Impact of prior SARS-CoV-2 acquisition on binding and neutralizing antibody responses following COVID-19 vaccination: A cross-protocol analysis of individual-level data from six phase 3 clinical trials

Aaron Hudson¹, Scott Borgetti², Anne-Marie Rick³, Matthew B Laurens⁴, Samuel T Robinson⁵, Cynthia L Gay⁶, Lindsey R Baden⁷, Paul A Goepfert⁸, Nadine Rouphael⁹, Hana M El Sahly¹⁰, Glenda E Gray¹¹, Beatriz Grinsztejn¹², Magdalena E Sobieszczyk¹³, Ann R Falsey¹⁴, Yunda Huang⁵, Holly Janes¹⁵, Dean Follmann¹⁶, Richard A Koup¹⁷, Frances Priddy¹⁸, Jenny Hendriks¹⁹, Kathryn Shoemaker²⁰, Lisa M Dunkle²¹, Guy de Bruyn²², Louis Devlin²², Kathleen M Neuzil²³, James G Kublin⁵, Lawrence Corey⁵, Stephen R Walsh⁷, Karen L Kotloff²³, Peter B Gilbert⁵

Affiliations

¹ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Electronic address: ahudson@fredhutch.org.
² Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
³ Department of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
⁴ Department of Pediatrics, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA.
⁵ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
⁶ University of North Carolina School of Medicine, Chapel Hill, NC, USA.
⁷ Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁸ University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, USA.
⁹ Hope Clinic, Emory University, Atlanta, GA, USA.
¹⁰ Department of Molecular Virology and Microbiology, Infectious Diseases Section, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
¹¹ Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South African Medical Research Council, Cape Town, South Africa.
¹² Evandro Chagas National Institute of Infectious Diseases-Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
¹³ Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
¹⁴ Division of Infectious Diseases, Department of Medicine, University of Rochester, NY, USA.
¹⁵ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Bioinformatics and Epidemiology Program, Seattle, WA, USA.
¹⁶ Biostatistics Research Branch, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA.
¹⁷ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
¹⁸ Moderna, Cambridge, MA, USA.
¹⁹ Janssen Vaccines & Prevention BV, Leiden, Netherlands.
²⁰ Biometrics, Vaccines & Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
²¹ Novavax, Gaithersburg, MD, USA.
²² Sanofi Pasteur, Swiftwater, PA, USA.
²³ Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA.

PMID: 41730823
DOI: 10.1016/j.vaccine.2026.128380

Free article

Impact of prior SARS-CoV-2 acquisition on binding and neutralizing antibody responses following COVID-19 vaccination: A cross-protocol analysis of individual-level data from six phase 3 clinical trials

Aaron Hudson et al. Vaccine. 2026.

Free article

. 2026 Feb 22:77:128380.

doi: 10.1016/j.vaccine.2026.128380. Online ahead of print.

Authors

Affiliations

¹ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Electronic address: ahudson@fredhutch.org.
² Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
³ Department of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
⁴ Department of Pediatrics, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA.
⁵ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
⁶ University of North Carolina School of Medicine, Chapel Hill, NC, USA.
⁷ Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁸ University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, USA.
⁹ Hope Clinic, Emory University, Atlanta, GA, USA.
¹⁰ Department of Molecular Virology and Microbiology, Infectious Diseases Section, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
¹¹ Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South African Medical Research Council, Cape Town, South Africa.
¹² Evandro Chagas National Institute of Infectious Diseases-Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
¹³ Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
¹⁴ Division of Infectious Diseases, Department of Medicine, University of Rochester, NY, USA.
¹⁵ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Bioinformatics and Epidemiology Program, Seattle, WA, USA.
¹⁶ Biostatistics Research Branch, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA.
¹⁷ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
¹⁸ Moderna, Cambridge, MA, USA.
¹⁹ Janssen Vaccines & Prevention BV, Leiden, Netherlands.
²⁰ Biometrics, Vaccines & Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
²¹ Novavax, Gaithersburg, MD, USA.
²² Sanofi Pasteur, Swiftwater, PA, USA.
²³ Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA.

PMID: 41730823
DOI: 10.1016/j.vaccine.2026.128380

Abstract

Background: The COVID-19 Prevention Network (CoVPN) co-conducted six COVID-19 phase 3 vaccine efficacy (VE) trials that featured harmonized immunogenicity analyses using validated antibody assays. These trials enabled a uniquely comprehensive characterization of immunogenicity produced by different vaccine platforms and regimens in individuals with and without prior SARS-CoV-2 acquisition.

Methods: Comparisons of serum binding antibody concentration and serum neutralization antibody ID50 titers were performed across three strata: vaccine immunity (vaccination in SARS-CoV-2-naïve individuals), natural immunity (placebo with prior SARS-CoV-2 acquisition), and hybrid immunity (vaccination after prior SARS-CoV-2 acquisition). We compared immunogenicity across immunity strata for each trial and each dose, adjusting for age, sex assigned at birth, and body mass index. Antibody levels were also examined in relation to VE.

Results: Antibody levels in response to a single vaccine dose varied across trials and generally increased most substantially after a second dose in naïve participants. Fold rise in antibody levels after a single dose were more pronounced in participants with hybrid immunity: a single dose of any of the tested vaccine yielded responses comparable to or exceeding the post-dose-two (peak) response of any two-dose vaccine in naïve participants. Population-level antibody levels demonstrated high concordance with VE across trials and immunity strata.

