Health

BNT162b2 Vaccine Booster and Mortality Due to Covid-19

study design

The study period began on August 6, 2021, 7 days after the booster was approved for use in people aged 60 or over in Israel. The study period ended on September 29, 2021, the last date for which data on confirmed deaths due to Covid-19 were available on the day the data was extracted (October 3, 2021). The study schedule is illustrated in Figure S1 in the Supplementary Appendix, which is available with the full text of this article at NEJM.org.

The Helsinki Community Health Services (CHS) Committee and the Basic Human Standard Data Use Committee approved the study. The study was excluded from the requirement to obtain informed consent.

Population Study

The study included all BHS members who were 50 years of age or older at the start date of the study and who had received two doses of BNT162b2 at least 5 months prior. CHS covers about 52% of the population of Israel and is the largest of the four healthcare institutions in Israel that provide compulsory healthcare. Participants with missing data regarding date of birth or gender were excluded from the study. In addition, participants were excluded if they had been infected with SARS-CoV-2 or had received a booster dose prior to August 6, 2021; Early administration of the booster has been indicated in immunocompromised subjects. Finally, participants who received the booster and had a confirmed case of Covid-19 within 3 days prior to the effective booster date (defined as 7 days after the booster was given) were excluded.

The study population was divided into two groups: those who received a booster dose during the study period (booster group) and those who did not receive a booster dose (non-booster group). Participants in the booster group were included on the effective booster date to allow time for the antibody to be actively built up.4,8 Up to 7 days after receiving the booster, participants were still included in the nonbooster group. The transition of participants from the non-supporting group to the reinforcer group is described in Figure S2.

Data sources and organization

We analyzed patient-level data extracted from electronic medical records for the Human Core Standard. A database specific for this study was created which combined patient-level data from two main sources: the CHS Operational Database and the CHS Covid-19 Database. The Humanitarian Core Standard operational database includes comprehensive sociodemographic data and clinical information, such as coexistence of chronic conditions, community care visits, hospitalizations, medication, laboratory test results and imaging studies. The CHS Covid-19 database includes information collected centrally by the Israeli Ministry of Health and converted daily into the Humanitarian Core, such as vaccination dates, quantitative reverse transcription-polymerase chain reaction (RT-qPCR) dates and results, hospitalizations and deaths related to Covid-19. 19.

Basic Human Standard databases were used in the primary studies that evaluated efficacy1 and safety9 BNT162b2 vaccine in a realistic environment. In addition, the Israeli Ministry of Health’s Covid-19 database was used as the basis for the initial study that evaluated the efficacy of the BNT162b2 booster among people aged 60 years or older.10 The Basic Human Standard data repositories that were used in this study are described in the Supplementary Appendix.

For each study participant, the following sociodemographic data were extracted: age, gender, population sector (general Jewish population, Arab population, or ultra-Orthodox Jewish population), and socioeconomic status scores (scores range from 1 [lowest] up to 10 [highest]; Details are provided in the Supplementary Appendix). The following clinical data were extracted: dates of vaccination (first, second and booster doses), dates and results of RT-qPCR test, death due to Covid-19 and any clinical risk factors for death due to Covid-19 identified in the general population,11 Such as diabetes mellitus, COPD, asthma, chronic renal failure, hypertension, ischemic heart disease, chronic heart failure, obesity, lung cancer, a history of cerebrovascular accident, transient ischemic attack, or smoking.

Results

The primary outcome was death from Covid-19. In the preliminary analysis of booster efficacy with respect to this outcome, we compared the mortality rate due to Covid-19 in the booster group with the mortality rate in the nonbooster group.

Because the initial approval of the enhanced drug by the Food and Drug Administration was for use in subjects 65 years of age or older, we performed a subgroup analysis according to age group. We performed an additional analysis of the subgroup according to gender.

In a secondary analysis of the efficacy of the booster in preventing SARS-CoV-2 infection, we compared the frequency of positive RT-qPCR tests in the booster group with that in the non-booster group.

statistical analysis

The chi-square test was used to compare categorical variables according to the study group. Given that the independent variable (reinforcement condition) changed over time, univariate and multivariate survival analyzes were performed using time-dependent covariates, in accordance with the study design.12 Kaplan-Meier analysis with log-rank test was used for univariate analysis. Comparison of survival curves and the global Schoenfeld test were used to test the assumption of relative hazards for each dependent variable. Variables meeting the test criteria were inputs to the multivariate regression analysis.

A Cox proportional hazards regression model with time-dependent covariates was used to estimate the association of reinforcement status with death due to Covid-19. A regression model was used to estimate the hazard ratio of death due to Covid-19 in the booster group, compared to the non-booster group, with baseline sociodemographic and clinical characteristics used as independent variables.

The assumption that there was a 7-day delay between the administration of the reinforcer and the date of the effective reinforcement, during which participants were included in the non-reinforcer group, was tested to verify that this group did not create any bias. Validation of the delay time used to ensure the efficacy of the booster was performed by estimating the risk of death due to Covid-19 in participants up to 7 days after the administration of the booster, compared to the non-booster group. The use of an alternative 14-day lag period was also tested in the same way.

The R statistical software, version 3.5.0 (R Foundation for Statistical Computing), was used for univariate and multivariate survival analyzes with time-dependent covariates. SPSS software, version 26 (IBM), was used for all other statistical analyses. An AP value less than 0.05 was considered to indicate significance in all analyses.

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