This observational, retrospective cohort study was based on data obtained from the electronic medical records of Clalit Health Services (CHS), a large healthcare organization covering approximately 52% of the entire Israeli population and almost two-thirds of the country's older population. The study included all CHS members aged 60 years to 100 who were entitled to receive a second-booster vaccine at the study start date.
The exclusion criteria included participants with a documented previous SARS-CoV-2 infection, participants who received a first-booster dose less than four months before, or a 4th Covid-19 vaccine dose before the study start date. To minimize calendar time bias, participants who became entitled to the second-booster during the study follow-up period were also excluded from the study as well. Since CHS started administering the mRNA-1273 (ModernaTX) vaccine in August 2021, primarily to patients who already had recovered from Covid-19, mRNA-1273 recipients were also excluded. Participants who received an oral anti-Covid-19 therapy (nirmatrelvir-ritonavir or molnupiravir) during the study period were also excluded.
The study period started on January 10, 2022, 7 days after the initiation of Israel's second booster vaccination campaign for the population aged 60 and above. The study period ended on February 20, 2022, the last date with confirmed Covid-19 mortality at the data extraction date (February 27, 2022). During the study period, the dominant SARS-CoV-2 variant in Israel was the B.1.1.529 (omicron) (Figure S2).
The study population was divided into two groups, those who had received a second-booster dose ('second-booster' group) and those who had not ('first-booster' group). Participants were included in the 'second-booster' group seven days after receiving their second-booster vaccine dose (effective date) to allow time for antibodies to build effectively (5,6). To that date, participants were evaluated as part of the 'first-booster' group. Participants infected with SARS-CoV-2 during the seven-day period after receiving the second-booster dose were excluded from the analysis. A description of participants' transition from the 'first-booster' to the 'second-booster' status is presented in Figure S2.
The study was approved by the CHS Community Helsinki Committee and the CHS Data Utilization Committee. The study was exempt from the requirement for informed consent from the patients, owing to the retrospective design. No financial or in-kind support was provided for the conduct of the study.
The study's primary outcome was death due to Covid-19. A subgroup analysis was performed according to three age groups: 60 to 69, 70 to 79, and 80 to 100.
Data sources and organization
We evaluated integrated patient-level data maintained by CHS from two primary sources: the primary-care operational and Covid-19 databases. The operational database includes sociodemographic data and comprehensive clinical information, such as coexisting chronic illnesses, history of community care visits, medications, and results of laboratory tests. The Covid-19 database includes PCR and state-regulated rapid antigen tests, vaccinations, and Covid-19-related hospitalizations and mortality and is updated daily from the central Covid-19 repository of the Israeli Ministry of Health. These same databases were used in the primary studies that evaluated the effectiveness of the BNT162b2 vaccine in real-world settings (6,7). A description of the data repositories used in this study is provided in the Supplementary Appendix.
For each participant in the study, the following sociodemographic data were extracted: age, sex, demographic group (general Jewish population, ultra-Orthodox Jewish population, or Arab population), the score for socioeconomic status (ranging from 1 [lowest] to 10 [highest], as described in the Supplement).
The following Clinical data were extracted: Covid-19 vaccination dates and vaccine type, PCR and state-regulated rapid antigen test dates and results, and death due to Covid-19. Data regarding the following clinical risk factors for severe Covid-19 in the general population (6) were also collected: diabetes mellitus, chronic obstructive pulmonary disease, asthma, chronic kidney failure, lung cancer, hypertension, ischemic heart disease, chronic heart failure, obesity, and a history of stroke, transient ischemic attack and smoking. The utilization of the two oral anti-Covid-19 medications approved in Israel since January 2022 for high-risk populations, molnupiravir, and nirmatrelvir/ritonavir, was also extracted.
Descriptive statistics were used to characterize the study participants. Kaplan-Meier analysis with log-rank testing was performed for univariate analysis. Since the independent variable (second booster) varied over time, univariate and multivariate survival analyses were performed with time-dependent covariates according to the study design. Participants were censored in cases of death from any cause or at the end of follow-up. Participants were censored from the first-booster group seven days after receiving a second-booster vaccine as per the study design. We used a multivariate Cox proportional-hazards regression model to estimate the association of all covariates and second-booster vaccination uptake.
The association of second-booster and mortality was estimated using a multivariate Cox proportional-hazards regression model with time-dependent covariates, adjusted for sociodemographic factors and coexisting illnesses. All covariates were tested for interactions with the variable of interest (second-booster vaccination). The proportional-hazards assumption was tested for each variable by comparing survival curves and by performing Schoenfeld's global test. Variables that met the testing criteria and were significantly associated with the outcome served as the inputs for multivariate regression analysis.
R statistical software version 3.5.0 (R Foundation) was used for the univariate and multivariate survival analysis with time-dependent covariates. SPSS software, version 26 (IBM), was utilized for all other statistical analyses. A two-sided P value of less than 0.05 was considered to indicate statistical significance in all analyses.
Due to the Clalit Health Services data privacy regulations, and per the institutional Helsinki and data utilization committee approvals for the study, the patient-level data used for this study cannot be shared.
R statistical software version 3.5.0 (R Foundation) was used for the univariate and multivariate survival analysis with time-dependent covariates. The following R packages were used: survival, foreign, ggplot2, ggfortify, ggpubr, survminer, gmodels, and g summary. All R packages are freely available. SPSS software, version 26 (IBM), was utilized for all other statistical analyses.