Protective and pathogenic antibody responses from a primate <i>Shigella</i> outbreak inform vaccine design
There is currently no approved vaccine for <i>Shigella</i> spp., a leading cause of diarrhea that are increasingly resistant to antimicrobials. <i>Shigella</i> vaccine development is complicated in part by an incomplete understanding of the structural and molecular determinants of immunity. To address this, we isolated monoclonal antibodies (mAbs) against candidate <i>Shigella</i> vaccine antigens using samples from a <i>Shigella flexneri</i> outbreak in a non-human primate (NHP) research facility. We found that antibodies targeting the <i>Shigella</i> O-antigen (O-Ag) can undergo significant affinity maturation (>10%) to acquire broad cross-reactivity across <i>S. flexneri</i> serotypes. We also found that the virulence-associated type III secretion system (T3SS) proteins IpaD and IpaB elicit moderate T cell and robust antibody responses. T3SS antibodies either inhibit, or - surprisingly - enhance bacterial virulence <i>in vitro</i> and <i>in vivo</i> depending on their epitope specificity. These findings provide key insights into protective and deleterious immune responses against <i>Shigella</i> that directly inform vaccine immunogen design.
Authors
- Jennifer M. Hayes (ORCID: https://orcid.org/0000-0002-7473-1688)
- Nicholas L. Xerri (ORCID: https://orcid.org/0000-0001-7880-3987)
- Zackary K. Dietz (ORCID: https://orcid.org/0009-0003-9823-5392)
- Robert M. Gallant (ORCID: https://orcid.org/0000-0003-1741-5336)
- María Teresa Ochoa (ORCID: https://orcid.org/0000-0001-6550-5008)
- Stephen Baker (ORCID: https://orcid.org/0000-0003-1308-5755)
- Timothy A. Scott (ORCID: https://orcid.org/0000-0001-7042-8609)
- Devin Sok (ORCID: https://orcid.org/0000-0002-9354-1740)
- Ti Lu (ORCID: https://orcid.org/0000-0003-2706-3223)
- Wendy L. Picking (ORCID: https://orcid.org/0000-0001-7998-0643)
- Robert W. Kaminski (ORCID: https://orcid.org/0000-0002-4015-5694)
- Tyrone Williams
- Morgan S. A. Gilman (ORCID: https://orcid.org/0000-0001-6746-6284)
- Saverio Capuano (ORCID: https://orcid.org/0000-0003-2505-9124)
- Hayden R. Schmidt (ORCID: https://orcid.org/0000-0003-1886-6534)
- Andrew C. Kruse (ORCID: https://orcid.org/0000-0002-1467-1222)
- Faye A. Hartmann
- Eric Peterson (ORCID: https://orcid.org/0000-0002-5093-0631)
- Sophia Pulido
- Paul Savarino
Institutions
- Boston University (US)
- Biogen (United States) (US)
- International AIDS Vaccine Initiative (US)
- University of Wisconsin–Madison (US)
- Harvard University (US)
- Duke University (US)
- Missouri College (US)
- Global Health Corps (US)
- NIHR Imperial Biomedical Research Centre (GB)
- Boston VA Research Institute (US)
- Institute for American Values (US)
- National Centre for Infectious Diseases (SG)
- MRC Epidemiology Unit (GB)
- Imperial College London (GB)
- University of Missouri (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2025-12-19
- DOI
- https://doi.org/10.64898/2025.12.16.694763
- Primary Topic
- Escherichia coli research studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00