BACKGROUND:Background incidence rates (IRs) of safety outcomes in the absence of vaccination of interest and IRs following the infection targeted by the vaccine, are integral for contextualizing vaccine benefit-risk. As new respiratory vaccines are developed, contemporaneous IR estimates for outcomes commonly assessed in vaccine safety surveillance are needed in the COVID-19 endemic era. METHODS:This retrospective cohort study used four administrative claims data sources in the United States (HealthVerity Closed Claims, Optum's de-identified Clinformatics® Data Mart, Humana and Medicare Fee-For-Service) to estimate IRs for 30 safety outcomes across five organ systems between 1 August 2022 and 31 July 2023. Analyses were conducted overall and stratified by age and sex in five cohorts: the general population, influenza vaccine recipients, and those with medically attended SARS-CoV-2, respiratory syncytial virus, or influenza infection. RESULTS:IRs following influenza vaccination were generally similar to or lower than those in the general population, whereas rates after respiratory infections were generally higher and confounded by marked baseline differences. Among adults ≥65 years, heart failure, atrial fibrillation, ischemic coronary artery disease, and venous thromboembolism had the highest IRs across cohorts. Among adults aged 18-64 years, seizure, anaphylaxis and cardiovascular outcomes were most frequent after respiratory infections. The highest IRs in children were febrile seizures in those ≤5 years and seizures in <18 years; most other outcomes were rare. IRs were similar to or higher in males than females, except for autoimmune disorders. CONCLUSION:This study estimated IRs for 30 safety outcomes relevant to vaccine safety monitoring in a COVID-19 endemic period. Variation across demographic groups and cohorts underscores the importance of accounting for confounders including age and sex when estimating expected rates. Elevated IRs after respiratory infections provide context for future benefit-risk assessments for vaccines targeting these viruses before more rigorous adjusted analyses become available.

Background: Myocarditis and pericarditis are recognised risks following COVID-19 vaccination, including the mRNA-1273 vaccine. Most cases occur shortly following the second dose of this vaccine, and incidence is highest among young males. However, little is known about risk factors beyond age and sex and about the longer-term clinical course. This study aims to identify possible risk factors for myocarditis and pericarditis following mRNA-1273 vaccination, to characterise the clinical course of myocarditis and pericarditis, both associated with mRNA-1273 vaccination and not associated with vaccination, and to identify risk factors for severe outcomes (i.e., cardiac or thromboembolic complications, severe hospital outcomes, all-cause hospital readmission, and death). Methods: This study is being conducted within the Vaccine Monitoring Collaboration for Europe (VAC4EU) association using routinely collected healthcare data from five data sources from four European countries (Denmark, Norway, Spain, and the United Kingdom). The study is being performed using a common data model, and all analyses are performed separately in each data source in a federated manner following a common protocol. A case–cohort analysis set is identified within each data source for identifying potential risk factors for myocarditis and pericarditis following mRNA-1273 vaccination using logistic regression analysis. The clinical course of myocarditis and pericarditis is being assessed using a cohort study design and describes all cases (i.e., cases associated with mRNA-1273 and unexposed cases). Cox regression analysis is applied to assess the associations between risk factors and several follow-up outcomes. Conclusions: This protocol describes the study methodology of an international collaborative initiative with the aim of assessing the risk factors and clinical course of myocarditis and pericarditis following mRNA-1273 vaccination using a federated network of five European data sources.

Introduction & Objective: Diabetes is associated with an increased risk for severe COVID-19. A subanalysis of a retrospective observational cohort study was conducted to evaluate the relative vaccine effectiveness (rVE) of 2 previously approved bivalent vaccines that target the ancestral SARS-CoV-2 and the omicron BA.4/BA.5 variant, mRNA-1273.222 (Moderna, Inc.) and BNT162b2 bivalent (Pfizer-BioNTech), in US adults with diabetes. Methods: The study used a US electronic health record dataset (Veradigm) linked with medical claims data of adults aged ≥18 years with ≥1 underlying medical condition associated with increased risk of severe COVID-19 who received a dose of mRNA-1273.222 or BNT162b2 bivalent vaccines between August 31, 2022, and February 28, 2023. The current analysis included a subgroup of individuals with type 1 or type 2 diabetes identified in the dataset by ICD-10 diagnostic code. The rVE was measured against COVID-19-related hospitalizations and COVID-19-related outpatient visits. Follow-up started 7 days after vaccination until May 31, 2023. Propensity score weighting was used to adjust for baseline differences between groups. Results: Of 639,868 individuals with diabetes included in the analysis, 252,635 received mRNA-1273.222, and 387,233 received BNT162b2 bivalent (post-weighting). After weighting, no variables had an SMD >0.1 therefore no adjustments were made to rVE estimates. The adjusted rVEs of mRNA-1273.222 versus BNT162b2 bivalent vaccine against COVID-19-related hospitalizations and outpatient visits were 15.1% (95% CI, 8.7%-21.0%) and 3.7% (95% CI, 1.2%-6.2%), respectively. Conclusion: We found greater effectiveness of mRNA-1273.222 compared with the BNT162b2 bivalent vaccine in preventing COVID-19—related hospitalizations in this cohort of individuals with diabetes. This study emphasizes the importance of assessing COVID-19 vaccine formulations in high-risk adults, including those with diabetes. Disclosure H. Kopel: Employee; Moderna, Inc. Stock/Shareholder; Moderna, Inc. V. Nguyen: Employee; VHN Consulting Inc. Other Relationship; Moderna, Inc. A. Bogdanov: Employee; Veradigm. Other Relationship; Moderna, Inc. I. Winer: Employee; Veradigm. Other Relationship; Moderna, Inc. C. Boileau: Employee; VHN Consulting Inc. Other Relationship; Moderna, Inc. T. Ducruet: Employee; VHN Consulting Inc. Other Relationship; Moderna, Inc. N. Zeng: Employee; Veradigm. Other Relationship; Moderna, Inc. M. Bausch-Jurken: Employee; Moderna, Inc. Stock/Shareholder; Moderna, Inc. D.B. Esposito: Employee; Moderna, Inc. Stock/Shareholder; Moderna, Inc. E. Beck: Employee; Moderna, Inc. Stock/Shareholder; Moderna, Inc. M. Bonafede: Employee; Veradigm. Other Relationship; Moderna, Inc. J.A. Mansi: Employee; Moderna, Inc. Stock/Shareholder; Moderna, Inc.

