Mucosal and Systemic Antibody Responses After Boosting With a Bivalent Messenger RNA Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine

Robert L Atmar¹, Kirsten E Lyke², Christine M Posavad^{3

4}, Meagan E Deming², Rebecca C Brady⁵, David Dobrzynski⁶, Srilatha Edupuganti⁷, Mark J Mulligan⁸, Richard E Rupp⁹, Christina A Rostad¹⁰, Lisa A Jackson¹¹, Judith M Martin¹², Mallory C Shriver², Kumaravel Rajakumar¹², Rhea N Coler^{13

14}, Hana M El Sahly¹, Angelica C Kottkamp⁸, Angela R Branche⁶, Robert W Frenck⁵, Christine Johnston^{3

4

15}, Tara M Babu¹⁵, Martín Bäcker¹⁶, Janet I Archer¹⁷, Sonja Crandon¹⁸, Aya Nakamura¹⁸, Seema U Nayak¹⁸, Daniel Szydlo¹⁹, Clara P Dominguez Islas⁴, Elizabeth R Brown⁴, Sarah E O'Connell²⁰, David C Montefiori^{21

22}, Amanda Eaton²², Kathleen M Neuzil², David S Stephens⁷, John H Beigel¹⁸, Marcela Pasetti², Paul C Roberts¹⁸

Affiliations

¹ Departments of Medicine and Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA.
² Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA.
³ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.
⁴ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
⁵ Cincinnati Children's Hospital Medical Center, Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
⁶ Division of Infectious Diseases, Department of Medicine, University of Rochester, Rochester, New York, USA.
⁷ Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
⁸ New York University Langone Vaccine Center and Division of Infectious Diseases and Immunology, Department of Medicine, New York University Grossman School of Medicine, New York, New York, USA.
⁹ Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, Texas, USA.
¹⁰ Department of Pediatrics and Center for Childhood Infections and Vaccines, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
¹¹ Kaiser Permanente Washington Health Research Institute, Seattle, Washington, USA.
¹² Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
¹³ Seattle Children's Research Institute, Seattle, Washington, USA.
¹⁴ Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA.
¹⁵ Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.
¹⁶ New York University Langone Hospital-Long Island Vaccine Center Research Clinic and Division of Infectious Disease, Department of Medicine, New York University Grossman Long Island School of Medicine, Mineola, New York, USA.
¹⁷ FHI, Durham, North Carolina, USA.
¹⁸ Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
¹⁹ Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
²⁰ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
²¹ Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
²² Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.

PMID: 40298376
DOI: 10.1093/infdis/jiaf176

Mucosal and Systemic Antibody Responses After Boosting With a Bivalent Messenger RNA Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine

Robert L Atmar et al. J Infect Dis. 2025.

. 2025 Apr 29:jiaf176.

doi: 10.1093/infdis/jiaf176. Online ahead of print.

Authors

Affiliations

¹ Departments of Medicine and Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA.
² Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA.
³ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.
⁴ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
⁵ Cincinnati Children's Hospital Medical Center, Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
⁶ Division of Infectious Diseases, Department of Medicine, University of Rochester, Rochester, New York, USA.
⁷ Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
⁸ New York University Langone Vaccine Center and Division of Infectious Diseases and Immunology, Department of Medicine, New York University Grossman School of Medicine, New York, New York, USA.
⁹ Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, Texas, USA.
¹⁰ Department of Pediatrics and Center for Childhood Infections and Vaccines, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
¹¹ Kaiser Permanente Washington Health Research Institute, Seattle, Washington, USA.
¹² Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
¹³ Seattle Children's Research Institute, Seattle, Washington, USA.
¹⁴ Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA.
¹⁵ Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.
¹⁶ New York University Langone Hospital-Long Island Vaccine Center Research Clinic and Division of Infectious Disease, Department of Medicine, New York University Grossman Long Island School of Medicine, Mineola, New York, USA.
¹⁷ FHI, Durham, North Carolina, USA.
¹⁸ Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
¹⁹ Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
²⁰ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
²¹ Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
²² Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.

PMID: 40298376
DOI: 10.1093/infdis/jiaf176

Abstract

Background: Mucosal immunity plays a critical role in preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and replication. Understanding the capacity of coronavirus disease 2019 (COVID-19) vaccines to elicit both mucosal and systemic antibodies could help optimize vaccination strategies.

