Study the population
Our analysis, which was based on data from the Israeli Ministry of Health’s national database, focused on infections that were confirmed during the study period, from August 1 to August 30. September 2021. During this period, Israel was in the middle of a fourth pandemic wave that was dominated by variant B.1.617.2 (delta) .17 Israel had already conducted a campaign offering two doses of the BNT162b2 vaccine. and had launched a campaign offering the third and fourth booster doses (see Supplementary Methods 1). in the Supplementary Appendix, available with the full text of this article at NEJM.org). In addition, as of March 2021, unvaccinated individuals who had recovered from coronavirus disease 2019 (Covid-19) at least 3 months earlier were eligible to receive a single dose of the BNT162b2 vaccine.
In this study, SARS-CoV-2 reinfection was defined as a positive polymerase chain reaction (PCR) test in a person who had a positive test of a sample obtained at least 90 days before the day of the study.18 The definition. of severe Covid-19 was consistent with that of the National Institutes of Health19, i.e., a resting respiratory rate of more than 30 breaths per minute, an oxygen saturation of less than 94% while the person was breathing ambient air, or a proportion. of partial pressure of arterial oxygen to fraction of inspired oxygen less than 300. The database of the Ministry of Health of Israel includes, for all residents who have received a vaccine against Covid-19, have been tested by Covid-19 or have been previously infected with SARS-CoV-2, basic demographic information such as sex, age, place of residence, and population, as well as complete records of confirmed vaccinations and infections.
Figure 1. Figure 1. Study population.
Eligible people in the study did not have a documented positive polymerase chain reaction assay between July 1 and July 30, 2021, had received a maximum dose of vaccine before recovery or after recovery. 2019 coronavirus disease recovery (Covid-19) and had received no vaccine against Covid-19 other than BNT162b2 before August 1, 2021. Age groups are shown from on January 1, 2021. SARS-CoV-2 denotes severe acute respiratory syndrome coronavirus 2.
Using these data at the individual resident level, we studied confirmed infections among people 16 years of age or older who had tested positive for SARS-CoV-2 infection before July 1, 2021, or who had received at least two dose of BNT162b2 vaccine at least 7 days before the end of the study period. The following individuals were excluded from the analysis: those whose data did not include information on age or sex; those who tested positive for SARS-CoV-2 between July 1 and July 31, 2021; those who had recovered from a PCR-confirmed SARS-CoV-2 infection and then received more than one dose of BNT162b2 vaccine (a small group with limited follow-up data); those who had received more than one dose of BNT162b2 vaccine and then recovered from a PCR-confirmed SARS-CoV-2 infection (a small group); those who had completed the entire period of study abroad; and those who had received a vaccine other than BNT162b2 before August 1, 2021 (Figure 1).
Study design and supervision
The incidences of confirmed infection during the study period were compared between cohorts of people with a history of events conferring immunity (i.e., infection or vaccination). The recovered and unvaccinated cohort included people who had had a confirmed infection 90 or more days before the day of the study. There were two “hybrid” cohorts (i.e., cohorts with participants who had natural immunity and immunization from vaccination); the cohort of a recovered dose consisted of people who had recovered from Covid-19 and then received a single dose of vaccine at least 7 days before the day of the study, and the cohort of a recovered dose included those who had received a single dose. dose of vaccine, followed by a confirmed infection at least 90 days before the study day. The two-dose cohort consisted of people who had not been infected before the start of the study and who had received the second dose of vaccine at least 7 days before the day of the study, and the three-dose cohort was formed by those who had not been infected before the start of the study and who had received the third (booster) dose of the vaccine at least 12 days before the day of the study.
These cohorts were divided into subcohorts according to the time that had elapsed since the last event that conferred immunity. We used 2 months as the basic time interval to define the subcohorts, but we combined 12 to 18 months for the recovered and unvaccinated cohort and omitted the 8 to less than 10 month period for the vaccinated and hybrid cohorts. due to the small number of people in these cohorts.
