Protection and decline of natural and hybrid immunity against SARS-CoV-2

Survey population

An analysis based on data from the Israeli Ministry of Health’s national database focused on infectious diseases identified during the study period from August 1, 2021 to September 30, 2021. During this period, Israel was the fourth pandemic wave dominated by the B.1.617.2 (Delta) variant.^{17 17} Israel has already launched a campaign to provide two doses of the BNT162b2 vaccine and launched a campaign to provide third and fourth boosters (). Supplementary appendix, Available at NEJM.org with the full text of this article). In addition, unvaccinated individuals who recovered from coronavirus disease 2019 (Covid-19) at least three months ago after March 2021 were eligible for 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 individuals who had a positive test for samples taken at least 90 days before the study date.^{18 18} The definition of severe Covid-19 was consistent with the definition of the National Institutes of Health.^{19 19} — That is, a resting breath rate of more than 30 breaths per minute, oxygen saturation of less than 94% while breathing the surrounding air, or the ratio of arterial oxygen partial pressure to inspiratory oxygen concentration is less than 300. The database contains basic information such as gender, age, and location for all residents who received the Covid-19 vaccine, were tested for Covid-19, or were previously infected with SARS-CoV-2. Contains demographic information. Complete records of place of residence, population sector, and confirmed infections as vaccination.

Figure 1. Figure 1. Surveyed population.

Subjects in the study did not have a positive polymerase chain reaction assay documented between 1 July and 30 July 2021 and up to 1 before recovery or after recovery from coronavirus disease. He had been vaccinated several times (Covid-19). I have not been vaccinated with Covid-19 vaccines other than BNT162b2 before August 1, 2021. The age group as of January 1, 2021 is shown. SARS-CoV-2 indicates severe acute respiratory syndrome coronavirus 2.

Using these data at the resident level, confirmation of persons 16 years or older who were positive for SARS-CoV-2 infection prior to July 1, 2021 or who received the BNT162b2 vaccine more than once. I investigated the infection that was done. At least 7 days before the end of the study period. The following people have been excluded from the analysis. A person whose data does not contain information about age or gender. Persons who tested positive for SARS-CoV-2 between July 1st and July 31st, 2021. Persons who recovered from the SARS-CoV-2 infection confirmed by PCR and subsequently received multiple doses of the BNT162b2 vaccine (small group with limited follow-up data). People who recovered from SARS-CoV-2 infection confirmed by PCR after multiple doses of BNT162b2 vaccine (small group). Those who spent the entire research period abroad. Persons vaccinated with vaccines other than BNT162b2 before August 1, 2021 (Figure 1).

Study design and monitoring

We compared the incidence of infections identified during the study between cohorts of individuals with different histories of immunizing events (ie, infection or vaccination). The recovered unvaccinated cohort included individuals who were confirmed to be infected more than 90 days before the study date. There were two “hybrid” cohorts (ie, a cohort of participants who had both innate immunity and immunity from vaccination). The recovered single-dose cohort consisted of those who recovered from Covid-19 and then received a single dose of the vaccine at least 7 days prior to the study day, and the single-dose recovered cohort received a single dose. It consisted of the recipients. Infection confirmed at least 90 days before vaccination and subsequent study days. The 2-dose cohort consisted of persons who were not infected prior to the start of the study and were vaccinated at least 7 days before the study date, and the 3-dose cohort was infected prior to the start of the study. Those who received the third (boost) vaccine at least 12 days before the study date.

These cohorts were divided into subcohorts according to the time elapsed since the last immunization event. We used 2 months as the basic time interval to define the subcohort, but combined 12 to 18 months in the recovered unvaccinated cohort and 8 months in the vaccinated and hybrid cohort. The period of less than 10 months has been omitted. People in those cohorts.

A person can provide follow-up dates to different subcohorts and can also move from one cohort to another according to the following rules: Those who recovered from Covid-19 and received the first dose of BNT162b2 vaccine during the study period left the unvaccinated unvaccinated cohort that recovered on the day of vaccination and entered the single-dose cohort that recovered 7 days later. rice field. Those who recovered from Covid-19 and received the first vaccination, but who received the second vaccination during the study period, completed the single-dose cohort that recovered during the second vaccination. Persons in the double-dose cohort who received the third (boosting) dose during the study period completed the double-dose cohort on the day of booster immunization and entered the triple-dose cohort 12 days later.²⁰ Those who tested positive for SARS-CoV-2 infection between May 1 and June 30, 2021 and who also received a single dose of the BNT162b2 vaccine were collected in a single dose cohort or a single dose. Participated in one of the recovered cohorts of dosing (depending on whether infection was confirmed prior to vaccination) 90 days after a positive test. Those who received a vaccine other than BNT162b2 completed the study on the day of the vaccination.

Studies often compare the infection rate of people who have recovered or have been vaccinated to that of unvaccinated people who have never been infected before. However, due to the high immunization rates in Israel, the latter cohort is small and does not represent the entire population. In addition, the Israeli Ministry of Health database does not contain complete information about such persons. Therefore, we did not include unvaccinated, previously uninfected persons in the analysis.

This study was approved by the Institutional Review Board of the Sheva Medical Center. The Israeli Minister 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 a method similar to that used in previous studies.^8,20,21 The risk of infection in each cohort is assumed to be independent of the time spent in the cohort before the infection was confirmed (that is, the time spent in the cohort before the infection was confirmed), and the proportional hazard survival model and Poisson regression model.^{twenty two} (See the section on Supplementary Method 2). Specifically, we counted the number of infections identified during the study period and the number of days at risk for each subcohort.

Poisson regression model fits, age group as of January 1, 2021 (16-39 years, 40-59 years, or over 60 years), gender, population sector (general Jewish, Arab, or super) Orthodox Jews) have been adjusted. ), Calendar week, and exposure risk measure. The latter was calculated for each person on each follow-up day, depending on the rate of newly confirmed infections in the person’s area of ​​residence in the last 7 days. This continuous measurement was then classified into 10 risk groups according to the decile.²⁰ Persons lacking residence data were subject to an average exposure risk. A descriptive comparison of those with and without missing data and a multiple substitution analysis were performed to ensure that the impact of the missing data was small (see Supplemental Analysis 1 section). .. The goodness of fit of the model was checked by examining the Pearson residuals across the category.

The supplemental analysis fitted a model with interactions between age groups and subcohorts to estimate the age-specific incidence of each subcohort. Each case of infection brought an event to each subcohort. Based on the estimated parameters of the fitted regression model, the incidence of each subcohort adjusted for confounding factors is the expected number of events per 100,000 days if all at-risk human days are included in that subcohort. Estimated (see Supplementary Method 3 section). The 95% confidence interval was calculated using a simulation approach such as bootstrap.^{twenty three} No multiplicity adjustment. Repeated analysis of the subcohort at 1-month intervals (rather than at 2-month intervals), those who previously opted for vaccination and those who later opted for vaccination (or previously infected and later infected).

To investigate the effect of human misclassification on the cohort due to undocumented infections, a sensitivity analysis was performed assuming that 50% or 70% of true infections were undocumented. There were too few cases to closely compare the incidence of serious illness within and between cohorts of innate and hybrid immunity. Therefore, only descriptive analysis was performed. Results comparing the incidence of severe Covid-19 in people who received the BNT162b2 vaccine twice and those who received the third (booster) vaccine have been reported elsewhere.^{twenty one}