The efficacy of BNT162b2 vaccine against critical Covid-19 in adolescents
The efficacy of BNT162b2 vaccine against critical Covid-19 in adolescents

The efficacy of BNT162b2 vaccine against critical Covid-19 in adolescents

Study design

We used a case-control, test-negative design to assess the effectiveness of vaccination against Covid-19, resulting in hospitalization, intensive care unit, or life-support interventions by comparing the odds of prior vaccination among laboratory-confirmed case patients and hospitalized controls without Covid19.2,6,7 Vaccine efficacy evaluations have commonly used test-negative controls to reduce skewness of health-seeking behaviors and to improve logistics.8-11 Vaccine efficacy estimates generated by case-control or test-negative designs are expressed as percentages and can be interpreted as the portion of the specified outcome that is prevented during vaccination.7,8,12 The monitoring protocol and the statistical analysis plan (i Supplementary appendices, both available in full text of this article on NEJM.org) were reviewed by the Centers for Disease Control and Prevention (CDC) and by the other participating institutions as public health monitoring; this review was conducted in accordance with applicable federal laws and CDC policies.13 CDC’s technical staff served as co-researchers and were involved in the study design, participated in the data collection and analysis and in the preparation of the manuscript, and were involved in the decision to submit the manuscript for publication.

Enrollment of case patients and controls

To identify case patients and controls, we conducted active monitoring of adolescents between the ages of 12 and 18 who had been admitted to 31 hospitals in 23 states in the CDC-funded Overcoming Covid-19 Network.14.15 The network was funded to evaluate the efficacy of the vaccine against severe Covid-19 and multisystem inflammatory syndrome in children (MIS-C) in vaccine-qualified participants. Following the award of the CDC contract, 39 pediatric outpatient referral health centers were contacted based on their previous experience in enrolling patients with Covid-19 or in conducting vaccine efficacy evaluations against influenza.15.16 Representatives from 31 centers agreed to participate during this period.

During the monitoring period at each study site, investigators attempted to capture all cases that met the inclusion criteria. All case patients and controls were enrolled regardless of the availability of information on their vaccination status. In the period from May 30 to October 25, 2021, investigators began screening for potentially qualified patients through a review of hospitalization logs and electronic medical records. For this report, the date of admission for the first enrolled patient was July 1, when the percentage of fully vaccinated adolescents exceeded 20% in the United States and was thus sufficient for an evaluation of the vaccine’s effectiveness.10.17 The start of registration varied depending on local occurrence and ethical approval on site.

Case patients were selected from adolescents who were hospitalized with Covid-19 as the primary cause of hospitalization or who had a clinical syndrome consistent with acute Covid-19 (one or more symptoms of fever, cough, shortness of breath, loss of taste, loss of odor , gastrointestinal symptoms, respiratory support or new lung findings on breast imaging). All case patients had positive results for SARS-CoV-2 on reverse transcriptase polymerase chain reaction (RT-PCR) assay or on antigen test within 10 days after symptom onset or within 72 hours after hospitalization. Results of documented positive tests before admission were accepted in 28 case patients. We excluded 23 adolescents who had been diagnosed with MIS-C during their current hospitalization (Table S1 in Supplementary appendices).

Due to potential inequalities related to the selection of controls,18-20 we included two groups of inpatients as controls: those who had negative results for SARS-CoV-2 on RT-PCR assay or antigen test (test-negative), but who had Covid-19-like symptoms; and those without Covid-19-like symptoms who may or may not have undergone SARS-CoV-2 testing (syndrome negative). At each location, investigators targeted a case-to-control ratio of approx. 1: 1 for each of the two control groups. Eligible controls were selected from patients closest to the ward where the case patients were admitted within 3 weeks of the case patient’s admission date.

Data collection

The parent or guardian of each participant was contacted by trained investigators or electronic medical records of all case patients, and controls were reviewed to collect data on demographic characteristics, clinical information on current disease, and SARS-CoV-2 test history. Parents or guardians were asked about the patient’s Covid-19 vaccination history, including the number of doses and whether the most recent administration had taken place during the previous 14 days, the place where the vaccination had taken place, the vaccine manufacturer and the availability of a Covid -19 vaccination card. Investigators searched sources, including state vaccination records, electronic medical records, or other sources (including pediatrician documentation), to verify reported or unknown vaccination status.

Vaccination status

Patients were considered to have received Covid-19 vaccination based on source documentation or by plausible self-report if vaccination dates and place were provided by a parent or guardian at the time of the interview. As the mRNA-1273 vaccine (Moderna) and the Ad26.COV2.S vaccine (Johnson & Johnson-Janssen) had not been approved for use in adolescents at the time of initiation, patients receiving these vaccines were excluded. Patients were categorized as being unvaccinated (no reception of the BNT162b2 vaccine before disease onset) or vaccinated if the most recent dose (first or second dose of the BNT162b2 vaccine) had been administered at least 14 days before disease onset. Adolescents who had received only one dose of vaccine, or who had received another dose less than 14 days before disease onset, were considered partially vaccinated; those who had received two doses at least 14 days before disease onset were considered fully vaccinated. Patients who had received only one dose less than 14 days before disease onset were excluded from the analysis.2

Results

The pre-specified primary outcomes were Covid-19, which resulted in hospitalization, intensive care unit, receipt of life-support interventions, or death. Life support was defined as the receipt of non-invasive or invasive mechanical ventilation, vasoactive infusions, or extracorporeal membrane oxygenation.

Statistical analysis

We first performed bivariate analyzes to assess for differences between groups in characteristics based on case status (case patients vs. controls) and vaccination status (fully vaccinated vs. unvaccinated). We then constructed logistic-regression models for the pre-specified primary outcomes to calculate odds ratios for prior vaccination (fully or partially vaccinated vs. unvaccinated) in patients compared to controls, with associated 95% confidence intervals. A priori, we adjusted models for the U.S. Census Region, calendar date of admission, age, gender, and race or ethnic group.6.10 To assess cluster formation by hospital, we also included the hospital as a random effect in mixed-effects regression models, an analysis that did not change the results significantly. Using a change-in-estimation approach, we assessed other potential confusing factors (the presence of underlying health conditions, specific underlying conditions, and the score on the Social Vulnerability Index) that were not included in the final models because these factors did not change the odds ratio. for vaccination by more than 5%.6.21

We calculated vaccine efficacy relative to the primary outcomes by comparing the odds of full vaccination against Covid-19 among case patients and controls using the equation of vaccine efficacy (1-adjusted odds ratio) × 100, as determined from logistic regression models. We used Firth logistic regression (a punishable probability-based method) for models with fewer than five vaccinated patients.22 Pre-planned subgroup analyzes included efficacy against Covid-19 hospitalization by age group (12 to 15 years vs. 16 to 18 years) and protection of partial vaccination with the BNT162b2 vaccine against Covid-19 hospitalization. We calculated the efficiency separately with each control group and together with the two control groups combined. The width of the confidence intervals has not been adjusted for multiplicity, so the intervals should not be used to derive vaccine efficacy for the subgroup analyzes. All statistical analyzes were performed using SAS software, version 9.4 (SAS Institute).

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