Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Pfizer-BioNTech COVID-19 Vaccine for Children 5-11 Years

Overview

A Grading of Recommendations, Assessment, Development and Evaluation (GRADE) review of the evidence for benefits and harms for Pfizer-BioNTech coronavirus disease 2019 (COVID-19) vaccine for children aged 5─11 years was presented to the Advisory Committee for Immunization Practices (ACIP) on November 2, 2021. GRADE evidence type indicates the certainty in estimates from the available body of evidence. Evidence certainty ranges from type 1 (high certainty) to type 4 (very low certainty).1

The policy question was, "Should vaccination with Pfizer-BioNTech COVID-19 vaccine (2 doses, 10 µg) be recommended for children aged 5─11 years under an Emergency Use Authorization?" The potential benefits pre-specified by the ACIP COVID-19 Vaccines Work Group included prevention of the following outcomes: symptomatic laboratory-confirmed COVID-19 (critical), hospitalization due to COVID-19 (important), multisystem inflammatory syndrome in children (MIS-C) (important), and asymptomatic SARS-CoV-2 infection (important). The two pre-specified harms were serious adverse events (SAEs) (critical) and reactogenicity grade ≥3 (important).

A systematic review of evidence on the efficacy and safety of a two-dose regimen of Pfizer-BioNTech COVID-19 vaccine among children 5─11 years was conducted. The quality of evidence from one Phase II/III randomized controlled trial (RCT) was assessed using a modified GRADE approach.

A lower risk of symptomatic COVID-19 was observed with vaccination compared with placebo (relative risk [RR] 0.10; 95% confidence interval [CI]: 0.03─0.31; evidence type 1). The available data indicated that SAEs were more common in vaccine recipients, but certainty in the estimate was very low (RR 0.49; 95% CI 0.03─7.89; evidence type 4), and none of these SAEs were assessed by the Food and Drug Administration (FDA) as related to study intervention. Reactogenicity grade ≥3 was associated with vaccination (RR 2.53; 95% CI 1.19─5.38; evidence type 2). About 2.7% of vaccine recipients and 1.1% of placebo recipients reported any grade ≥3 local or systemic reactions following either dose 1 or dose 2.

Introduction

On October 29, 2021, the FDA updated the Emergency Use Authorization (EUA) for Pfizer-BioNTech COVID-19 (BNT162b2) vaccine for prevention of symptomatic COVID-19 to include children aged 5─11 years.2 As part of the process employed by the ACIP, a systematic review and GRADE evaluation of the evidence for Pfizer-BioNTech COVID-19 vaccine was conducted and presented to ACIP. The ACIP adopted a modified GRADE approach in 2010 as the framework for evaluating the scientific evidence that informs recommendations for vaccine use. Evidence of benefits and harms were reviewed based on the GRADE approach.1

The policy question was, "Should vaccination with Pfizer-BioNTech COVID-19 vaccine (2 doses, 10 µg) be recommended for children aged 5─11 years under an Emergency Use Authorization?" (Table 1).

Methods

We conducted a systematic review of evidence on the efficacy and safety of a two-dose regimen (10 µg per dose) of Pfizer-BioNTech COVID-19 vaccine in children aged 5─11 years. We assessed outcomes and evaluated the quality of evidence using a modified GRADE approach.

During Work Group calls, members were asked to pre-specify and rate the importance of relevant patient-important outcomes (including benefits and harms) before the GRADE assessment. No conflicts of interest were reported by CDC and ACIP COVID-19 Vaccines Work Group members involved in the GRADE analysis. Outcomes of interest included individual benefits and harms (Table 2). The critical benefit of interest was prevention of symptomatic laboratory-confirmed COVID-19. Other important outcomes included prevention of hospitalization due to COVID-19, prevention of MIS-C, and prevention of asymptomatic SARS-CoV-2 infection. The critical harm of interest was serious adverse events, including death; reactogenicity grade ≥3 was deemed an important harm. Hospitalization, MIS-C, and asymptomatic SARS-CoV2 infection were not included in the evidence profile because no data were available.

We identified clinical trials through clinicaltrials.gov. Records of relevant Phase I, II, or III RCTs of COVID-19 vaccine were included if they 1) provided data on children aged 5─11 years vaccinated with BNT162b2; 2) involved human subjects; 3) reported primary data; and 4) included data relevant to the efficacy and safety outcomes being measured. We identified relevant observational studies through an ongoing systematic review conducted by the International Vaccine Access Center (IVAC) and the World Health Organization (WHO), as previously described.3 Relevant observational studies were restricted to the defined population, intervention, comparison, and outcome outlined in the policy question, or related outcomes if direct data were not available. In addition, unpublished and other relevant data were obtained by hand-searching reference lists, and consulting with vaccine manufacturers and subject matter experts. Characteristics of all included studies are shown in Appendix 1,4 and evidence retrieval methods are shown in Appendix 2.