Introduction To compare the real-world effectiveness of a third dose of mRNA-1273 versus a third dose of BNT162b2 against breakthrough COVID-19 hospitalizations among adults age ≥65 years who completed a primary series of an mRNA-based COVID-19 vaccine (regardless of which primary series was received). Materials and methods This observational comparative vaccine effectiveness (VE) study was conducted using administrative claims data from the US HealthVerity database (September 22, 2021, to August 31, 2022). A third dose of mRNA-1273 versus BNT162b2 was assessed for preventing COVID-19 hospitalizations and medically attended COVID-19 among adults ≥65 years. Inverse probability of treatment weighting was applied to balance baseline characteristics between vaccine groups. Incidence rates from patient-level data and hazard ratios (HRs) with 95% confidence intervals (CIs) using weighted Cox proportional hazards models were calculated to estimate relative VE for each outcome. Results Overall, 94,587 and 92,377 individuals received a third dose of mRNA-1273 and BNT162b2, respectively. Among the weighted population, the median age was 69 years (interquartile range, 66-74), 53% were female, and 46% were commercially insured. COVID-19 hospitalization rates per 1000 person-years (PYs) were 5.61 (95% CI, 5.13-6.09) for mRNA-1273 and 7.06 (95% CI, 6.54-7.57) for BNT162b2 (HR, 0.82; 0.69-0.98). Medically attended COVID-19 rates per 1000 PYs (95% CI) were 95.05 (95% CI, 93.03-97.06) for mRNA-1273 and 106.55 (95% CI, 104.53-108.57) for BNT162b2 (HR, 0.93; 0.89-0.98). Conclusions Results from this observational comparative VE database study provide evidence that among older adults, a third dose of mRNA-1273 was more effective in preventing breakthrough COVID-19 hospitalization and medically attended COVID-19 infection compared with a third dose of BNT162b2.

e23057 Background: Despite the decline in COVID-19–related hospitalizations and mortality during the period of omicron predominance, immunocompromised individuals, including those with cancer, remain at an increased risk for severe COVID-19 outcomes. A subanalysis of a retrospective observational cohort study assessed the relative vaccine effectiveness (rVE) of 2 previously approved bivalent vaccines targeting the ancestral SARS-CoV-2 and the omicron BA.4/BA.5 variant, mRNA-1273.222 (Moderna, Inc., Cambridge, MA, USA) and BNT162b2 bivalent (Pfizer Inc., New York, NY, USA; BioNTech GmbH, Mainz, Germany), in immunocompromised adults in the United States. Methods: The study used a US electronic health record dataset (Veradigm) linked with medical and pharmacy claims data of adults aged ≥18 years with at least 1 underlying medical condition associated with increased risk of severe COVID-19 who received a dose of mRNA-1273.222 or BNT162b2 bivalent vaccines between August 31, 2022, and February 28, 2023. A subgroup analysis was conducted among an immunocompromised population, encompassing cancer patients, organ or stem cell transplant recipients, individuals with primary immunodeficiency, individuals with HIV, and individuals receiving immunosuppressing medications. Comorbid conditions were based on prior medical encounters in the 365 days before vaccination. The outcomes measured were rVE of the two bivalent mRNA vaccines against COVID-19-related hospitalizations (primary outcome) and outpatient visits (secondary outcome). Follow-up started 7 days after vaccination until May 31, 2023 (end of available claims data). Propensity score weighting was used to adjust for baseline differences between groups. Results: The subanalysis included 427,260 immunocompromised individuals, of which 250,573 (58.6%) were identified as having cancer. In the overall weighted immunocompromised population, 169,509 individuals received mRNA-1273.222, and 257,751 received BNT162b2 bivalent. The adjusted rVEs of mRNA-1273.222 versus BNT162b2 bivalent vaccine against COVID-19–related hospitalizations and outpatient visits were 15.0% (95% CI, 7.2%-22.0%; P< 0.001) and 4.8% (95% CI, 1.8%-7.7%; P= 0.002), respectively. Conclusions: In this study, the mRNA-1273.222 vaccine offered greater protection against COVID-19–related hospitalization compared with the BNT162b2 bivalent vaccine among immunocompromised individuals. This study emphasizes the importance of assessing COVID-19 vaccine formulations and optimizing protection, especially in immunocompromised adults, including those with cancer.