Hospitalized patients with severe COVID-19 during the Omicron wave in Israel – benefits of a fourth vaccine dose

Importance: Waning immunity against COVID-19 in parallel with an increased incidence during the Omicron outbreak led the Israeli Ministry of Health to recommend a second booster dose of BNT162b2 (Pfizer) to high-risk individuals. Israel was the first country to recommend this, allowing evaluation of the added protection of a fourth vaccine dose to hospitalized patients with severe diseases. Objective: To assess the effect of a fourth dose for hospitalized patients with severe/critical breakthrough COVID-19. Design: A cohort study of hospitalized adults from 01/15/2022-01/31/2022. Settings: A multi center study of 14 medical centers in Israel. Participants: Hospitalized adult patients with PCR-confirmed severe/critical COVID-19. Excluded were patients lacking data on vaccination status. Exposure: Cases were divided according to the total number of vaccine doses received up to 7 days before diagnosis. Unvaccinated adults and single-dose recipients were grouped into an unvaccinated group. Main Outcome: A composite of mechanical ventilation or in-hospital death was defined as poor outcome. Outcomes were compared between 3- and 4-dose vaccinees. Results: Included were 1,049 patients with severe/critical COVID-19, median age 80 (IQR 69-87), 51% males. Among them, 360 unvaccinated, 34, 172, 386 and 88 were after 1, 2, 3 or 4 doses, respectively. Patients after 3 doses were older, had more males and immunosuppression, but with similar outcomes, 49% vs. 51% compared to unvaccinated patients (p=0.72). Patients after 4 doses were similarly older and immunosuppressed, but had improved outcomes compared to unvaccinated patients, 34% vs. 51% (p<0.01). We proceeded to examine independent predictors for poor outcome in fully-vaccinated patients with either 3 doses given a median of 161 (IQR 147-168) days earlier, or 4 doses given a median of 14 (IQR 10-18) days before diagnoses. Receipt of the fourth dose conferred significant protection: OR 0.51 (95%CI 0.30.87). Conclusion and Relevance: Within a population of hospitalized patients with severe/critical breakthrough COVID-19, a recent fourth dose was associated with significant protection against mechanical ventilation or death, compared to fully-vaccinated single boosted individuals.