Protection by a fourth dose of BNT162b2 against Omicron in Israel
For this analysis, we included people who, as of January 1, 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 a confirmed SARS-CoV-2 infection before the start of the study, determined using a polymerase chain reaction (PCR) test or a rapid l-regulated antigen test ‘state ; those who had received a third dose before its approval for all elderly residents (i.e. before July 30, 2021); those who had been abroad for the entire study period (January 10 to March 2; individuals were considered to be abroad 10 days before traveling until 10 days after returning to Israel); and those who had received a dose of vaccine of a type other than BNT162b2.
For individuals who met the inclusion criteria, we extracted information on March 4, 2022 regarding SARS-CoV-2 infection (confirmed either by state-regulated rapid antigen test or PCR) and severe Covid-19 (defined with use of the National Institutes of Health Definition2 such as a resting respiratory rate > 30 breaths per minute, oxygen saturation 3 We also extracted data regarding vaccination (dates and brands of first, second, third, and fourth doses) and demographic variables such as age, gender, and demographic group (generally Jewish, Arab, or ultra-Orthodox Jew) , as determined by the person’s statistical area of residence (similar to a census block4).
The study period began on January 10, 2022 and ended on March 2, 2022 for confirmed infection and ended on February 18, 2022 for severe illness. The start date was set at 7 days after the start of the vaccination campaign (January 3, 2022) so that at least the first group of four doses (days 8 to 14 after vaccination) would be represented throughout the campaign. study period (Fig. S1 in the Supplementary Appendix, available with the full text of this article on NEJM.org). End dates were chosen to minimize the effects of missing data on outcomes due to delays in reporting PCR or antigen test results and to allow time for the development of severe disease.
The study design was similar to that of a previous study in which we assessed the protection conferred by the third dose of vaccine compared to the second dose.5 We calculated the total number of person-days at risk and the incidence of confirmed infections and severe cases of Covid-19 during the defined study period for each outcome. For people who received the fourth dose, the treatment groups were defined according to the number of weeks that had passed since receiving that dose, starting from the second week (8 to 14 days after vaccination). These four-dose groups were compared to two control groups. The first control group included people who were eligible for a fourth dose but had not yet received it (three-dose group). Because people who received the fourth dose might differ from those who did not on unmeasured confounding variables, a second control group was defined as people 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 for a period in which 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 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 guarantee the accuracy and completeness of the data contained 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 infection and severe Covid-19 per 100,000 person-days for each study group (included as factors in the model), with adjustment for demographic variables following: age group (60-69, 70-79, or ≥ 80), gender, and demographic group (generally Jewish, Arab, or ultra-Orthodox Jew). Because the incidence of confirmed infections and serious illness increased rapidly in January 2022, the risk of exposure at the start of the study period was lower than at the end of the study period. Moreover, the fraction of the population in each study group changed throughout the study period (Fig. S1). Therefore, we included calendar date as an additional covariate to account for changes in exposure risk.6 The end of the study period for severe Covid-19 was set at 14 days before the data retrieval date (March 4), allowing at least 14 days of follow-up time for the development of severe disease. 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 of confirmation of infection. The date used to count severe Covid-19 events was defined as the date of the test confirming infection which then led to severe illness.
People who received four doses were divided into groups based on the number of weeks since receiving the fourth dose; for each outcome, we estimated the incidence rate in each of these four dose groups and in the two control groups. We calculated two rate ratios for each treatment group and each outcome: first, the ratio of the rate in the three-dose group to that in each four-dose group; and second, the ratio of the rate in the internal control group to that in each four-dose group. It should be noted that the higher this rate ratio, the greater the protection conferred by the fourth dose of vaccine. Additionally, the adjusted rate differences per 100,000 person-days over the study period were estimated with a method similar to that used in our previous analysis.7 Confidence intervals were calculated by exposing the 95% confidence intervals for the regression coefficients, without adjusting for multiplicity. Thus, confidence intervals should not be used to infer differences between study groups.
To check for possible biases, we performed several sensitivity analyses. First, we estimated the confirmed infection 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 could not be applied to the analysis of severe Covid-19 cases due to the small number of cases. Second, we examined the results of using data on infections confirmed only by PCR testing and excluding data on 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 taking into account the risk of exposure 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. Further details on the sensitivity analyzes are provided in the supplementary appendix.