Relative risks (RR) were calculated from numerators and denominators available in the body of evidence. Vaccine efficacy estimates were defined as 100% x (1-RR). Immunobridging data comparing geometric mean neutralizing antibody titers (GMTs) in 5─11-year-olds to those in 16─25-year-olds in whom clinical efficacy was previously established was used in support of efficacy; geometric mean ratios and 95 study records.

The evidence certainty assessment addressed risk of bias, inconsistency, indirectness, imprecision, and other characteristics. The GRADE assessment across the body of evidence for each outcome was presented in an evidence profile; the evidence certainty of Type 1, 2, 3, or 4 corresponds to high, moderate, low, or very low certainty, respectively.

Results

The results of the GRADE assessment were presented to ACIP on November 2, 2021. One study was reviewed that met the criteria for evidence synthesis and provided data on outcomes specified for GRADE (Appendix 1). Data were reviewed from one Phase II/III randomized controlled trial using data provided by the sponsor. The final GRADE assessment was limited to the Phase II/III RCT data. Among children with and without prior evidence of SARS-CoV-2 infection in the all-available efficacy population (all randomized participants who received two doses), the Pfizer-BioNTech COVID-19 vaccine reduced risk of symptomatic laboratory-confirmed COVID-19 when compared with placebo (crude VE: 90.9%; 95% CI: 68.3%─98.3%; based on RR: 0.03; 95% CI: 0.10, 0.31) over a median follow-up of three months (Table 3a, Table 4). Concern for indirectness was noted because of the short duration of follow-up (i.e., observed vaccine efficacy at three months may differ from vaccine efficacy over a longer duration). Among participants without prior evidence of SARS-CoV-2 infection up to 1 month after dose 2, the geometric mean ratio (GMR) of SARS-CoV-2 50% neutralizing antibodies in children 5─11 years compared with persons aged 16─25 years was 1.04 (95% CI: 0.93─1.18), and met the prespecified noninferiority criteria (i.e., lower bound of the 2-sided 95% confidence interval for GMR >0.67 and GMR point estimate was ≥0.8) (Table 3b). For evaluation of potential harms, data were reviewed from the Phase II/III RCT. Serious adverse events were more common in vaccine recipients, but certainty in the estimate was very low (RR: 0.49; 95% CI: 0.03─7.89). Serious concern of indirectness was noted because the body of evidence does not provide certainty that rare serious adverse events were captured due to the short follow-up and small sample size. There was also very serious concern for imprecision, due to the width of the confidence interval. No SAEs were judged by the investigator to be related to vaccination (Table 3c). No vaccine-associated enhanced disease or deaths occurred in the Phase II/III RCT. Grade ≥3, or severe, local or systemic reactions within 7 days following either dose occurred more frequently in the vaccine group (2.7%) than in the placebo group (1.1%) (Table 3d). No serious concerns impacted the certainty of the estimate of reactogenicity.

GRADE Summary

The initial GRADE evidence level was type 1 (high) for each outcome because the body of evidence was from an RCT (Table 4). In terms of benefits, the available data indicated that the vaccine was efficacious for preventing symptomatic, laboratory-confirmed COVID-19, and no serious concerns impacting certainty in the estimate were identified for this outcome (type 1, high). The certainty in the estimate of the effect for serious adverse events was downgraded because of serious concern of indirectness related to the short follow-up (median three months) and very serious concern for imprecision because of the width of the 95% confidence interval (type 4, very low certainty). The certainty in the estimate of effect for reactogenicity was downgraded due to serious concern for imprecision (type 2, moderate) (Table 4).

Table 1: Policy Question and PICO

Abbreviations: IM = intramuscular.

Table 2: Outcomes and Rankings

^a No events were observed in study identified in the review of evidence.

^b Data on outcome not available in studies identified in the review of evidence.

Table 3a: Summary of Studies Reporting Symptomatic Laboratory-confirmed COVID-19

References in this table: 2

Abbreviations: RT-PCR = real-time polymerase chain reaction; CI = confidence interval; RR = relative risk.

^a 1,528 and 757 children aged 5–11 years were randomized to vaccine and placebo, respectively.

^b Based on data cutoff October 8, 2021; participants had a median follow-up of three months.

^c Primary outcome, defined as SARS-CoV-2 RT-PCR-positive symptomatic illness ≥7 days post second dose.

^d Symptomatic illness defined as least one respiratory or other COVID-19-related symptom (fever, cough, shortness of breath, chills, muscle pain, loss of taste/smell, sore throat, diarrhea, vomiting), confirmed with PCR during or ±4 days of symptom onset.

^e Vaccine efficacy estimate includes children with and without prior evidence of SARS-CoV-2 infection in the all-available efficacy population (all randomized participants who received two doses).

