The emergence of Omicron variants coincided with declining vaccine-induced protection against SARS-CoV-2. Two bivalent mRNA vaccines, mRNA-1273.222 (Moderna) and BNT162b2 Bivalent (Pfizer-BioNTech), were developed to provide greater protection against the predominate circulating variants by including mRNA that encodes both the ancestral (original) strain and BA.4/BA.5. We estimated their relative vaccine effectiveness (rVE) in preventing COVID-19-related outcomes in the US using a nationwide dataset linking primary care electronic health records and pharmacy/medical claims data. The study population (aged ≥18 years) received either vaccine between 31 August 2022 and 28 February 2023. We used propensity score weighting to adjust for baseline differences between groups. We estimated the rVE against COVID-19-related hospitalizations (primary outcome) and outpatient visits (secondary) for 1,034,538 mRNA-1273.222 and 1,670,666 BNT162b2 Bivalent vaccine recipients, with an adjusted rVE of 9.8% (95% confidence interval: 2.6–16.4%) and 5.1% (95% CI: 3.2–6.9%), respectively, for mRNA-1273.222 versus BNT162b2 Bivalent. The incremental relative effectiveness was greater among adults ≥ 65; the rVE against COVID-19-related hospitalizations and outpatient visits in these patients was 13.5% (95% CI: 5.5–20.8%) and 10.7% (8.2–13.1%), respectively. Overall, we found greater effectiveness of mRNA-1273.222 compared with the BNT162b2 Bivalent vaccine in preventing COVID-19-related hospitalizations and outpatient visits, with increased benefits in older adults.

Background/Objectives: This retrospective cohort study evaluated the relative vaccine effectiveness (rVE) of two bivalent (original/Omicron BA.4/BA.5) vaccines mRNA-1273.222 versus the BNT162b2 Bivalent in preventing COVID-19-related outcomes in adults with underlying medical conditions associated with increased risk for severe COVID-19. Methods: In a linked electronic health record/claims dataset, US adults (≥18 years) with ≥1 underlying medical condition of interest who received either the bivalent vaccine between 31 August 2022 and 28 February 2023 were identified. The inverse probability of treatment weighting was used to adjust for cohort differences. Cohorts were followed up for COVID-19-related hospitalizations and outpatient encounters until 31 May 2023. Hazard ratios and rVEs were estimated using Cox regression. Subgroup analyses were performed on individuals with pre-specified comorbid conditions. Results: 757,572 mRNA-1273.222 and 1,204,975 BNT162b2 Bivalent recipients were identified. The adjusted rVE over a median follow-up of 198 days was 10.9% (6.2%–15.2%) against COVID-19-related hospitalization and 3.2% (1.7%–4.7%) against COVID-19-related outpatient encounters. rVE estimates for COVID-19 hospitalizations among subgroups with comorbid conditions were as follows: diabetes 15.1% (8.7%–21.0%), cerebro- and cardiovascular disease 14.7% (9.0%–20.1%), chronic lung disease 11.9% (5.1%–18.2%), immunocompromised 15.0% (7.2%–22.2%), chronic kidney disease 8.4% (0.5%–15.7%). Conclusions: Overall, among adults with underlying medical conditions, mRNA-1273.222 was more effective than BNT162b2 Bivalent, especially in preventing COVID-19-related hospitalizations.