BNT162b2 vaccine booster and Covid-19 mortality

Study design

The study period began on August 6, 2021, 7 days after the recall was approved for use in people 60 years of age or older in Israel. The study period ended on September 29, 2021, which was the last date for which data regarding confirmed deaths from Covid-19 was available on the day the data was extracted (October 3, 2021). The study timeline is illustrated in Figure S1 of the Supplementary Annex, available with the full text of this article on NEJM.org.

The Helsinki Community Health Services Committee Clalit (CHS) and the CHS Data Use Committee approved the study. The study was exempt from the requirement to obtain informed consent.

Study population

The study included all CHS members who were 50 years of age or older at the start of the study and had received two doses of BNT162b2 at least 5 months earlier. The CHS covers around 52% of the Israeli population and is the largest of the four healthcare organizations 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 before August 6, 2021; early booster administration has been indicated in immunocompromised individuals. Finally, participants who received the booster and had a confirmed case of Covid-19 within 3 days before the recall effective date (defined as 7 days after the booster was administered) were excluded.

The study population was divided into two groups: those who received a booster during the study period (booster group) and those who did not receive a booster (non-booster group). Participants were included in the booster group on the effective date of the booster to allow time for the antibodies to form effectively.4.8 Up to 7 days after receiving the booster, participants were still included in the group without a booster. A description of the transition of participants from the non-booster group to the booster group is provided in Figure S2.

Data sources and organization

We analyzed patient-level data extracted from the CHS electronic medical records. A specific database was created for this study which integrated patient-level data from two main sources: the CHS operational database and the CHS Covid-19 database. The CHS operational database includes socio-demographic data and comprehensive clinical information, such as coexisting chronic diseases, community care visits, hospitalizations, medications, and results of laboratory tests and imaging studies. The CHS Covid-19 database includes information collected centrally by the Israeli Ministry of Health and transferred daily to the CHS, such as vaccination dates, dates and results of quantitative polymerase chain reaction tests. (RT-qPCR), and hospitalizations and deaths related to Covid-19.

CHS databases were used in primary studies that assessed the effectiveness1 and security9 BNT162b2 vaccine in a real environment. Additionally, the Israeli Ministry of Health’s Covid-19 database was used as the basis for the initial study that assessed the effectiveness of the BNT162b2 booster in people 60 years of age or older.ten A description of the CHS data repositories that were used in this study is provided in the Supplementary Annex.

For each study participant, the following socio-demographic data were extracted: age, sex, sector of the population (general Jewish population, Arab population, or ultra-Orthodox Jewish population) and score for socio-economic status (scores range from 1 [lowest] to 10 [highest]; details are provided in the additional annex). The following clinical data were extracted: vaccination dates (first, second and booster doses), dates and results of RT-qPCR tests, death due to Covid-19 and possible clinical risk factors for death due to Covid-19 which have been identified in the general population,11 such as diabetes mellitus, chronic obstructive pulmonary disease, asthma, chronic renal failure, hypertension, ischemic heart disease, chronic heart failure, obesity, lung cancer or a history of stroke, transient ischemic attack, or smoking.

Study results

The main outcome was death from Covid-19. In the primary analysis of the effectiveness of the booster against this outcome, we compared the mortality due to Covid-19 in the booster group with that in the non-booster group.

Since the Food and Drug Administration’s initial approval of the recall was for people 65 years of age or older, we performed a subgroup analysis based on age group. We performed additional subgroup analysis by gender.

In a secondary analysis of the effectiveness 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 analyzes

A chi-square test was used to compare categorical variables by study group. Since the independent variable (recall status) varied over time, univariate and multivariate survival analyzes were performed with time-dependent covariates, according to the study design.12 Kaplan-Meier analysis with a log-rank test was used for the univariate analysis. The comparison of survival curves and the global Schoenfeld test were used to test the proportional hazards hypothesis for each dependent variable. Variables that met the test criteria served as inputs for multivariate regression analysis.

A Cox proportional hazards regression model with time-dependent covariates was used to estimate the association between recall status and death from Covid-19. The regression model was used to estimate the risk ratio of death from Covid-19 in the booster group, compared to the group without booster, with the use of baseline socio-demographic and clinical characteristics as independent variables.

The hypothesis of a 7-day delay between the administration of the booster and the effective date of the booster, during which the participants were included in the group without a booster, was further tested to verify that this grouping was not created no bias. The validation of the latency time used to ensure the effectiveness of the booster was carried out by estimating the risk ratio of death due to Covid-19 in participants up to 7 days after administration of the booster, compared to the group without callback. The use of an alternate 14-day delay was also tested with the same method.

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 analyzes. An AP value of less than 0.05 was considered indicative of significance in all analyzes.

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