Skip to main content

Effectiveness of a third dose of the BNT162b2 mRNA COVID-19 vaccine for preventing severe outcomes in Israel: an observational study

Our take —

This matched case-control study from Israel, taking place between July 30, 2020 and September 23, 2021, found that a third booster dose of the Pfizer BNT162b2 vaccine was 93% (95% CI, 88-97) more effective in protecting individuals against COVID-19 hospitalizations, 92% (95% CI, 82-97) more effective against severe disease, and 81% (95% CI, 59-97) more effective against COVID-19 related death compared to two vaccine doses received at least five months prior. Severe disease was defined as having SpO2 <94% on room air at sea level, PaO2/FiO2 30 breaths/min, or lung infiltrates >50%, according to US National Institutes of Health criteria. However, these outcomes were rare among individuals in both groups, with only 53 combined hospital admissions, cases of severe disease, and deaths in the three-dose group and 432 combined in the two-dose group. Individuals at high risk for severity and death, including the elderly and those with pre-existing comorbidities, benefitted most from a third booster dose.

Study design

Retrospective Cohort

Study population and setting

Due to many countries experiencing a resurgence of COVID-19 which may be associated with loosening of restrictions, possible waning immunity over time, and the Delta variant wave, some are beginning to administer third doses of vaccine. This retrospective study, designed to emulate a target trial, studied the effectiveness of a third/booster dose of Pfizer’s BNT162b2 vaccine in preventing severe COVID-19 outcomes. Data from Clalit Health Services, the largest healthcare provider in Israel, was examined from between July 30, 2020 and September 23, 2021. Individuals who received a third dose between these dates were matched with individuals who were demographically and clinically similar and had only received two doses. Controls who later received a third dose on a future date then became eligible to be “recruited” to the third dose group. All participants had received their second dose at least five months prior to their recruitment date, had no previous documented SARS-CoV-2 infection, and no contact with the healthcare system in the three days prior to recruitment. Individuals had to be eligible to receive a third dose at least one of the days during the study period in order to be included. Immunocompromised individuals as well as people who were healthcare workers, living in long-term care facilities, or were medically confined to their homes were excluded. The primary outcomes of this study were COVID-19 related hospital admission, severe disease, and COVID-19 related death. Secondary outcomes were SARS-CoV-2 infection confirmed by PCR test and symptomatic infection. All outcomes were assessed starting seven days after administration of the third dose. Third dose effectiveness for each outcome was estimated by calculating 1 – risk ratio using a Kaplan-Meier estimator.

Summary of Main Findings

Both the third dose and control groups included 728,321 individuals after matching. In both the booster and control groups, cases of hospital admission, sever COVID-19 and death were incredibly rare. The effectiveness of the third dose compared to two doses of BNT162b2 vaccine against hospital admission was estimated to be 93% (95% CI, 88-97), 92% (95% CI, 82-97) against severe disease, and 81% (95% CI, 59-97) against COVID-19 related death. The incidence of hospitalization began to diverge between the two groups around six days following the third dose. There was also a divergence seen between the groups at 8-9 days following the third dose in the rates of severe disease and COVID-19 related deaths. The third dose effectiveness against documented infection was estimated to be 88% (95% CI, 87-90) and 91% (95% CI, 89-92) for symptomatic infection. It was also observed that the incidence trends began to decline in each age group shortly after the third dose was approved for that particular age group compared to other ineligible groups. The vast majority of the protective effect of a third dose was seen in older (>70 years) individuals and people with multiple co-morbidities, whereas efficacy in younger healthier people, while significant, was limited in magnitude.

Study Strengths

This study included patients with many common comorbidities and COVID-19 risk factors as defined by the CDC, which is reflective of the general population. The controls were also matched by a wide-ranging list of criteria, including age, sex, place of residence, number of pre-existing comorbidities/risk factors, month that they received their second vaccine dose, and the number of SARS-CoV-2 PCR tests they had performed in the nine months prior to their index date. The latter two criteria served as indicators of health-seeking behaviors.


This study had several limitations that should be noted. First, the optimal time in order to achieve maximum protection from a third vaccine dose is not known. The estimated effectiveness here was calculated starting from seven days after receipt of the third dose, but it is possible that protection could begin earlier to some degree. Next, the secondary outcomes of symptomatic infection and PCR confirmed infection could be biased due to differing testing frequencies between groups due to differences in health seeking behaviors, although this was partially accounted for in the matching criteria. Third dose effectiveness could not be estimated in individuals younger than 40 years old due to low numbers of the outcomes of interest. Additionally, this study was performed in a smaller country with a fairly homogenous population compared to other countries. Finally, specific high-risk populations were excluded from the analyses even though they are the groups likely to be targeted to get booster doses first.

Value added

Important data on third dose effectiveness for the Pfizer BNT162b2 vaccine.

This review was posted on: 8 December 2021