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

Abstract

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.

Fig 1

Adjusted fourth dose effectiveness of BNT162b2 vaccine against SARS-CoV-2 infection, relative to receipt of only three doses. Data based on results from primary matched analysis. Relative vaccine effectiveness=100%×(1−odds ratio) for each week since vaccination; error bars=95% confidence intervals

Fig 2

Adjusted fourth dose effectiveness of BNT162b2 vaccine against severe covid-19, relative to receipt of only three doses. Severe disease was defined as hospital admission or death related to covid-19. Relative vaccine effectiveness=100%×(1−odds ratio) for each week since vaccination; error bars=95% confidence intervals

Fig 3

Directed acyclic graph illustrating biases and their attempted mitigation in this test negative design study. S=sex; A=older age groups; CM=comorbidities; AL=assisted living or nursing home; SES=socioeconomic status; Ct=city of residence; TW=week of testing; Tb=time passed since third dose or first booster. (A) Known confounders by a priori knowledge of previous studies possibly confounding the association between time from the fourth dose (4V) and SARS-CoV-2 related outcomes (S-C-2). (B) For simplicity, all confounders in panel A were combined as C; healthcare seeking behaviour (HsB) possibly confounds the association between a fourth dose (4V) and S-C-2; additionally, some confounders in panel A could be causes of HsB, such as age or comorbidities. (C) In this test negative design, only study participants with a measurable and reasonable healthcare seeking behaviour (that is, HsB=1) were included, thus removing this biasing path. (D) Healthcare seeking behaviour potentially influences the propensity to be tested (PtbT); hence, when a test negative design includes only patients tested for SARS-CoV-2 (or conditioning on the possible collider, PtbT), this inclusion could create a collider bias. (E) When healthcare seeking behaviour is controlled, as attempted by the test negative design, the path is blocked