The emergence of COVID-19 variants and reports of post-vaccination infections highlight the need to assess the real-world effectiveness of available vaccines. Both mRNA-1273 (Moderna) and BNT162b2 (Pfizer-BioNTech) vaccines have demonstrated high efficacy in preventing severe COVID-19, but data suggests differences in humoral antibody responses, with mRNA-1273 inducing a significantly higher response. This difference is clinically relevant as higher antibody responses correlate with enhanced protection. Observational data, particularly regarding the Delta variant, indicates potentially higher infection rates in individuals vaccinated with BNT162b2 compared to mRNA-1273. This study aimed to investigate the comparative real-world effectiveness of these vaccines by examining the incidence and severity of COVID-19 infection and its outcomes in a large US population.

Several studies have shown that the mRNA-1273 vaccine generates a stronger humoral antibody response compared to the BNT162b2 vaccine. This difference in antibody response is significant because it is associated with increased protection against COVID-19. Previous observational data, including cases with the Delta variant, suggested a higher infection rate among individuals vaccinated with BNT162b2. These findings motivated this study to investigate the comparative effectiveness of the two vaccines in a real-world setting.

This retrospective cohort study utilized de-identified administrative claims data for Medicare Advantage and commercially insured individuals. The study included over 3.5 million fully vaccinated individuals, with 8,848 experiencing documented COVID-19 infections. The primary outcome was the rate of COVID-19 infection at 30, 60, and 90 days post-second dose. Sub-analyses examined hospitalization, ICU admission, and death/hospice transfer. Analyses were stratified by age (above/below 65) and prior COVID-19 diagnosis. Kaplan-Meier curves were used to estimate time-to-infection and time-to-severe outcomes. Multivariable logistic regressions and Cox proportional hazards models were used to estimate adjusted odds ratios and hazard ratios, respectively, adjusting for various confounders including age, timing of vaccination, residence, prior COVID-19 diagnosis, and socioeconomic status. Inverse probability of treatment weighting (IPTW) was employed to address potential selection bias.

The study, encompassing over 3.5 million vaccinated individuals and 8,848 COVID-19 infections, revealed that mRNA-1273 provided slightly better protection against SARS-CoV-2 infection than BNT162b2. This difference was statistically significant at 90 days post-vaccination, with a number needed to vaccinate (NNV) of ≥290. However, there were no statistically significant differences between the vaccines in preventing hospitalization, ICU admission, or death/hospice transfer. These findings were consistent across various analytical models, including those adjusted for multiple confounding factors and those using IPTW to mitigate selection bias. Both binary outcome analysis and time-to-event analysis yielded consistent results. Subgroup analyses, stratified by age and prior COVID-19 infection status, also showed similar trends. The study also identified chronic heart failure, hypertension, and lymphoma as risk factors for severe adverse events, even after adjusting for vaccine type and other covariates. The risk difference between mRNA-1273 and BNT162b2 for infection and composite outcomes increased over time.

This large-scale real-world study provides valuable insights into the comparative effectiveness of mRNA-1273 and BNT162b2 vaccines. While mRNA-1273 showed a small but statistically significant advantage in preventing infection at 90 days, both vaccines demonstrated comparable efficacy in preventing severe COVID-19 outcomes. The finding of a slightly higher infection rate with BNT162b2, albeit with no difference in severe outcomes, warrants further investigation. This study's large sample size and comprehensive adjustment for confounders enhance the reliability of the findings. The results are relevant for public health decision-making, informing vaccine allocation strategies and communication about vaccine effectiveness.

This study demonstrates a slight but statistically significant advantage of mRNA-1273 over BNT162b2 in preventing SARS-CoV-2 infection at 90 days post-vaccination. However, both vaccines showed comparable protection against severe disease. Future research could explore the underlying mechanisms contributing to the observed differences in infection rates, investigate the long-term effectiveness of both vaccines against emerging variants, and examine the impact of booster doses on comparative effectiveness.

The study's reliance on administrative claims data may limit the accuracy of diagnosis and outcome ascertainment. The study population primarily comprised Medicare Advantage and commercially insured individuals, potentially limiting the generalizability of the findings to other populations. Moreover, the observation period was limited to 151 days, necessitating further research to assess long-term effectiveness.