Serum IgA proteomics reveals clonal composition and neutralization of dimeric and monomeric IgA repertoires against human norovirus
Protection against human norovirus correlates with attachment ligand blockade antibody titers, fecal IgA titers, and serum IgA titers. IgA responses in serum comprise approximately 80 to 95% of monomeric IgA (mIgA) and 5 to 20% of dimeric IgA (dIgA). Using serum LC-MS/MS proteomics, we established clonal relationships between circulating IgG and IgA, as well as between dIgA and mIgA. We observed a modest degree of clonal overlap between circulating IgG and IgA at steady state and found that more than 80% of antigen-specific mIgA was also detectable as dIgA. We biochemically characterized neutralizing epitopes on norovirus GII.4 virus-like particles (VLPs) targeted by serum IgA clonotypes and demonstrated that dIgA markedly enhances neutralization potency relative to mIgA and IgG in an epitope-specific manner. Cryoelectron microscopy and cryoelectron tomography revealed that whether IgA dimerization enhances viral neutralization depends on epitope accessibility on the VLP and antibody binding orientation. Together, these findings provide molecular-level resolution of the serum IgA response and define the structural basis by which dIgA enhances neutralization potency in an epitope-specific manner.
Authors
- Michael L. Mallory (ORCID: https://orcid.org/0000-0003-0768-572X)
- Becca A. Flitter (ORCID: https://orcid.org/0000-0002-3478-8751)
- Ralph Steven Baric (ORCID: https://orcid.org/0000-0001-6827-8701)
- Sean N. Tucker (ORCID: https://orcid.org/0000-0002-6233-225X)
- Daechan Park (ORCID: https://orcid.org/0000-0003-4991-5247)
- Ted M. Ross (ORCID: https://orcid.org/0000-0003-1947-7469)
- Whitney Pickens (ORCID: https://orcid.org/0000-0001-6100-8231)
- Julianna Han (ORCID: https://orcid.org/0000-0002-3402-2609)
- Zunlong Ke (ORCID: https://orcid.org/0000-0002-8408-850X)
- Jason J. Lavinder (ORCID: https://orcid.org/0000-0001-6044-1332)
- Jan Vinjé (ORCID: https://orcid.org/0000-0002-1530-3675)
- Lisa C. Lindesmith (ORCID: https://orcid.org/0000-0001-9567-0522)
- Paul D. Brewer-Jensen (ORCID: https://orcid.org/0000-0003-0965-8477)
- Verónica Costantini (ORCID: https://orcid.org/0000-0002-1532-4345)
- Andrew B. Ward (ORCID: https://orcid.org/0000-0001-7153-3769)
- Yaoska I Reyes (ORCID: https://orcid.org/0000-0001-9467-2438)
- Gyunghee Jo (ORCID: https://orcid.org/0000-0001-7221-2561)
- Mark R. Zweigart (ORCID: https://orcid.org/0000-0001-5765-3203)
- Ed Satterwhite
- Jiwon Lee (ORCID: https://orcid.org/0000-0001-7835-3621)
- Juyeon Park (ORCID: https://orcid.org/0000-0001-9549-4645)
- Daeun Kim (ORCID: https://orcid.org/0000-0002-5301-1286)
- Dae Sung Kim (ORCID: https://orcid.org/0000-0002-3191-437X)
- Rocio Zapata-Bustos (ORCID: https://orcid.org/0000-0003-0876-4956)
- Alexandra Beaver
- George Georgiou
- Jeffrey Marchioni
- Victoria Longo (ORCID: https://orcid.org/0009-0000-6892-4136)
- Chang Liu
Institutions
- Dartmouth College (US)
- University of North Carolina at Chapel Hill (US)
- Scripps Research Institute (US)
- International Vaccine Institute (KR)
- Seoul National University (KR)
- University of Georgia (US)
- Cleveland Clinic Lerner College of Medicine (US)
- Cleveland Clinic Florida (US)
- Advanced Institute of Convergence Technology (KR)
- Vaxart (United States) (US)
- Ajou University (KR)
- The University of Texas at Austin (US)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2026-08-17
- DOI
- https://doi.org/10.1073/pnas.2603905123
- Primary Topic
- Viral gastroenteritis research and epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Bill and Melinda Gates Foundation
- Welch Foundation
- Cancer Prevention and Research Institute of Texas
- National Research Foundation of Korea
- National Institutes of Health