We used a case-control, test-negative design to assess the effectiveness of vaccination against COVID-19 resulting from hospitalization, ICU admission, or life-supporting interventions compared to laboratory-confirmed cases. Comparison of the odds of prior vaccination between patients and hospitalized controls. COVID-19.2,6,7 Test-negative controls are commonly used in the evaluation of vaccine effectiveness to reduce bias from health care-seeking behavior and to improve logistics.8-11 Estimates of vaccine effectiveness that are generated by case–control or test–negative design are expressed as a percentage and can be interpreted as the fraction of a specified outcome withheld in association with vaccination.7,8,12 The surveillance protocol and statistical analysis plan (in Supplementary Appendix, both available with the full text of this article at NEJM.org) were reviewed by the Centers for Disease Control and Prevention (CDC) and other participating institutions of public health Was. Supervision; This review was conducted in accordance with applicable federal laws 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.
Case enrollment of patients and controls
To identify case patients and controls, we conducted active surveillance of adolescents aged 12 to 18 years who were admitted to 31 hospitals in 23 states on the CDC-funded COVID-19 network.14,15 The network was funded to evaluate vaccine effectiveness against severe COVID-19 in vaccine-eligible participants and multisystem inflammatory syndrome (MIS-C) in children. After the CDC contract was awarded, 39 referral health centers for pediatric patients were contacted based on their previous experience in enrolling patients with COVID-19 or to evaluate the effectiveness of the vaccine against influenza.15,16 During this, representatives of 31 centers agreed to participate.
During the monitoring period at each study site, investigators attempted to capture all cases meeting the inclusion criteria. All case patients and controls were enrolled regardless of the availability of information about their vaccination status. During the period May 30 to October 25, 2021, investigators began screening potentially eligible patients through review of hospital admission logs and electronic medical records. For this report, the date of hospitalization of the first enrolled case patient was July 1, when the percentage of fully vaccinated adolescents in the United States was greater than 20% and thus sufficient for evaluation of vaccine effectiveness. .10,17 The start of enrollment varies depending on local events and approval of on-site ethics.
Case patients were selected from adolescents who were hospitalized with COVID-19 as the primary reason for admission or who had acute COVID-19 (fever, cough, shortness of breath, loss of taste). , one or more signs of impairment) had a corresponding clinical syndrome. new pulmonary findings on odor, gastrointestinal symptoms, respiratory support, or chest imaging). In all cases, patients had positive results on reverse transcriptase-polymerase-chain-reaction (RT-PCR) assay or antigen test within 10 days of symptom onset or within 72 hours of hospitalization. Results of documented positive tests were accepted before admission in 28 cases of patients. We excluded 23 adolescents who had received a diagnosis of MIS-C during their current hospitalization (Table S1 in Supplementary Appendix).
Because of 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 assay or antigen test (test-negative) but who had COVID-19-like symptoms ; And those who do not have symptoms like Kovid-19, whether they have passed the SARS-CoV-2 test (syndrome-negative). At each site, the investigators targeted a case-to-control ratio of approximately 1:1 for each of the two control groups. Eligible controls were selected from patients closest to the ward where the case patients were hospitalized within 3 weeks after the patient’s hospitalization date.
Each participant’s parent or guardian was contacted by trained study personnel or electronic medical records on the patients of all cases and assessed for demographic characteristics, clinical information about current disease, and SARS-CoV-2 testing history. Controls were reviewed to collect data about The parent or guardian was asked about the patient’s COVID-19 vaccination history, including the number of doses and whether the most recent administration took place during the last 14 days, the location where the vaccination took place, the vaccine manufacturer and the availability of a COVID-19 vaccine. -19 vaccination card. Study personnel searched sources including state vaccination registries, electronic medical records, or other sources (including pediatrician’s documentation) to verify reported or unknown vaccination status.
Patients were considered to have received COVID-19 vaccination based on source documentation or plausible self-report if the date and place of vaccination was provided by the parent or guardian at the time of interview. Since the mRNA-1273 vaccine (Moderna) and the Ad26.COV2.S vaccine (Johnson & Johnson-Johnson) were not authorized for use in adolescents at the start of the study, patients who received those vaccines were excluded. Was placed. Patients were classified as unvaccinated (no receipt of BNT162b2 vaccine prior to disease onset) or vaccinated if the most recent dose (the first or second dose of BNT162b2 vaccine) was administered at least two weeks before disease onset. was administered at least 14 days ago. Adolescents who received only one dose of vaccine or who received a second dose less than 14 days before disease onset were considered partially vaccinated; Those who received two doses at least 14 days before the onset of illness were considered fully vaccinated. Patients who had received only one dose 14 days before disease onset were excluded from the analysis.2
The primary outcome determined was COVID-19 resulting in hospitalization, ICU admission, receipt of life-supporting intervention, or death. Life support was defined as the attainment of non-invasive or invasive mechanical ventilation, vasoactive infusion, or extracorporeal membrane oxygenation.
We first performed bivariate analysis to assess differences between groups in characteristics based on case status (case patient versus control) and vaccination status (fully vaccinated versus non-vaccinated). We then constructed logistic-regression models for the predefined primary outcomes, so that patients with prior immunization (fully or partially vaccinated versus non-vaccinated) compared with controls, with corresponding 95% confidence intervals. The odds ratio can be calculated. A priori, we adjusted models for US census area, calendar date of entry, age, sex, and race or ethnic group.6,10 To evaluate clustering according to hospital, we also included hospital as a random effect in the mixed-effects regression model, an analysis that did not significantly change the results. Using a change-in-estimate approach, we assessed other potential confounding factors (presence of underlying health conditions, specific underlying conditions and scores on the social vulnerability index), which were not included in the final model because these factors were not were changed. The odds ratio for vaccination is greater than 5%.6,21
We calculated vaccine effectiveness against primary outcomes by comparing the odds of complete vaccination against COVID-19 between patients and controls using the equation of vaccine effectiveness of (1-adjusted odds ratio) × 100 determined from a logistic-regression model . We used Forth logistic regression (a penalized probability-based method) for models with fewer than five vaccinated patients.22 Pre-planned subgroup analysis included the effectiveness against covid-19 hospitalization by age group (12 to 15 years vs 16 to 18 years) and the safety of partial immunization with BNT162B2 vaccine against covid-19 hospitalization Was. We calculated the effectiveness with each control group separately and combined with the two control groups in total. The width of the confidence interval has not been adjusted for multiplicity, so the interval should not be used to estimate vaccine effectiveness for subgroup analyses. All statistical analyzes were performed using SAS software version 9.4 (SAS Institute).