To assess the effectiveness of messenger RNA vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) in preventing emergency department (ED) presentations for acute respiratory illness.

We conducted a retrospective study assessing adult presentations (age ≥ 18) to the University of Miami Hospital's ED from January 1st through August 25th, 2021, with a SARS-COV-2 PCR test and acute respiratory infection symptoms. Vaccine effectiveness was calculated using a test-negative design. Both univariable and multivariable (adjusted for age, gender, race, insurance status, imputed body mass index [BMI], vaccine type, week of presentation) regression analyses were conducted for the full cohort and subgroups.

The cohort consisted of 13,203 ED presentations—3134 (23.7%) fully vaccinated and SARS-COV-2 negative, 108 (0.8%) fully vaccinated and SARS-COV-2 positive, 8817 (66.8%) unvaccinated and SARS-COV-2 negative, and 1144 (8.7%) unvaccinated and SARS-COV-2 positive. Unadjusted vaccination effectiveness was 73.4% (95% confidence interval: 67.5%,78.3%) and, after adjustment, 73.8% (66.2%,79.7%). The Moderna vaccine's effectiveness was numerically higher (unadjusted: 78.2% [68.8%, 84.7%]; adjusted: 78.0% [68.1%, 84.9%]) than the Pfizer vaccine's (unadjusted: 70.8% [62.9%, 76.9%]; adjusted: 73.9% [66.3%,79.8%]). We found a significant difference in adjusted vaccine effectiveness across categories was BMI (p < 0.001)—BMI <25: 66.3% (45.3%,79.2%); BMI 25–29: 71.3% (56.1%, 81.2%); BMI 30–34: 84.5% (71.7%, 91.5%); and BMI ≥35: 72.7% (50.5%, 84.9%).

We demonstrated excellent real-world effectiveness of mRNA vaccines in preventing ED presentation for SARS-COV-2 in a diverse U.S. cohort. Notably, vaccine effectiveness improved with increasing BMI (until class 2 obesity).