Largest real-world study evaluates effectiveness of third ‘booster’ dose of COVID-19 vaccine


The Clalit Research Institute, in collaboration with researchers at Harvard University, analyzed one of the largest integrated databases of health records in the world to examine the effectiveness of the third dose of Pfizer / BioNTech BNT162B2 vaccine against the Delta variant of SARS-CoV-2. The study provides the largest peer-reviewed assessment of the effectiveness of a third “booster” dose of a COVID-19 vaccine in a national mass immunization setting. The study was conducted in Israel, one of the world’s first leaders in third-dose COVID-19 vaccination rates.

Many countries are currently experiencing a resurgence of SARS-CoV-2 infections despite previously successful vaccination campaigns. This may be due to the greater infectivity of the delta variant (B.1.617.2) of SARS-CoV-2 and the decreased immunity of vaccines given months earlier. Faced with the current resurgence, several countries are planning to administer a third booster dose of the COVID-19 mRNA vaccine.

This study suggests that a third dose of vaccine is effective in reducing severe COVID-19-related outcomes compared to people who received two doses of the vaccine at least 5 months ago. He is the first to estimate the effectiveness of a third dose of a COVID-19 mRNA vaccine – specifically BNT162b2 – against serious outcomes with adjustment for various possible confounders, including comorbidities and behavioral factors . The large size of the study also allows a more precise assessment of the efficacy of the vaccine over different time periods, different subpopulations (by sex, age and number of comorbidities) and different serious outcomes (which are rarer and therefore require further investigation. larger sample size). A recent clinical trial conducted by BioNTech included a smaller sample and did not estimate the effects of the third dose for more severe results.

The study ran from July 30, 2021 to September 23, 2021, coinciding with the fourth wave of coronavirus infection and disease in Israel, in which the Delta variant (B.1.617.2) was the dominant strain in the country for new infections (with very few exceptions).

The researchers looked at data from 728,321 people aged 12 or older who had received the third dose of the BNT162b2 vaccine. These individuals were carefully matched 1: 1 with 728,321 individuals who had received only two injections of the BNT162b2 vaccine at least five months previously. The match was based on a broad set of demographic, geographic, and health attributes associated with risk of infection, risk of serious illness, health status, and care-seeking behavior. Individuals were dynamically assigned to each group based on their changing immunization status (198,476 individuals moved from the unvaccinated to the vaccinated cohort during the study). Multiple analyzes were carried out to ensure that the estimated efficacy of the vaccine was robust to potential biases. The study included a total of over 12,000,000 person-days of follow-up.

The results show that, compared to people who received only two doses five months previously, people who received three doses of the vaccine (7 days or more after the third dose) had a 93% lower risk of hospitalization. related to COVID-19, 92% lower risk of severe COVID-19 disease and 81% lower risk of death from COVID-19. The efficacy of the vaccine was found to be similar for different sexes, age groups (40-69 years and 70+) and number of co-morbidities.

The study also included a population-level analysis which found that infection rates began to decline for each age group 7-10 days after that age group became eligible for the third dose.

The research was conducted by Dr Noam Barda, Dr Noa Dagan, Professor Cyrille Cohen and Professor Ran Balicer of the Clalit Research Institute, as well as Professor Miguel Hernán and Professor Marc Lipsitch of the Harvard TH Chan School of Public Health , Professor Isaac S. Kohane of Harvard Medical School and Professor Ben Reis of Boston Children’s Hospital and Harvard Medical School.

Large, nation-wide rollout of Israel’s third-dose COVID-19 ‘booster’ vaccination campaign has provided the Clalit Research Institute with a unique opportunity to assess, thanks to its rich and comprehensive digital data sets , the effectiveness of the third dose in a real context against the less common but serious complications of COVID-19. “

Teacher. Ran Balicer, lead author of the study, director of the Clalit Research Institute and director of innovation for Clalit

“These results convincingly show that the third dose of the vaccine is highly effective against severe COVID-19-related outcomes in different age groups and subgroups of the population, one week after the third dose. These data should facilitate a informed political decision-making, “added Prof Balicer, who is also chairman of Israel’s national team of advisory experts on the response to COVID-19.

Professor Ben Reis, director of the Predictive Medicine Group at the Boston Children’s Hospital Computational Health Informatics Program and Harvard Medical School, said: “To date, one of the main drivers of vaccine hesitancy has been the lack of information This careful epidemiological study provides reliable information on the efficacy of the vaccine at the third dose, which we hope will be useful for those who have not yet decided to vaccinate with a third dose.

Professor Miguel Hernán, Director of CAUSALab and Professor at Harvard TH Chan School of Public Health, said: “This research is a perfect example of the complementarity of randomized trials and observational databases in healthcare. The Pfizer / BioNTech vaccine trial provided compelling evidence for its effectiveness in preventing symptomatic infections, but estimates for severe disease and specific age groups were too imprecise. This analysis of Clalit’s high-quality database emulates the original trial design, uses its results as a benchmark, and expands on them to confirm vaccine efficacy in adolescents. This combination of evidence from randomized trials and observational studies is a model for effective medical research, which is especially important in the age of COVID.

Professor Marc Lipsitch, director of the Center for Communicable Disease Dynamics and professor at Harvard TH Chan School of Public Health, said: “In all studies of vaccine effectiveness, a major challenge is to ensure that those that we compare to identify the vaccine effect are similar in other characteristics that can predict whether they are infected or sick. This is particularly difficult in the context of a rapidly growing age-targeted vaccination campaign. in a way that gives great confidence in the inferences that emerge from the study. “

The research was funded in part by the recently announced collaboration between Ivan and Francesca Berkowitz Family Living Laboratory at Harvard Medical School and the Clalit Research Institute.

“The strengthening of the scientific collaboration between Harvard and Clalit made possible by the Berkowitz Living Laboratory Collaboration is already bearing fruit and giving us a taste of the value of instrumented health systems for research,” said Prof. Isaac Kohane, Chairman of the Department of Biomedical Informatics at Harvard Medical School and Co-Director of the Ivan and Francesca Berkowitz Family Living Laboratory collaboration with Professor Balicer. “Israel offers a unique environment in which to study the vaccine and its effects, and this study is a prime example of what can be accomplished through such close scientific collaborations. “


Journal reference:

Barda, N., et al. (2021) Effectiveness of a third dose of the COVID-19 mRNA vaccine BNT162b2 in preventing severe outcomes in Israel: an observational study. The Lancet.


Sara H. Byrd

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