 10.7 22/1129 1.9

a. Reactogenicity outcome includes local and systemic events, grade ≥3. Grade 3: prevents daily routine activity. 

Grade 4: requires emergency room visit or hospitalization. One participant in the vaccine group reported grade 4 

pyrexia (40.4 °C).
Evidence Table: Reactogenicity, Severe (Grade ≥3)

26

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 12-15 years.

Certainty assessment No of patients Effect

Certainty Importance

No 

of 

stud

ies

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 121/1131 

(10.7%)

22/1129 

(1.9%)

RR 5.49

(3.51 to 8.58)

Type 1 IMPORTANT
Summary of GRADE

27

OutcomeImportance Design

(# of studies)

FindingsEvidence

type

Benefits

Symptomatic lab-confirmed 

COVID-19

Critical RCT (1) Pfizer-BioNTech COVID-19 vaccine is effective in preventing symptomatic 

COVID-19

1

Hospitalization due to COVID19

Important No studies Data not available from any studies ND

Multisystem inflammatory 

syndrome in children (MIS-C) Important No studies Data not available from any studies ND

SARS-CoV-2 seroconversion Important No studies Data not available from any studies ND

Asymptomatic SARS-CoV-2 

infection Important No studies Data not available from any studies ND

Harms

Serious adverse eventsCritical RCT (1)

5 SAEs among vaccinated and 2 among unvaccinated; certainty in the 

estimate was very low. No SAEs were judged to be related to 

vaccination.

4

Reactogenicity Important RCT (1) Severe reactions were more common in vaccinated; any grade ≥3 

reaction was reported by 10.7% of vaccinated vs. 1.9% of placebo group 1

Evidence type: 1=high; 2=moderate; 3=low; 4=very low; ND, no data
Conclusion – GRADE for Pfizer-BioNTech COVID-19 

vaccine in adolescents

 Phase 2/3 RCT conducted among persons aged 12-15 years in the United States.

 Vaccine efficacy estimate of 100% for symptomatic laboratory-confirmed COVID-19.

 Serious adverse events were more common among vaccine than placebo participants 

(0.4% vs 0.2%), but our certainty in the estimate was very low. No SAEs were judged 

to be related to vaccination.

 Grade ≥3 local or systemic reactions more common among vaccine than 

placebo recipients and were reported by ~11% of vaccine participants.

 Certainty for critical benefits was type 1 (high).

 Certainty for critical harms was type 4 (very low).
Acknowledgements

 CDC Data team

–

–

–

Julia Gargano

Amy Blain

Danielle Moulia

 Sara Oliver

 Heather Scobie

 Steven Hadler

 Jack Gersten

 Eddie Shanley

 Mary Chamberland

 Megan Lindley

 Nicole Reisman

 Karen Broder

 Naomi Tepper

 Rebecca Morgan

 Doug Campos-Outcalt
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