For this analysis, we included subjects who, on 1 January 2022, were 60 years of age or older and had received three doses of BNT162b2 at least 4 months before the end of the study period (March 2). We excluded the following people from the analysis: those who died before the start of the study period (January 10); those for whom no information regarding their age or gender was available; Those who had confirmed SARS-CoV-2 infection before the start of the study, which was identified using a polymerase chain reaction (PCR) assay or a rapid state-regulated antigen test; Those who received a third dose before it was approved in all older populations (ie before July 30, 2021); Those who were abroad for the entire period of study (10 January – 2 March; persons considered abroad 10 days prior to travel up to 10 days after their return to Israel); and those who received a vaccine dose of a type other than BNT162b2.
For subjects who met the inclusion criteria, we extracted information on March 4, 2022, regarding SARS-CoV-2 infection (confirmed either by state-regulated rapid antigen testing or by PCR) and severe Covid-19 (defined using the National Institutes definition for health2 As a resting respiration rate of more than 30 breaths per minute, or an oxygen saturation of less than 94% during breathing in ambient air, or a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen of less than 300) within 14 days after confirmation of infection. During the study period, the omicron variable controlled infection.3 We also extracted data regarding vaccination (dates and brands of first, second, third, and fourth doses), demographic variables such as age, gender, and demographic group (general Jewish, Arab, or ultra-Orthodox), as determined by the population-based statistical area (similar to census block).4).
The study period began on January 10, 2022, and ended on March 2, 2022, for confirmation of infection and ended on February 18, 2022, due to severe illness. The start date is set at 7 days after the start of the vaccination campaign (January 3, 2022) so that at least the first four dose group (days 8-14 after vaccination) is represented throughout the study period (Figure S1) in the Supplementary Appendix, available with the full text of these Article at NEJM.org). Completion dates were chosen to minimize the effects of missing outcome data due to delays in reporting PCR or antigen test results and to allow time for severe disease progression.
The study design was similar to that of a previous study in which we evaluated protection conferred with the third vaccine dose compared with the second dose.5 We calculated the total number of days of people at risk and the incidence of confirmed infection and severe Covid-19 during the given study period for each outcome. For people who received the fourth dose, treatment groups were determined according to the number of weeks that had passed since receiving that dose, starting in the second week (8 to 14 days after vaccination). These four-dose groups were compared with two control groups. The first control group included people who were eligible for a fourth dose but had not yet received it (a group of three doses). Because subjects who received the fourth dose may have differed from those who were not measured according to unmeasured confounding variables, the second control group was defined as subjects who received a fourth dose 3 to 7 days earlier (internal control group). This control group included the same people as the four dose groups, but during a period when the fourth dose was not expected to affect the rate of confirmed infection or severe disease. Membership in these groups was dynamic, and participants contributed risk days to the different study groups on different calendar days, depending on their vaccination status.
The study was approved by the Sheba Medical Center Institutional Review Board. All authors contributed to the conceptualization of the study, critically reviewed the results, approved the final version of the manuscript, and made the decision to submit the manuscript for publication. The authors certify the accuracy and completeness of the data provided in this report. The Israeli Ministry of Health and Pfizer have a data-sharing agreement, but only the final results of this study have been shared.
Using quasi-Poisson regression, we estimated rates of confirmed and severe COVID-19 virus infection per 100,000 person-days for each study group (included as factors in the model), adjusting for the following demographic variables: age group (60 to 69) years, 70 to 79 years, or 80 years old), gender, and demographics (generally Jewish, Arab, or ultra-Orthodox). Due to the rapid increase in the incidence of confirmed infections and acute illness during January 2022, the exposure risk at the beginning of the study period was lower than at the end of the study period. Furthermore, the proportion of the population in each study group changed throughout the study period (Fig. S1). Therefore, we included the calendar date as an additional variable to calculate the variable exposure risk.6 The end of the study period for severe Covid-19 was set 14 days prior to the data retrieval date (4 March), allowing at least 14 days of follow-up time for severe disease progression. To ensure the same follow-up time for severe Covid-19 in all people, we only considered cases of severe illness that developed within 14 days after confirmation of infection. The date used to calculate severe Covid-19 events was defined as the date of testing confirming infection that subsequently led to severe illness.
Subjects who received four doses were divided into groups according to the number of weeks that had passed since receiving the fourth dose; For each outcome, we estimated the incidence in each of these four dose groups and in the two control groups. We calculated an average rate for each treatment group and for each outcome: first, the ratio of the rate in the three-dose group to the ratio in each four-dose group; and second, the ratio of the rate in the internal control group to that in each four dose group. Note that the higher this rate, the more protection the fourth dose of the vaccine confers. In addition, adjusted average differences per 100,000 person-days over the study period were estimated in a manner similar to that used in our previous analysis.7 Confidence intervals were calculated by subtracting the 95% confidence intervals of the regression coefficients, without adjustment for multiplicity. Thus, confidence intervals should not be used to infer differences between study groups.
To check for potential biases, we performed several sensitivity analyses. First, we estimated confirmed incidence rate ratios using an alternative matching-based statistical method (similar to that used by Dagan et al.8), as detailed in the Supplementary Appendix; This approach cannot be applied to severe Covid-19 analysis due to the small case numbers. Second, we examined results using data for infections confirmed only by PCR testing and excluding data for those confirmed by state-regulated antigen testing. Third, we repeated the analyzes with data from the general Jewish population only. Fourth, we analyzed the data while calculating exposure risk over time in each person’s area of residence. Fifth, we analyzed the data taking into account the time of vaccination since the third dose. More details on sensitivity analyzes are provided in the Supplementary Appendix.