Effectiveness of Heterologous and Homologous Ad26.COV2.S Vaccine Boosting in Preventing COVID-19-Related Outcomes Among Individuals with a Completed Primary Vaccination Series in the United States.

Background/Objectives: COVID-19 vaccines have significantly reduced the mortality and morbidity associated with SARS-CoV-2. In the fall of 2021, the U.S. Food and Drug Administration amended its emergency use authorization guidelines for COVID-19 vaccines to allow the administration of booster vaccine doses based on sound scientific evidence of the increase in effectiveness conferred by boosters. The effectiveness of the Ad26.COV2.S COVID-19 booster vaccine during the periods of Delta and Omicron variant dominance is unknown. This study used real-world data to estimate the effectiveness of booster heterologous or homologous Ad26.COV2.S vaccination compared to that of a primary Ad26.COV2.S or mRNA COVID-19 vaccination series. Methods: A retrospective, observational, longitudinal cohort study design was used with a total eligible sample population consisting of 72,461,026 individuals in the HealthVerity dataset. The study cohort consisted of individuals ≥18 years in the United States with evidence of a COVID-19 primary vaccination series (Ad26.COV2.S or mRNA) administered between 1 January 2021 and 6 July 2022. Two exposure groups were considered based on retrospective database classification: a heterologous Ad26.COV2.S booster and a homologous Ad26.COV2.S booster. Individuals eligible for the referent groups, defined as those with a primary vaccine series alone, were identified through exact matching by age, sex, time since primary series vaccine, location, and Gagne comorbidity score. Propensity score-matched Cox proportional hazards models were used to evaluate outcomes, including COVID-19-related hospitalization and medically attended COVID-19. Results: Depending on the comparison group of interest, the adjusted hazard ratios for COVID-19-related hospitalization ranged from 0.63 (95% CI: 0.56, 0.72) to 0.82 (95% CI: 0.75, 0.90), and 0.93 (95% CI: 0.90, 0.96) to 0.94 (95% CI: 0.91, 0.97) for medically attended COVID-19, both favoring booster vaccination. Conclusions: The results of this study demonstrate the effectiveness of an Ad26.COV2.S booster vaccination compared to primary series vaccination in preventing COVID-19 hospitalization and medically attended COVID-19 for at least 12 months. This study adds to the scientific evidence that demonstrates the importance of COVID-19 booster vaccinations to support public health policy.