Effectiveness of the BNT162b vaccine fourth dose in reducing SARS-CoV-2 infection among healthcare workers in Israel, a multi-center cohort study

Abstract During December 2021 the fifth COVID-19 wave started in Israel, caused mostly by the Omicron variant, affecting the unvaccinated and vaccinated population. Ninety percent of the Israeli adults, including most healthcare workers (HCWs), received three doses of the BNT162b2 vaccine until September 2021. Following the success and safety of the 3rd dose in preventing infection and severe disease, on December 30, 2021, the Israeli Ministry of Health recommended a voluntary 4th vaccine dose to adults above 60 years, immunocompromised, and HCWs. We compared breakthrough infections in HCWs, between 3 and 4-dose recipients. Hospitals collected data on personnel vaccinations and infections dates. The study cohort included all HCWs in eleven hospitals in Israel, who have been vaccinated with three doses up to September 30, 2021, and had not contracted COVID-19 before the vaccination campaign (January 2, 2022). We calculated breakthrough infection rates in 4-dose recipients (more than six days after vaccination) vs. 3-dose recipients. Rate-ratios were calculated for the entire cohort and for subgroups (hospital, sex, age-groups, and profession). Additionally, we repeated the calculations on 4-dose and 3-dose recipients who received the 3rd dose on the same date and were matched for sex, age group, profession and hospital. We generated time-dependent Cox-regression models to account for 4th dose administration timing (Supplement). There were 29,612 HCWs who received 3 vaccine doses between August and September 2021; of these, 5,331 (18.0%) received the 4th dose during January 2022 and were not infected by the first week after vaccination. Overall breakthrough infection rates in the 4-dose and 3-dose groups were 368/5331 (6.9%) and 4802/24280 (19.8%), respectively. The RR (95%CI) was 0.35 (0.32 to 0.39) for crude analysis, and 0.61 (0.54 to 0.71) in the matched analysis. The adjusted HR in the Cox-regression model was 0.56 (0.50 to 0.63). In both groups, severe disease and death were not reported. Our data shows that the 4th BNT162b2 dose resulted in reduced breakthrough infection rates among HCWs. This reduction, similar to the findings in the Israeli elderly population, is lower than that observed after the 3rd dose. Nevertheless, considering the high infectivity of the Omicron variant, which led to critical medical staff shortages, a 4th vaccine dose should be considered to mitigate the infection rate among HCWs.