The neutralizing antibody titer correlate of COVID-19 risk in the COVID-19 variant immunologic landscape (COVAIL) trial was not modified by SARS-CoV-2 amino acid sequence distances

Authors

• Fei Heng, Department of Mathematics and Statistics, University of North Florida, Jacksonville, FL, USA.
• Craig A. Magaret, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
• Nadine G. Rouphael, Hope Clinic, Emory University, Decatur, GA, USA.
• Angela R. Branche, Vaccine and Treatment Evaluation Unit, University of Rochester, Rochester, NY, USA.
• Youyi Fong, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA, USA.
• Lindsay N. Carpp, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
• Chenchen Yu, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
• Shiyu Chen, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
• Bo Zhang, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
• David J. Diemert, George Washington Vaccine Research Unit, George Washington University, Washington, DC, USA.
• Ann R. Falsey, Vaccine and Treatment Evaluation Unit, University of Rochester, Rochester, NY, USA.
• Daniel S. Graciaa, Hope Clinic, Emory University, Decatur, GA, USA.
• Lindsey R. Baden, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
• Sharon E. Frey, Center for Vaccine Development, Saint Louis University, MO, USA.
• Jennifer A. Whitaker, Department of Molecular Virology and Microbiology and Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
• Susan J. Little, Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California, La Jolla, San Diego, CA, USA.
• Satoshi Kamidani, Center for Childhood Infections and Vaccines, Children's Healthcare of Atlanta, GA, USA; Department of Pediatrics, Emory University, Atlanta, GA, USA.
• Emmanuel B. Walter, Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA.
• Richard M. Novak, Project WISH, University of Illinois at Chicago, Chicago, IL, USA.
• Richard Rupp, Department of Pediatrics, University of Texas Medical Branch, Galveston, TX, USA.
• Lisa A. Jackson, Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
• Tara M. Babu, Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA, USA.
• Angelica C. Kottkamp, Vaccine and Treatment Evaluation Unit, Manhattan Research Clinic, New York University Grossman School of Medicine, New York, NY, USA.
• Anne F. Luetkemeyer, Division of HIV, Infectious Diseases and Global Medicine, Zuckerberg San Francisco General Hospital, University of California, San Francisco, CA, USA.
• Lilly C. Immergluck, Clinical Research Center, Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA, USA.
• Rachel M. Presti, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
• Martín Bäcker, Vaccine and Treatment Evaluation Unit, Long Island Research Clinic, New York University, Long Island School of Medicine, Mineola, NY, USA.
• Patricia L. Winokur, Department of Medicine, University of Iowa College of Medicine, Iowa City, IA, USA.
• Siham M. Mahgoub, Howard University College of Medicine, Howard University Hospital, Washington, DC, USA.
• Paul A. Goepfert, Department of Medicine, University of Alabama at Birmingham, AL, USA.
• Dahlene N. Fusco, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
• Robert L. Atmar, Department of Molecular Virology and Microbiology and Department of Medicine, Baylor College of Medicine, Houston, TX, USA.

Document Type

Journal Article

Publication Date

2-15-2026

Journal

Vaccine

Volume

76

DOI

10.1016/j.vaccine.2026.128348

Keywords

Deep mutational scanning; Immune correlate of protection; Neutralizing antibody escape; Randomized clinical trial; Recombinant protein vaccine; mRNA vaccine

Abstract

In the Coronavirus Variant Immunologic Landscape Trial (COVAIL) conducted in the United States in 2022-2023, 985 participants received a second COVID-19 booster with one of twelve monovalent or bivalent mRNA inserts. Pseudovirus serum inhibitory dilution 50% neutralizing antibody titer (nAb titer) measured two-weeks post booster significantly associated with lower COVID-19 incidence over six months follow-up in this trial. COVAIL investigators sequenced SARS-CoV-2 Spike amino acid sequences for all COVID-19 cases, with a sequence successfully obtained from 129 of 195 cases. For COVID-19 endpoint cases we calculated five distances of the case-causing sequence to a reference sequence, the first two physico-chemical weighted Hamming distances of Spike or receptor binding domain (RBD) to a participant's nearest Spike or RBD vaccine-insert sequence, and the other three estimated degrees of neutralizing antibody escape from the XBB.1.5 RBD strain calculated with deep mutational scanning. Hypothesizing that the nAb titer correlate of risk may have a stronger association with COVID-19 when focusing on COVID-19 infections more closely matched to the vaccine insert in Spike or RBD amino acid sequence or with lower RBD antibody escape score, we tested this hypothesis for the combined group receiving a monovalent Prototype (ancestral strain) booster (n = 143) and for the combined group receiving an Omicron-containing booster (n = 744). For both combined groups, the nAb titer correlate of risk did not significantly vary across any of the assessed sequence distances from the vaccine insert (all p-values >0.10), although RBD Hamming distance had point estimates consistent with a weakening correlate with distance, motivating further exploration in settings with greater antigenic heterogeneity. Indeed, statistical power was bounded by the limited antigenic variability of viruses infecting trial participants over the follow-up period (April 21, 2022 to May 25, 2023), which spanned only a 3.02-fold nAb titer range of differential sensitivity to sera from XBB.1.5-infected individuals. ClinicalTrials.gov Identifier: NCT05289037.

APA Citation

Heng, Fei; Magaret, Craig A.; Rouphael, Nadine G.; Branche, Angela R.; Fong, Youyi; Carpp, Lindsay N.; Yu, Chenchen; Chen, Shiyu; Zhang, Bo; Diemert, David J.; Falsey, Ann R.; Graciaa, Daniel S.; Baden, Lindsey R.; Frey, Sharon E.; Whitaker, Jennifer A.; Little, Susan J.; Kamidani, Satoshi; Walter, Emmanuel B.; Novak, Richard M.; Rupp, Richard; Jackson, Lisa A.; Babu, Tara M.; Kottkamp, Angelica C.; Luetkemeyer, Anne F.; Immergluck, Lilly C.; Presti, Rachel M.; Bäcker, Martín; Winokur, Patricia L.; Mahgoub, Siham M.; Goepfert, Paul A.; Fusco, Dahlene N.; and Atmar, Robert L., "The neutralizing antibody titer correlate of COVID-19 risk in the COVID-19 variant immunologic landscape (COVAIL) trial was not modified by SARS-CoV-2 amino acid sequence distances" (2026). GW Authored Works. Paper 8710.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/8710

Department

Medicine