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.