Relative Effectiveness of Four Doses Compared to Three Dose of the BNT162b2 Vaccine in Israel

Objectives: The rapid spread of the Omicron variant (B.1.1.529) alongside evidence of a relatively rapid waning of the third dose prompted Israel to administer a fourth dose of the BNT162b2 vaccine on January 2022. Thus far, sufficient real-world evidence demonstrating the effectiveness of a fourth dose against infection and severe COVID-19 are lacking. This study examined the short-term effectiveness of a fourth dose compared to three doses over the span of 10 weeks. Design: A retrospective test-negative case-control study, performing both a matched analysis and an unmatched multiple-tests analysis. Setting: Nationally centralized database of Maccabi Healthcare Services (MHS), an Israeli national health fund that covers 2.5 million people. Participants: The study population included 97,499 MHS members aged 60 or older who were eligible to receive a fourth vaccine dose and performed at least one PCR test during the study period. Of them, 27,876 received the fourth dose and 69,623 received only three doses. Main outcomes and measures: Analyses focused on the period from January 10, 2022 (7 days after the fourth dose was first administered to eligible individuals) to March 13, 2022, an Omicron-dominant period in Israel. We evaluated two SARS-CoV-2-related outcomes: (1) breakthrough infection, defined as a positive PCR test performed 7 or more days after inoculation with the BNT162b2 vaccine; and (2) breakthrough infection resulting in a severe disease, defined as COVID-19-related hospitalization or COVID-19 associated mortality. Results: A fourth dose provided considerable additional protection against both SARS-CoV-2 infection and severe disease relative to three doses of the vaccine. However, vaccine effectiveness against infection varied over time, peaking during the third week with a VE of 64% (95% CI: 62.0%-65.9%) and declining to 29.2% (95% CI: 17.7%-39.1%) by the end of the 10-week follow-up period. Unlike VE against infection, the relative effectiveness of a fourth dose against severe COVID-19 was maintained at high level (>73%) throughout the 9-week follow-up period. Importantly, severe disease was a relatively rare event, occurring in <1% of both fourth dose and third dose only recipients. Conclusions: A fourth dose of the BNT162b2 vaccine provided considerable additional protection against both SARS-CoV-2 infection and severe disease relative to three doses of the vaccine. However, effectiveness of the fourth dose against infection wanes sooner than that of the third dose.