IgA is necessary and sufficient to protect against norovirus infection 2258197

Abstract Introduction Human norovirus (HNV) causes up to 700 million infections and 200,000 deaths each year, primarily affecting young children in low-resource settings. Despite this significant public health and economic impact, no licensed vaccines or anti-viral therapies exist for HNV. Several vaccine candidates are currently in advanced clinical trials, including virus-like particle (VLP), adenoviral (Ad5), and mRNA lipid nanoparticle (LNP) based vaccines. While these candidates show promise, none have demonstrated complete or long-term protection. The mechanisms underlying protective immunity to HNV remain poorly defined, posing a major barrier to rational vaccine design. Technical limitations make it challenging to directly interrogate mechanisms of HNV immunity, as there are no scalable cell culture, reverse genetics, or small animal models. Murine norovirus (MNV) is a genetically tractable model for HNV that shares many fundamental properties including minimal intestinal pathology, rare epithelial cell tropism, and fecal-oral transmission. Methods We used a panel of genetically and pharmacologically modified mice to investigate the correlates and cellular determinants of protection to MNV infection. Results T cell—dependent IgA is necessary to control MNV replication in the small intestine, whereas CD8+ T cells are dispensable. IgA plasma cells mediate protection from re-infection and dimeric IgA, but not monomeric, is sufficient to confer complete protection against MNV infection. In contrast, despite generating a robust systemic IgG response, systemic vaccination with the viral capsid protein (VP1) fails to protect mice, mirroring the recent failure of a systemic VLP vaccine in infants. Conclusion Our work shows that mucosal IgA is central to controlling norovirus infection in a murine model and provides important insights for rational vaccine design and HNV immunotherapeutics. Funding Source n/a Topic Categories Viral Immunology (VIR)