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Waning Immunity after the BNT162b2 Vaccine in Israel

Our take —

This study from Israel describes rates of breakthrough COVID-19 cases in July of 2021 among people who received two doses of the Pfizer vaccine. Among people older than 60 years, the rate of breakthrough infection was 2.2 times higher among those who were vaccinated six months before the study period compared to those who were vaccinated two months before the study.  Similarly, among people aged 40-59 years, the infection rate was 2.1 times higher among those who were vaccinated four and five months before the study compared to those who were vaccinated two months before the study; among those aged 16-39 years, the rate was 1.6 times higher. In all age groups, the risk of infection increased with time since full vaccination, however, estimated vaccine effectiveness against severe COVID-19 disease only declined modestly in people aged 60 years and older (from 92% to 85%). Although the authors attempted to control for some possible sources of bias, such as differences in rates of PCR testing, they could not adjust for others (e.g., comorbidities, differences in health care access, and differences in risk behaviors), so results should be interpreted cautiously. This study provides further evidence that vaccine induced immunity to infection wanes over time, but protection against severe disease remained strong. 


Study design

Retrospective Cohort

Study population and setting

The study was conducted in Israel between July 11 and July 31, 2021 among 4,791,398 residents who had been fully vaccinated (with the Pfizer vaccine) between January 16 and May 31, 2021 with no history of prior SARS-CoV-2 infection. By the start of the study period, the Delta variant accounted for over 98% of all new SARS-CoV-2 infections in the country; July 31, 2021 was selected as the end date of the study because of the rollout of the booster dose.  The study modeled the rate of SARS-CoV-2 infections and severe COVID-19 cases using Poisson regression.  Participants were stratified into the following age categories; 16-39 years, 40-59 years, and 60 years and older. Participants in each age category were grouped into vaccination intervals (using two-week periods) starting from each group vaccination eligibility date. Full vaccination status was defined as 7 days after the second dose of Pfizer vaccine. Severe infections were defined as COVID-19 pneumonia with a respiratory rate of more than 30, oxygen saturation less than 94% on ambient air, or P arterial O2 over FiO2 of <300. An interaction term between each age group and vaccination period was included to evaluate differences in waning immunity by age.  Regressions were adjusted for the following possible confounders: week of infection, the number of PCR tests that were done for each individual before vaccination (to account for possible ascertainment bias), sex, and population groups (general Jewish, Arab, and ultra-Orthodox). In sensitivity analyses, models were adjusted for socioeconomic status, and were restricted to the general Jewish population.

Summary of Main Findings

Across all age groups of fully vaccinated individuals, 13,426 people tested positive for SARS-CoV-2 infection, and 403 had severe COVID-19. In the adjusted model among individuals above the age of 60 years, the rate of SARS-CoV-2 infection was 2.2 times (95% CI: 1.3-3.6) higher among those vaccinated more than six months prior, relative to those who had their vaccine two months before the study.  Similar trends were noted among age groups 16-39 and 40-59 years, with rates of infection 1.6 (95% CI: 1.3-2.0) and 2.1 (95% CI: 1.4-3.0) times higher, respectively, among those who were vaccinated four months or more before the study period compared to those who were vaccinated two months before the study period. Comparing rates of severe COVID-19 among those above the age of 60 years, vaccinated persons six months or more before the study period had 1.8 times (95% CI: 1.1-2.9) the risk of severe disease compared to those vaccinated four months before the study period.  Among individuals below the age of 60 years, there were no statistically significant differences in the rates of severe COVID-19 across different vaccination periods.  In an additional analysis that used an unvaccinated cohort of individuals above the age of 60 years, vaccine efficacy for severe COVID-19 disease declined from 92% to 85% during the vaccination period. and efficacy against SARS-CoV-2 infection across all age groups declined from 82% to 57%. 

Study Strengths

The study accounted for the possibility of differential detection among individuals by adjusting for the number of PCR tests for each individual before the vaccination campaign. Several sensitivity analyses were done, including adjustment for socioeconomic status, and using ten-year age groups. 


The high risk of unmeasured confounding should result in caution when interpreting results as solely the consequence of waning immunity. No data regarding comorbid conditions were included in the study, which could have resulted in confounding.  Similarly, health-related behaviors may have differed between early and late vaccine recipients (e.g., mask-wearing, social distancing, etc.). Socioeconomic status was only included as a variable in sensitivity analysis, but this may have affected both exposure and outcome risk. The rates of severe COVID-19 disease among age groups below the age of 60 years were low, which limits the evaluation of vaccine effectiveness against severe COVID-19 disease. Also, the definition of severe COVID-19 disease included patients with oxygen saturation below 94%, which could overestimate disease severity if the prevalence of chronic lung disease was elevated in the study cohort.  

Value added

This study provides observational data that corroborate laboratory-based studies indicating a waning of immunity against SARS-CoV-2 infection after vaccination.

This review was posted on: 30 November 2021