Clinical Severity and mRNA Vaccine Effectiveness for Omicron, Delta, and Alpha SARS-CoV-2 Variants in the United States: A Prospective Observational Study.

Objectives: To characterize the clinical severity of COVID-19 caused by Omicron, Delta, and Alpha SARS-CoV-2 variants among hospitalized adults and to compare the effectiveness of mRNA COVID-19 vaccines to prevent hospitalizations caused by each variant.
Design: A case-control study of 11,690 hospitalized adults.
Setting: Twenty-one hospitals across the United States.
Participants: This study included 5728 cases hospitalized with COVID-19 and 5962 controls hospitalized without COVID-19. Cases were classified into SARS-CoV-2 variant groups based on viral whole genome sequencing, and if sequencing did not reveal a lineage, by the predominant circulating variant at the time of hospital admission: Alpha (March 11 to July 3, 2021), Delta (July 4 to December 25, 2021), and Omicron (December 26, 2021 to January 14, 2022).
Main Outcome Measures: Vaccine effectiveness was calculated using a test-negative design for COVID-19 mRNA vaccines to prevent COVID-19 hospitalizations by each variant (Alpha, Delta, Omicron). Among hospitalized patients with COVID-19, disease severity on the WHO Clinical Progression Ordinal Scale was compared among variants using proportional odds regression.
Results: Vaccine effectiveness of the mRNA vaccines to prevent COVID-19-associated hospitalizations included: 85% (95% CI: 82 to 88%) for 2 vaccine doses against Alpha; 85% (95% CI: 83 to 87%) for 2 doses against Delta; 94% (95% CI: 92 to 95%) for 3 doses against Delta; 65% (95% CI: 51 to 75%) for 2 doses against Omicron; and 86% (95% CI: 77 to 91%) for 3 doses against Omicron. Among hospitalized unvaccinated COVID-19 patients, severity on the WHO Clinical Progression Scale was higher for Delta than Alpha (adjusted proportional odds ratio [aPOR] 1.28, 95% CI: 1.11 to 1.46), and lower for Omicron than Delta (aPOR 0.61, 95% CI: 0.49 to 0.77). Compared to unvaccinated cases, severity was lower for vaccinated cases for each variant, including Alpha (aPOR 0.33, 95% CI: 0.23 to 0.49), Delta (aPOR 0.44, 95% CI: 0.37 to 0.51), and Omicron (aPOR 0.61, 95% CI: 0.44 to 0.85).
Conclusions: mRNA vaccines were highly effective in preventing COVID-19-associated hospitalizations from Alpha, Delta, and Omicron variants, but three vaccine doses were required to achieve protection against Omicron similar to the protection that two doses provided against Delta and Alpha. Among adults hospitalized with COVID-19, Omicron caused less severe disease than Delta, but still resulted in substantial morbidity and mortality. Vaccinated patients hospitalized with COVID-19 had significantly lower disease severity than unvaccinated patients for all the variants.