Methods: We conducted an open-label, phase 1/2 adaptive-design clinical trial to evaluate the safety and immunogenicity of COVID-19 immunizations. Healthy adults received 2 priming doses of mRNA-1273, a booster dose of mRNA-1273, and a second booster of bivalent (WA-1 and BA.4/BA.5) mRNA-1273.222. Adverse event data were collected. Serum and mucosal immunity were evaluated.

Results: One hundred six persons were enrolled. Thirty received all 4 study-related vaccine doses. All vaccines were well tolerated, with injection site pain, malaise, myalgias, and headache being the most frequently reported symptoms. Among those who received a second booster, 24 of 30 (80%) had serological evidence of SARS-CoV-2 infection. Following the second booster, increases in geometric mean binding and pseudovirus neutralization antibody titers to the ancestral strain and BA.1 and BA.5 variants were observed. Increases in mucosal immunoglobulin G and immunoglobulin A (IgA) antibodies in nasal and salivary samples were observed in both previously infected and infection-naive participants, although prior infection markedly boosted virus-specific mucosal IgA responses.

Conclusions: The mRNA-1273.222 booster vaccine was safe and immunogenic and induced mucosal antibody responses in previously infected and infection-naive persons.

Clinical trials registration: NCT04889209.

Keywords: COVID-19; SARS-CoV-2; booster; immunogenicity; vaccine.

Published by Oxford University Press on behalf of Infectious Diseases Society of America 2025.

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Conflict of interest statement

Potential conflicts of interest. K. E. L. receives grant awards from Pfizer Inc outside the current work. L. A. J.'s institution receives grant funding from NIH, the Centers for Disease Control and Prevention (CDC), and Pfizer for vaccine-related assessments, including those of COVID-19 vaccines. A. R. B. has grant funding from Pfizer, Janssen, Merck, and Cyanvac for non-COVID-19–related work and serves as a consultant for GSK and Janssen. C. A. R.'s institution has received funds to conduct clinical research from the NIH, CDC, BioFire Inc, Genentech, GSK, Janssen, MedImmune, Merck, Micron, Moderna, Novavax, PaxVax, Pfizer, Regeneron, and Sanofi Pasteur. She is coinventor of patented respiratory syncytial virus vaccine technology, which has been licensed to Meissa Vaccines, Inc. J. M. M. has served as a consultant for Merck, Sharp and Dohme for non-COVID-19–related work. C. J. receives funding from the Gates Foundation, NIH, and CDC; consults for Gilead, AbbVie, Assembly Biosciences, and GSK; and receives royalties from UpToDate. T. M. B. served on an advisory board for Sanofi. M. J. M. has laboratory research and clinical trials contracts for vaccines or monoclonal antibodies versus SARS-CoV-2 with Lilly, Pfizer (exclusive of the current work), and Sanofi; and personal fees for scientific advisory board service from Merck, Meissa Vaccines, and Pfizer. R. N. C. has funding from Cyanvac and HDT Bio to conduct COVID-19–related clinical immunology research. R. C. B. receives funding for vaccine trials from Path Nipah and Pfizer. R. W. F. receives funding to perform clinical trials from Pfizer, Moderna, AstraZeneca, and Emergent Health, and serves on advisory boards for Johnson & Johnson, Merck, Sanofi Pasteur, and Seqirus. S. E. receives funding to her institution from Sanofi Pasteur for a non-COVID-19 vaccine study. K. M. N. holds a grant from Pfizer, without salary support, for a COVID-19 vaccine study, and salary support from the NIH for work on multiple COVID-19 vaccine trials. D. S. S. is supported by grant awards from NIH/NIAID. P. C. R. and J. H. B. report a pending US patent application (number 63/025,918) entitled “Coronavirus RNA vaccines and methods of use.” D. C. M. receives funding from NIH and Moderna for laboratory studies of COVID-19 vaccine antibody responses. We would like to acknowledge Moderna, Inc, Johnson & Johnson/Janssen, and Pfizer/BioNTech Pharmaceuticals for their collaboration, scientific input, and sharing of documents needed to implement this trial. All products were acquired through the government procurement process. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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Mucosal and Systemic Antibody Responses After Boosting With a Bivalent Messenger RNA Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine

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Mucosal and Systemic Antibody Responses After Boosting With a Bivalent Messenger RNA Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine

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