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Sci. Transl. Med., Mar 05 2025, 17 (788) | https://doi.org/10.1126/scitranslmed.ads8214
Broadly neutralizing antibodies targeting pandemic GII.4 variants or seven GII genotypes of human norovirus
Juyeon Park 1 2 †, Lisa C Lindesmith 3 †, Adam S Olia 4 †, Veronica P Costantini 5, Paul D Brewer-Jensen 3, Michael L Mallory 3, Cynthia E Kelley 6, Ed Satterwhite 2, Victoria Longo 2, Yaroslav Tsybovsky 7, Tyler Stephens 7, Jeffrey Marchioni 8, Christina A Martins 2, Yimin Huang 1, Ridhi Chaudhary 4, Mark Zweigart 3, Samantha R May 3, Yaoska Reyes 3, Becca Flitter 9, Jan Vinjé 5, Sean N Tucker 9, Gregory C Ippolito 1 10, Jason J Lavinder 1 2, Joost Snijder 6, Peter D Kwong 4, George Georgiou 1 2 8 10 *, Ralph S Baric 3 *
1Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA.
2Department of Chemical Engineering, University of Texas at Austin, Austin, TX 78712, USA.
3Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27599, USA.
4Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
5Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30329, USA.
6Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute of Pharmaceutical Sciences, Utrecht University, 3584 CH, Utrecht, Netherlands.
7Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
8Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA.
9Vaxart Inc., South San Francisco, CA 94080, USA.
10Department of Oncology, University of Texas at Austin, Austin, TX 78712, USA.
2Department of Chemical Engineering, University of Texas at Austin, Austin, TX 78712, USA.
3Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27599, USA.
4Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
5Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30329, USA.
6Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute of Pharmaceutical Sciences, Utrecht University, 3584 CH, Utrecht, Netherlands.
7Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
8Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA.
9Vaxart Inc., South San Francisco, CA 94080, USA.
10Department of Oncology, University of Texas at Austin, Austin, TX 78712, USA.
†These authors contributed equally
*Corresponding authors: correspondence to George Georgiou or Ralph S Baric
*Corresponding authors: correspondence to George Georgiou or Ralph S Baric
Abstract
Human norovirus causes more than 700 million illnesses annually. Extensive genetic diversity and a paucity of information on conserved neutralizing epitopes pose major obstacles to the design of broadly protective norovirus immunogens. Here, we used high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS)-driven proteomics to quantitatively characterize the circulating serum IgG repertoire before and after immunization with an experimental monovalent norovirus GII.4 VP1 capsid-encoding adenoviral vaccine. Two participants were specifically selected on the basis of the breadth of serum neutralization responses either across GII.4 variants (participant A) or across GII genotypes (participant B). In participant A, vaccination back-boosted highly abundant serum antibody clonotypes targeting epitopes conserved among rapidly evolving GII.4 variants spanning from a strain identified in 1987 to a strain identified in 2019. In participant B, we identified a recall response consisting of broadly neutralizing monoclonal antibodies with remarkable cross-GII ligand-binding blockade (blocking ≥ seven GII genotypes) and virus neutralization breadth. The cocrystal structure of one of these antibodies, VX22, in complex with the VP1 capsid protruding (P) domain revealed a highly conserved epitope (residues 479 to 484 and 509 to 513) within two lateral loops of the P1 subdomain. Antibody evolutionary trajectory analysis further revealed that VX22 had originally evolved from an early heterologous infection, likely by a GII.12 strain. Together, our study demonstrates that norovirus human monoclonal antibodies with broad GII.4 potency and cross-GII breadth can be boosted in serum after immunization with an adenoviral vector-based vaccine, findings that may guide the design of immunogens for broadly protective norovirus vaccines.
ONLINE COVER: Neutralizing Norovirus. The cover image shows norovirus virions by transmission electron microscopy. Most individuals infected with norovirus recover after an acute bout of gastroenteritis. However, young children and older adults are at risk of more severe disease, highlighting the need for a vaccine for these populations. In two articles, Flitter et al. and Park et al. report immunological readouts for an orally-delivered, adenoviral-vectored norovirus vaccine platform. Flitter et al. reported that vaccination against the genogroup I, genotype 1 (GI.1) variant of norovirus elicited systemic and mucosal immunity in older adults. Park et al. demonstrated that a vaccine based on the genogroup II, genotype 4 (GII.4) variant of norovirus could elicit broadly neutralizing antibodies in two younger individuals. Together, these data highlight that norovirus immunity can be elicited by oral vaccination in older adults and that these vaccines may be capable of eliciting broad norovirus immunity.
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- Research article
- 2025년 03월 (BRIC 등록일 2025-03-07)
- 국외 연구진
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