Effectiveness of the BNT162b2 vaccine against critical Covid-19 in adolescents

study design

We used a test-negative case-control design to assess the effectiveness of vaccination against Covid-19 leading to hospitalization, ICU admission, or life-sustaining interventions by comparing the odds of prior vaccination in patients laboratory-confirmed cases and hospitalized controls without Covid19.2,6,7 Vaccine effectiveness evaluations have commonly used negative controls to reduce biases related to health care-seeking behavior and to improve logistics.8-11 Vaccine efficacy estimates that are generated by the case-control or test-negative design are expressed as percentages and can be interpreted as the fraction of the specified outcome averted in association with vaccination.7,8,12 The surveillance protocol and statistical analysis plan (in the Supplementary Appendix, both available with the full text of this article on NEJM.org) have been 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 law and CDC policy.13 CDC technical staff members served as co-investigators and were involved in study design, participated in data collection and analysis and manuscript preparation, and were involved in the decision to submit the manuscript for publication.

Recruitment of patient and control cases

To identify cases, patients, and controls, we conducted active surveillance of adolescents ages 12 to 18 who had been admitted to 31 hospitals in 23 states of the CDC-funded Overcoming Covid-19 Network.14.15 The network was funded to assess the effectiveness of vaccines against severe Covid-19 and multisystem inflammatory syndrome in children (MIS-C) in vaccine-eligible participants. After the CDC contract was awarded, 39 referral health centers for pediatric patients were approached based on their previous experience recruiting patients with Covid-19 or conducting vaccine efficacy evaluations against influenza.15.16 Representatives from 31 centers agreed to participate during this period.

During the surveillance period at each study site, investigators attempted to capture all cases that met the inclusion criteria. All cases, patients and controls were enrolled regardless of the availability of information regarding their vaccination status. During the period May 30 to October 25, 2021, investigators began screening potentially eligible patients by reviewing hospital admission records and electronic medical records. For this report, the date of hospitalization of the first enrolled case was July 1, when the percentage of fully immunized adolescents exceeded 20% in the United States and was therefore sufficient for an assessment of vaccine effectiveness.10.17 The start of enrollment varied depending on local incidence and site ethics approval.

The case patients were selected among adolescents hospitalized with Covid-19 as the main reason for admission or presenting a clinical syndrome compatible with acute Covid-19 (one or more symptoms of fever, cough, shortness of breath, loss of taste, loss of smell, gastrointestinal symptoms, respiratory support or new lung findings on lung imaging). All cases tested positive for SARS-CoV-2 in the reverse transcriptase-polymerase chain reaction (RT-PCR) test or antigen test within 10 days of symptom onset or within 72 hours following hospitalization. Documented positive test results prior to admission were accepted in 28 patients. We excluded 23 adolescents who had been diagnosed with MIS-C during their current hospitalization (Table S1 in the Supplementary Appendix).

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

Data gathering

Parent or guardian of each participant was approached by trained study staff or electronic medical records of all cases and controls were screened to collect data regarding demographic characteristics, clinical information about current illness and SARS-CoV-2 testing history. Parents or guardians were asked about the patient’s history of vaccination against Covid-19, including number of doses and whether the most recent administration had taken place within the previous 14 days, where the vaccination had taken place. occurred, the vaccine manufacturer and the availability of a Covid -19 vaccination record. Study staff searched sources, including state vaccination registries, electronic medical records, or other sources (including documentation from pediatricians), to verify reported or unknown vaccination status.

Vaccination status

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

Results

The prespecified primary outcomes were Covid-19 resulting in hospitalization, ICU admission, receipt of life-saving interventions, or death. Life support was defined as receiving noninvasive or invasive mechanical ventilation, vasoactive infusions, or extracorporeal membrane oxygenation.

Statistical analyzes

We first performed bivariate analyzes to assess between-group differences in characteristics based on case status (patient cases vs controls) and vaccination status (fully vaccinated vs unvaccinated). We then constructed logistic regression models for prespecified primary outcomes to calculate odds ratios of prior vaccination (fully or partially vaccinated versus unvaccinated) in case patients versus controls, with intervals 95% trust associated. A priori, we adjusted the models for US census region, calendar date of admission, age, sex, and race or ethnicity.6.10 To assess grouping by hospital, we also included hospital as a random effect in the mixed-effects regression models, an analysis that did not significantly change the results. Using a change-of-estimate approach, we assessed other potential confounders (the presence of underlying health conditions, specific underlying conditions, and Social Vulnerability Index score) that n were not included in the final models because these factors did not change. the odds ratio of vaccination over 5%.6.21

We calculated vaccine efficacy against primary outcomes by comparing the odds of full vaccination against Covid-19 in patients and controls using the vaccine efficacy equation of (1 – adjusted odds ratio) × 100, as determined from logistic regression models. We used Firth’s logistic regression (a method based on penalized likelihood) for models with fewer than five vaccinated cases.22 Preplanned subgroup analyzes included efficacy against Covid-19 hospitalization by age group (12–15 years versus 16–18 years) and protection of partial vaccination with BNT162b2 vaccine against hospitalization Covid-19. We calculated efficacy separately with each control group and overall with both control groups combined. The widths of the confidence intervals have not been adjusted for multiplicity, so the intervals should not be used to infer vaccine efficacy for subgroup analyses. All statistical analyzes were performed using SAS software, version 9.4 (SAS Institute).

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