Neutralizing antibody immune correlates in COVAIL trial recipients of an mRNA second COVID-19 vaccine boost

Bo Zhang, Youyi Fong, Lauren Dang, Jonathan Fintzi, Shiyu Chen, Jing Wang, Nadine G. Rouphael, Angela R. Branche, David J. Diemert, Ann R. Falsey, Daniel S. Graciaa, Lindsey R. Baden, Sharon E. Frey, Jennifer A. Whitaker, Susan J. Little, Satoshi Kamidani, Emmanuel B. Walter, Richard M. Novak, Richard Rupp, Lisa A. Jackson, Chenchen Yu, Craig A. Magaret, Cindy Molitor, Bhavesh Borate, Sydney Busch, David Benkeser, Antonia Netzl, Derek J. Smith, Tara M. Babu, Angelica C. Kottkamp, Anne F. Luetkemeyer, Lilly C. Immergluck, Rachel M. Presti, Martín Bäcker, Patricia L. Winokur, Siham M. Mahgoub, Paul A. Goepfert, Dahlene N. Fusco, Robert L. Atmar, Christine M. Posavad, Jinjian Mu, Mat Makowski, Mamodikoe K. Makhene, Seema U. Nayak, Paul C. Roberts, Peter B. Gilbert and Dean Follmann ()
Additional contact information
Bo Zhang: Fred Hutchinson Cancer Center
Youyi Fong: Fred Hutchinson Cancer Center
Lauren Dang: National Institutes of Health
Jonathan Fintzi: National Institutes of Health
Shiyu Chen: Fred Hutchinson Cancer Center
Jing Wang: Frederick National Laboratory for Cancer Research
Nadine G. Rouphael: Emory University
Angela R. Branche: University of Rochester
David J. Diemert: George Washington University
Ann R. Falsey: University of Rochester
Daniel S. Graciaa: Emory University
Lindsey R. Baden: Harvard Medical School
Sharon E. Frey: Saint Louis University
Jennifer A. Whitaker: Baylor College of Medicine
Susan J. Little: University of California, San Diego
Satoshi Kamidani: Children’s Healthcare of Atlanta
Emmanuel B. Walter: Duke University School of Medicine
Richard M. Novak: University of Illinois at Chicago
Richard Rupp: University of Texas Medical Branch
Lisa A. Jackson: Kaiser Permanente Washington Health Research Institute
Chenchen Yu: Fred Hutchinson Cancer Center
Craig A. Magaret: Fred Hutchinson Cancer Center
Cindy Molitor: Fred Hutchinson Cancer Center
Bhavesh Borate: Fred Hutchinson Cancer Center
Sydney Busch: Emory University
David Benkeser: Emory University
Antonia Netzl: University of Cambridge
Derek J. Smith: University of Cambridge
Tara M. Babu: University of Washington
Angelica C. Kottkamp: New York University Grossman School of Medicine
Anne F. Luetkemeyer: University of California
Lilly C. Immergluck: Morehouse School of Medicine
Rachel M. Presti: Washington University School of Medicine
Martín Bäcker: University of Utah Schoole of Medicine
Patricia L. Winokur: University of Iowa College of Medicine
Siham M. Mahgoub: Howard University Hospital
Paul A. Goepfert: University of Alabama at Birmingham
Dahlene N. Fusco: Tulane University School of Medicine
Robert L. Atmar: Baylor College of Medicine
Christine M. Posavad: Fred Hutchinson Cancer Center
Jinjian Mu: The Emmes Company LLC
Mat Makowski: The Emmes Company LLC
Mamodikoe K. Makhene: National Institutes of Health
Seema U. Nayak: National Institutes of Health
Paul C. Roberts: National Institutes of Health
Peter B. Gilbert: Fred Hutchinson Cancer Center
Dean Follmann: National Institutes of Health

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Neutralizing antibody titer has been a surrogate endpoint for guiding COVID-19 vaccine approval and use, although the pandemic’s evolution and the introduction of variant-adapted vaccine boosters raise questions as to this surrogate’s contemporary performance. For 985 recipients of an mRNA second bivalent or monovalent booster containing various Spike inserts [Prototype (Ancestral), Beta, Delta, and/or Omicron BA.1 or BA.4/5] in the COVAIL trial (NCT05289037), titers against 5 strains were assessed as correlates of risk of symptomatic COVID-19 (“COVID-19”) and as correlates of relative (Pfizer-BioNTech Omicron vs. Prototype) booster protection against COVID-19 over 6 months of follow-up during the BA.2-BA.5 Omicron-dominant period. Consistently across the Moderna and Pfizer-BioNTech vaccine platforms and across all variant Spike inserts assessed, both peak and exposure-proximal (“predicted-at-exposure”) titers correlated with lower Omicron COVID-19 risk in individuals previously infected with SARS-CoV-2, albeit significantly less so in naïve individuals [e.g., exposure-proximal hazard ratio per 10-fold increase in BA.1 titer 0.74 (95% CI 0.59, 0.94) for naïve vs. 0.41 (95% CI 0.23, 0.64) for non-naïve; interaction p = 0.013]. Neutralizing antibody titer was a strong inverse correlate of Omicron COVID-19 in non-naïve individuals and a weaker correlate in naïve individuals, posing questions about how prior infection alters the neutralization correlate.

Date: 2025
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DOI: 10.1038/s41467-025-55931-w

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