Protection of Israeli Omicrons with a fourth dose of BNT162b2

Survey population

This analysis included those who were 60 years of age or older on January 1, 2022 and who received three doses of BNT162b2 at least 4 months before the end of the study period (March 2). The following people were excluded from the analysis. Those who died before the start of the study period (January 10). People for whom information about age and gender was not available. Those who had been confirmed to have SARS-CoV-2 infection prior to the start of the study and were determined using either the polymerase chain reaction (PCR) assay or a state-regulated rapid antigen test. Those who received a third dose prior to approval of all seniors (ie, prior to July 30, 2021). The entire survey period (January 10th to March 2nd; considered to be abroad from 10 days before the trip to 10 days after returning to Israel). And those who received vaccines of types other than BNT162b2.

For those who met the selection criteria, on March 4, 2022, SARS-CoV-2 infection (confirmed by either state-regulated rapid antigen testing or PCR) and severe Covid-19 (National Health Study). Definition of place² Resting respiratory rate> 30 breaths / min for 14 days after infection confirmation, oxygen saturation during ambient air breathing <94%, or ratio of arterial oxygen partial pressure to inspired oxygen concentration <300). During the study, infections were predominantly dominated by Omicron mutants.³ Also, such as vaccination (date and brand of 1st, 2nd, 3rd, 4th dose) and age, gender, demographic group (general Jewish, Arab, or ultra-Orthodox Jewish). We have extracted data on demographic variables. People’s statistical residence area (similar to the census block)^Four).

Research design

The study period began on January 10, 2022, ended March 2, 2022 due to confirmed infection, and ended February 18, 2022 due to a serious illness.The start date is set 7 days after the start of the vaccination campaign (January 3, 2022) so that at least the first 4-dose group (8-14 days after vaccination) is represented throughout the study period. (In Figure S1 Supplementary appendix, Available at NEJM.org with the full text of this article). The end date was chosen to minimize the effects of missing result data due to delays in reporting PCR or antigen test results and to allow time for the onset of serious illness.

The design of the study was similar to the design of the previous study that evaluated the protection provided by the third vaccination compared to the second vaccination.^Five We calculated the total number of days at risk, the incidence of confirmed infections, and the incidence of severe Covid-19 during the study period defined for each outcome. For those who received the fourth dose, treatment groups were defined according to the number of weeks elapsed since the second dose (8-14 days after vaccination). These 4-dose groups were compared with 2 controls. The first control group included those who were eligible for a fourth dose but had not yet received it (three doses). The second control group was the person who received the fourth dose 3-7 days ago (internal control) because the person who received the fourth dose may differ from those who did not follow the unmeasured confounding variables. It was defined as a group). This control group included the same individuals as the 4-dose group, but during a period when the 4th dose was not expected to affect the confirmed rate of confirmed infection or serious illness. .. Membership in these groups was dynamic, and participants provided risk days to different study groups on different calendar days, depending on vaccination status.

Surveillance

This study was approved by the Organizational Review Board of the Sheva Medical Center. All authors contributed to the conceptualization of the study, critically reviewed the results, approved the final version of the manuscript, and decided to submit the manuscript for publication. The author guarantees the accuracy and completeness of the data in this report. The Israeli Ministry of Health and Pfizer have a data sharing agreement, but only the final results of this study were shared.

Statistical analysis

Using quasi-Poisson regression, we adjusted the following demographic variables to estimate the percentage of confirmed infections and severe Covid-19 per 100,000 person-day for each study group (included as a factor in the model): Did: age group (60-69 years, 70-79 years, or ≥80 years), gender, and demographic group (general Jews, Arabs, or ultra-Orthodox Jews). The risk of exposure at the beginning of the study period was lower than at the end of the study period, as the incidence of both confirmed infections and serious illnesses increased rapidly in January 2022. In addition, the proportion of the population in each study group changed throughout the study period (Fig. S1). Therefore, we included calendar days as an additional covariate to account for changes in exposure risk.⁶ The end of the study period for Severe Covid-19 was set 14 days prior to the data retrieval date (March 4) and was given a follow-up period of at least 14 days for the onset of severe illness. To ensure the same follow-up period for severe Covid-19 in all individuals, only severe cases that developed within 14 days of confirmation of infection were considered. The date used to count the severe Covid-19 events was defined as the date of the test that subsequently confirmed the infection that led to the severe illness.

Those who received the 4th dose were assigned to groups according to the number of weeks that had passed since the 4th dose. For each result, we estimated the incidence of each of these four dose groups and the two controls. Two ratios were calculated for each treatment group and each outcome. First, the ratio of the 3-dose group and the ratio of each 4-dose group. Second, the ratio of the ratio of the internal control group to the ratio of each 4-dose group. Keep in mind that the higher this ratio, the greater the protection provided by the fourth dose of the vaccine. In addition, the adjusted rate difference per 100,000 man-days during the study period was estimated in a manner similar to the method used in the previous analysis.⁷ The confidence interval was calculated by raising the 95% confidence interval of the regression coefficient to a power without adjusting the multiplicity. Therefore, confidence intervals should not be used to infer differences between study groups.

Several sensitivity analyzes were performed to check for possible bias. First, an alternative statistical method that relied on matching was used to estimate the rate of confirmed infections (similar to that used by Dagan et al.).⁸), As explained in detail Supplementary appendixThis approach was not applicable to the analysis of severe Covid-19 due to the small number of cases. Next, we examined the results of using data on infectious diseases confirmed only by PCR tests and excluding data on infectious diseases confirmed by antigen tests under national regulations. Third, we repeated the analysis using data from only the general Jewish population. Fourth, we analyzed the data taking into account the risk of exposure over time in each individual’s area of ​​residence. Fifth, we analyzed the data considering the vaccination time after the third vaccination. For details on sensitivity analysis, see Supplementary appendix..