Table 3b: Summary of Studies Reporting Symptomatic Laboratory-confirmed COVID-19 (indirect evidence assessed using immunobridging)

References in this table: 2

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

^a Among participants who had no serological or virological evidence (up to 1 month after receipt of the last dose) of past SARS-CoV-2 infection, had negative nucleic acid amplification test (NAAT) at any unscheduled visit up to one month after dose two, and had no medical history of COVID-19.

^b Sampling 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.

^d GMRs and 2-sided 95% CIs were calculated by exponentiating the mean difference of the logarithms of the titers (Group 1 [5–11 years] – Group 2 [16─25 years]) and the corresponding CI (based on the Student t distribution).

^e Noninferiority is declared if the lower bound of the 2-sided 95% CI for the GMR is greater than 0.67 and the point estimate of the GMR is ≥0.8.

Table 3c: Summary of Studies Reporting Serious Adverse Events ^a

References in this table: 2

^a Death, life-threatening event, hospitalization, incapacity to perform normal life functions, medically important event, or congenital anomaly/birth defect.

^b Number of participants experiencing SAEs (participants may experience more than one SAE), data cutoff October 8, 2021.

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

^d SAE (limb fracture) was reported in a participant in the BNT162b2 group. 3 SAEs (arthritis infective, foreign body ingestion of a penny, epiphyseal fracture) were reported in 3 children (1 each) in the pediatric safety expansion group through the data cut off 8 October 2021. All SAEs were assessed by the investigatory as not related to the study intervention.

^e 2 SAEs (pancreatitis and abdominal pain) occurred in 1 placebo recipient.

Table 3d: Summary of Studies Reporting Reactogenicity ^a

References in this table: 2

Abbreviations: RR = relative risk; CI = confidence interval; RCT = randomized controlled trial.

^a Reactogenicity outcome includes local and systemic events, grade ≥3. Grade 3: prevents daily routine activity or requires use of a pain reliever. Grade 4: requires emergency room visit or hospitalization. One participant in the vaccine group reported grade 4 pyrexia (40.4 °C).

^b Based on interim analysis, data cutoff September 6, 2021.

^c No participants reported a local grade 4 reaction. One participant in the vaccine group reported grade 4 pyrexia (>40.0 °C).

Table 4: Grade Summary of Findings Table

Abbreviations: CI = confidence interval; RR = relative risk; COVID-19 = coronavirus disease 2019; RCT = randomized controlled trial.

a. The RCT excluded children who were immunocompromised or had a prior history of MIS-C. The population included in the RCT may not represent all children aged 5─11 years. However, this was deemed not serious.

b. Indirectness was considered because the vaccine efficacy observed at a median 3-month follow-up may differ from that observed over a longer period. However, this was deemed not serious.

c. The effects noted are from an analysis of the observed VE at least 7 days after Dose 2, among children with or without prior evidence of SARS-CoV-2 infection in the all-available efficacy population (all randomized children who received 2 doses). The VE observed at least 7 days after Dose 2 among participant with or without prior evidence of SARS-CoV-2 infection in the evaluable efficacy population (excluded children who received Dose 2 outside the predefined window [19─41 days post Dose 1] or had other protocol deviations [mainly related to vaccine thawing, dilution and/or administration issues]) was 90.7% (95% CI: 67.7─98.3%) with 3 cases in vaccine arm and 16 cases in the placebo arm. The observed VE from the all-available efficacy population with or without prior evidence of SARS-CoV-2 infection was deemed the most directly applicable to the policy question.

d. Total surveillance time was 369 person-years.

e. Total surveillance time was 179 person-years.

f. 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 (median: 3.3 months).

g. The effects noted are from an analysis of the initial enrollment group. A safety expansion group of children aged 5–11 years (1591 children in the vaccine arm and 788 children in the placebo arm) were not included because of the short duration of follow-up (median: 2.4 weeks). At the time of the data cutoff (October 8, 2021) 3 SAEs (infection of the knee, foreign body ingestion of a penny, epiphyseal fracture) were reported in 3 children (1 each) in the vaccine group. The pooled relative risks for the initial enrollment group and safety expansion group was 1.98 (95% CI: 0.22─17.70). All SAEs were assessed by the investigator as not related to the study intervention.

h. Very serious concern for imprecision was noted based on the 95% confidence interval crossing the line of no effect (1). 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.

i. 1 SAE (limb fracture) was reported in a participant in the BNT162b2 group, which was determined by the investigator to be unrelated to the study intervention.

j. 2 SAEs (pancreatitis and abdominal pain) occurred in 1 placebo recipient.

k. Serious concern for imprecision given the wide 95% confidence interval, which cannot exclude the possibility of no difference between BNT162b2 and placebo.

Appendix 1. Studies Included in the Review of Evidence

References in this table: 2

Appendix 2. Databases and strategies used for systematic review

Articles were eligible for inclusion if published or available on a pre-print server before 10/21/2021.

^*Criteria included in the ongoing systematic review conducted by the International Vaccine Access Center (IVAC) 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.