Conclusions: In SARS-CoV-2-naïve individuals, a two-dose vaccine regimen is needed to provide antibody levels correlated with protection against disease caused by the cognate virus strain. In contrast, in individuals with prior SARS-CoV-2 acquisition, a single dose of any of the tested vaccines/platforms (mRNA/protein/vector) provides comparably high antibody levels.

Keywords: (3−10): COVID-19; Antibody; Correlate of protection; Efficacy; Hybrid immunity; Immunity; Natural immunity; SARS-CoV-2; Vaccination.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Anne-Marie Rick reports a relationship with National Institute of Allergy and Infectious Diseases that includes: funding grants. Anne-Marie Rick reports a relationship with I4kids that includes: funding grants. Anne-Marie Rick reports a relationship with Society to Improve Diagnosis in Medicine that includes: funding grants. Anne-Marie Rick reports a relationship with Beckwith Clinical Innovation Award that includes: funding grants. Anne-Marie Rick reports a relationship with CTSI COVID-19 Pilot Award that includes: funding grants. Anne-Marie Rick reports a relationship with Pfizer that includes: consulting or advisory. Anne-Marie Rick reports a relationship with IDweek that includes: travel reimbursement. Anne-Marie Rick reports a relationship with Human Milk Science Institute and Biobank that includes: board membership. Lindsey R. Baden reports a relationship with National Institute of Allergy and Infectious Diseases that includes: funding grants. Lindsey R. Baden reports a relationship with Ragon Institute of Mass General MIT and Harvard that includes: funding grants. Lindsey R. Baden reports a relationship with Bill & Melinda Gates Foundation that includes: funding grants. Lindsey R. Baden reports a relationship with Wellcome Trust that includes: funding grants. Hana M. El Sahly reports a relationship with Gilead Sciences Inc. that includes: funding grants. Hana M. El Sahly reports a relationship with Janssen Global Services LLC that includes: funding grants. Hana M. El Sahly reports a relationship with Merck & Co Inc. that includes: funding grants. Hana M. El Sahly reports a relationship with Sanofi Pasteur Inc. that includes: funding grants. Ann R. Falsey reports a relationship with Biofire Diagnostics Inc. that includes: funding grants. Ann R. Falsey reports a relationship with Janssen Biotech Inc. that includes: funding grants. Ann R. Falsey reports a relationship with Merck & Co Inc. that includes: funding grants. Ann R. Falsey reports a relationship with Pfizer Inc. that includes: funding grants. Ann R. Falsey reports a relationship with Novavax Inc. that includes: consulting or advisory. Frances Priddy reports a relationship with Moderna Inc. that includes: employment and equity or stocks. Jenny Hendriks reports a relationship with Janssen Vaccines and Prevention BV that includes: employment and equity or stocks. Kathryn Shoemaker reports a relationship with AstraZeneca that includes: employment and equity or stocks. Lisa M. Dunkle reports a relationship with Novavax Inc. that includes: employment and equity or stocks. Guy de Bruyn reports a relationship with Sanofi Pasteur Inc. that includes: employment and equity or stocks. Louis Devlin reports a relationship with Sanofi Pasteur Inc. that includes: employment and equity or stocks. Kathleen M. Neuzil reports a relationship with Pfizer Inc. that includes: funding grants. Peter B. Gilbert reports a relationship with Sanofi Pasteur Inc. that includes: consulting or advisory. Guy de Bruyn has patent pending to Sanofi and GSK. Matthew B. Laurens has conducted clinical trials evaluating COVID vaccines funded by NIH. Cynthia L. Gay has conducted clinical trials of COVID vaccines funded by NIH, Moderna, and Novavax. Lindsey R. Baden is a Deputy Editor at the New England Journal of Medicine, and is involved in HIV and COVID vaccine clinical trials conducted in collaboration with the NIH, HIV Vaccine Trials Network (HVTN), COVID Vaccine Prevention Network (CoVPN), International AIDS Vaccine Initiative (IAVI), Crucell/Janssen, Moderna, Military HIV Research Program (MHRP), Gates Foundation, and the Ragon Institute. Stephen R. Walsh has conducted clinical trials funded by Janssen Vaccines, Moderna, Pfizer, VIR Biotechnology, Worcester HIV Vaccine, and Sanofi Pasteur, and has participated on Independent Data Monitoring Committees for Janssen Vaccines and BioNTech; SRW's spouse is an employee of Regeneron Pharmaceuticals and may hold stock and/or stock options. Karen L. Kotloff has conducted clinical trials evaluating COVID vaccines funded by NIH, CDC, and Novavax. Peter B. Gilbert has participated on Sanofi Pasteur advisory committees with partial salary support and on Moderna advisory committees without payment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Impact of prior SARS-CoV-2 acquisition on binding and neutralizing antibody responses following COVID-19 vaccination: A cross-protocol analysis of individual-level data from six phase 3 clinical trials

Affiliations

Impact of prior SARS-CoV-2 acquisition on binding and neutralizing antibody responses following COVID-19 vaccination: A cross-protocol analysis of individual-level data from six phase 3 clinical trials

Authors

Affiliations

Abstract

Conflict of interest statement

LinkOut - more resources

Full Text Sources

Miscellaneous