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

Abstract

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.

Effectiveness of a Fourth Dose of COVID-19 Vaccine among Long-Term Care Residents in Ontario, Canada: Test-Negative Design Study

“…Recent studies in Israel among adults aged ≥60 years suggest that effectiveness of fourth doses of BNT162b2 against infection may wane faster than third doses, but similar to third doses, there is a lower degree of waning against severe disease. 15,16 Canadian studies have found that immune protection among LTC residents wanes much faster than younger, healthier adults after 2 doses; similar patterns may be expected for booster doses. 28,29…”

“…In Israel, among adults aged ≥60 years, the marginal effectiveness against any infection 7-13 days after a fourth dose versus a third dose of BNT162b2 received ≥4 months earlier was 46%, peaking 21-27 days after vaccination at 64%. 16 The marginal effectiveness against severe disease was 73% 7-27 days following a fourth dose and was highest 49-69 days after vaccination at 86%. 16 Similar to our study, there was considerable additional protection against infection and severe disease with a fourth dose relative to a third dose, though findings cannot be directly compared due to differences in study design, outcome definitions, population characteristics, settings, vaccine products, and dosing intervals.…”

“…16 The marginal effectiveness against severe disease was 73% 7-27 days following a fourth dose and was highest 49-69 days after vaccination at 86%. 16 Similar to our study, there was considerable additional protection against infection and severe disease with a fourth dose relative to a third dose, though findings cannot be directly compared due to differences in study design, outcome definitions, population characteristics, settings, vaccine products, and dosing intervals. Very few individuals (3%) in the Israeli study were nursing home residents.…”

“…12 Other jurisdictions have subsequently recommended fourth (second booster) doses for their LTC populations. Although evidence from Israel suggests that fourth doses compared to third doses provide additional protection against SARS-CoV-2 infection and severe COVID-19 among older adults, findings have been limited to the BNT162b2 (Pfizer-BioNTech Comirnaty) vaccine, 15,16 and no studies to date have reported both marginal effectiveness and vaccine effectiveness (VE) of fourth doses in the LTC population.…”

Genome wide screen of RNAi molecules against SARS-CoV-2 creates a broadly potent prophylaxis

“…Moreover, as all monoclonal antibody (mAb) treatments target this same protein, such antigenic shifts not only hamper the protection of vaccines, but can also reduce the efficacy of a wide range of other treatments. Second, multiple studies have shown that vaccines’ protection, including against severe disease, typically wanes within just a few months, after the second 9 , third 10,11 , or the fourth dose 12 . Third, recent lines of evidence in mice and NHP suggest that updated versions of vaccines have diminished efficacy and may be subject to original antigenic sin 13,14 .…”