Short Term, Relative Effectiveness of Four Doses Versus Three Doses of BNT162b2 Vaccine in People Aged 60 Years and Older in Israel: Retrospective, Test Negative, Case-control Study

Objective: To examine the relative effectiveness of a fourth dose of the Pfizer-BioNTech mRNA (BNT162b2) vaccine compared with three vaccine doses over the span of 10 weeks.

Design: Retrospective, test negative, case-control study, with a matched analysis and an unmatched multiple tests analysis.

Setting: Nationally centralised database of Maccabi Healthcare Services, an Israeli national health fund for 2.5 million people; from 10 January 2022 (seven days after the fourth dose was first given to eligible individuals) to 13 March 2022, an omicron dominant period in Israel.

Participants: 97 499 Maccabi Healthcare Services members aged 60 years and older, who were eligible to receive a fourth vaccine dose and obtained at least one polymerase chain reaction (PCR) test during the study.

Main Outcome Measures: Breakthrough SARS-CoV-2 infection, defined as a positive PCR test performed seven or more days after inoculation with the BNT162b2 vaccine; and breakthrough SARS-CoV-2 infection resulting in severe covid-19 disease, defined as hospital admission or death related to covid-19.

Results: 27 876 participants received the fourth BNT162b2 vaccine dose and 69 623 received three doses only. Of 106 participants who died during the follow-up period, 77 had had their third doses only and 23 had had their fourth doses during the first three weeks after inoculation. In the first three weeks, a fourth dose provided additional protection against both SARS-CoV-2 infection and severe disease relative to three doses of the vaccine. However, relative vaccine effectiveness against infection quickly decreased over time, peaking during the third week at 65.1% (95% confidence interval 63.0% to 67.1%) and falling to 22.0% (4.9% to 36.1%) by the end of the 10 week follow-up period. Unlike relative effectiveness against SARS-CoV-2 infection, the relative effectiveness of a fourth dose against severe covid-19 was maintained at a high level (>72%) throughout follow-up. However, severe disease was a relatively rare event, occurring in <1% of study participants who received four doses or three doses only.

Conclusions: A fourth dose of the BNT162b2 vaccine appears to have provided additional protection against both SARS-CoV-2 infection and severe covid-19 disease relative to three vaccine doses. However, relative effectiveness of the fourth dose against infection appears to wane sooner than that of the third dose.