A person could contribute follow-up days to different subcohorts and could also move from one cohort to another according to the following rules. One person who had recovered from Covid-19 and received a first dose of BNT162b2 vaccine during the study period left the recovered and unvaccinated cohort on the day of vaccination and entered the cohort of ‘a dose recovered 7 days later. A person who had recovered from Covid-19 and had received a first dose of vaccine but then received a second dose during the study period left the cohort of a dose recovered at the time of the second. vaccination. One person in the two-dose cohort who received a third (booster) dose during the study period left the two-dose cohort on the day of the booster dose and entered the three-dose cohort for 12 days. then.20 A person with a positive. test for SARS-CoV-2 infection between May 1 and June 30, 2021 and who also received a single dose of the BNT162b2 vaccine entered the cohort of a recovered dose or the cohort of a recovered dose (depending on whether or not). confirmed infection prior to vaccination) 90 days after positive test. One person who received a vaccine other than BNT162b2 left the study on the day of vaccination.
Studies often compare the rates of infection among recovered or vaccinated individuals with those of unvaccinated individuals who have not been previously infected. However, due to the high vaccination rate in Israel, the latter cohort is small and not representative of the general population. In addition, the database of the Ministry of Health of Israel does not include complete information about these people. Therefore, we did not include unvaccinated and uninfected individuals prior to our analysis.
The study was approved by the institutional review committee of Sheba Medical Center. The Israeli Ministry of Health and Pfizer have a data sharing agreement, but only the final results of this study were shared.
Statistical analysis
To analyze the data, we used methods similar to those used in our previous studies.8,20,21 We assumed that the risk of infection in each cohort would be independent of the length of stay in the previous cohorts (i.e. passed to the cohort). cohort before a confirmed infection), and we focused on the relationship between the proportional risk survival model and the Poisson regression model22 (see section Supplementary methods 2). Specifically, the number of confirmed infections and the number of person-days at risk during the study period were counted for each subhort.
A Poisson regression model was adjusted, with adjustment by age group from January 1, 2021 (16 to 39 years, 40 to 59 years or ≥ 60 years), sex, population sector (general Jew, Arab or ultra-Orthodox Jew). ), calendar week and an exposure risk measure. The latter was calculated for each person on each follow-up day according to the rate of new infections confirmed during the 7 days prior to the person’s area of residence; This continuous measure was then classified into 10 risk groups according to deciles.20 A medium exposure risk was attributed to people with lost residence data. In order to ensure that the effect of missing data was small, a descriptive comparison was made of people who had missing data with those who did not have data, as well as a multiple imputation analysis (see Analysis section). supplementary 1). The goodness of fit of the model was verified by examining Pearson waste through the categories.
In a supplementary analysis, we adjusted a model with an interaction between the age group and the subcohort in order to estimate age-specific incidence rates in each subcohort. Each case of infection contributed an event to the respective subcohort. Based on the estimated parameters of the adjusted regression model, the incidence rate of each subcohort, adjusted for confounding factors, was estimated as the expected number of events per 100,000 days if every person-at-risk at s ‘be included in this subcohort (see section Supplementary methods 3). 95% confidence intervals were calculated using a boot-like simulation approach23 without adjusting for multiplicity. We repeated the subcohort analysis at 1-month intervals (instead of 2-month intervals) to better distinguish between people who chose to get vaccinated earlier and those who chose to get vaccinated later (or between those who became infected earlier and those who became infected earlier). infected later).
To examine the effect of misclassifying people in cohorts due to undocumented infections, we performed a sensitivity analysis on the assumption that 50% or 70% of actual infections were undocumented. There were too few cases for an in-depth comparison of the incidence of serious disease within and between cohorts with natural immunity and those with hybrid immunity; thus, only a descriptive analysis was made. The results of a comparison of the incidence of severe Covid-19 between people who had received two doses of the BNT162b2 vaccine and those who had received a third (booster) dose are reported elsewhere.21