Effect of Omicron BA.1-based compared to prototype booster mRNA vaccination on incidence of COVID-19 in the COVAIL trial

David J. Diemert, Department of Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA. Electronic address: ddiemert@gwu.edu.
Daniel S. Graciaa, Hope Clinic of the Emory Vaccine Center, Division of Infectious Diseases, Emory University School of Medicine, Decatur, GA, USA.
Bo Zhang, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
Nadine G. Rouphael, Hope Clinic of the Emory Vaccine Center, Division of Infectious Diseases, Emory University School of Medicine, Decatur, GA, USA.
Angela R. Branche, Vaccine and Treatment Evaluation Unit, University of Rochester, Rochester, New York, USA.
Thomas C. Martin, University of California, San Diego, La Jolla, California, USA.
Lisa A. Jackson, Kaiser Permanente Washington Health Research Institute, Seattle, Washington, USA.
Rachel M. Presti, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
Satoshi Kamidani, Center for Childhood Infections and Vaccines, Children's Healthcare of Atlanta, GA, USA; Department of Pediatrics, Emory University, Atlanta, GA, USA.
Siham M. Mahgoub, Howard University College of Medicine, Howard University Hospital, Washington, DC, USA.
Tara M. Babu, Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington, USA.
Craig A. Magaret, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
Viviana Simon, Department of Microbiology, Icahn School of Medicine at Mount Sinai, NY, New York, USA; Center for Vaccine Research and Pandemic Preparedness (C-VaRPP), Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Harm van Bakel, Department of Microbiology, Icahn School of Medicine at Mount Sinai, NY, New York, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Artificial Intelligence and Human Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Paul C. Roberts, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
John H. Beigel, Center for Vaccine Research and Pandemic Preparedness (C-VaRPP), Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Peter B. Gilbert, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA; Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA; Department of Biostatistics, School of Public Health, University of Washington, Seattle, Washington, USA.
Dean Follmann, Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Document Type

Journal Article

Publication Date

9-9-2025

Journal

Vaccine

Volume

64

DOI

10.1016/j.vaccine.2025.127718

Keywords

COVID-19; SARS-CoV-2; Vaccine efficacy; Variant; mRNA vaccine

Abstract

BACKGROUND: Covid-19 vaccines are updated to match circulating strains based on reasoning that better strain-matched immunogenicity should provide better protection. Randomized evidence with disease endpoints to support strain matching is lacking. We evaluated COVID-19 incidence among adults randomized to a second booster of Prototype or Omicron-based vaccines. METHODS: COVAIL was a four-stage Phase 2 clinical trial; results from Stages 1 (mRNA-1273 [Moderna]) and 2 (BNT162b2 [Pfizer/BioNTech]) are described here. Adults who had received a primary series and one booster of an authorized COVID-19 vaccine were eligible. Participants received one dose of either Prototype vaccine or a monovalent or bivalent Omicron BA.1 vaccine. SARS-CoV-2 neutralization titers (ID) were measured pre- and post-vaccination. Covariate-adjusted cumulative COVID-19 incidence and Cox regression analyses were conducted separately for each stage. RESULTS: 706 participants with pre- and day 15 post-vaccination ID titers (n = 503 in Stage 1, n = 203 in Stage 2) were included. Within stages, participant characteristics and baseline ID titers were similar between Prototype and Omicron-based arms. There was no difference in cumulative COVID-19 incidence for Prototype vs. Omicron-based vaccine in Stage 1 (RR 1.04, 95 % CI 0.73-1.48), while incidence was higher among Prototype recipients in Stage 2 (RR 2.56, 1.44-4.52). Cox regression analysis showed no difference in Stage 1 (HR 1.04, 0.68-1.58), but higher incidence for Prototype recipients in Stage 2 (HR 2.95, 1.52-5.72). CONCLUSIONS: Omicron-based vaccines as second boosters were more protective against COVID-19 relative to Prototype among those receiving BNT162b2 but not mRNA-1273. Differences between stages such as force of infection, antigen matching, and vaccine differences may explain this finding. CLINICALTRIALS: govRegistry Number: NCT05289037.

Department

Medicine

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