Evaluation of Serum Antibodies as Correlates of Protection Against Norovirus Infection and Disease

BACKGROUND: Norovirus is a major cause of acute gastroenteritis. Several vaccines are in development. Identifying a reliable immunological correlate of protection (CoP) would aid vaccine development and evaluation; however, no strong CoP has been established to date. METHODS: We evaluated the relationships between pre-challenge GI.1 and GII.4 norovirus antibodies and clinical outcomes in two human vaccine-challenge studies. One study evaluated a monovalent intranasal GI.1 vaccine, and the other evaluated a bivalent intramuscular GI.1/GII.4 vaccine. We analyzed genotype-specific histo-blood group antigen (HBGA) blocking titers, serum IgA and IgG, and total antibody ELISA (Pan-Ig). We used Bayesian logistic regression models to assess relationships between antibody levels and protection against: PCR-confirmed infection (InfProt), vomiting or diarrhea any day post-challenge (VorDProt), and protocol-defined illness (PDIProt). We used Bayesian gamma-poisson models to assess relationships between antibody levels and a modified Vesikari scoring (MVS) scale for disease severity. RESULTS: Associations between antibody titers and protection were generally weak, and varied by genotype and vaccination status. GI.1 antibodies showed the strongest relationships, particularly among vaccinated participants, whereas naturally acquired GI.1 antibodies in unvaccinated individuals were weakly or not associated with protection. In contrast, GII.4 antibodies exhibited weak and inconsistent relationships among vaccinated participants, while unvaccinated participants showed only modest and more stable positive associations. CONCLUSIONS: Currently measured serum antibodies do not provide reliable and robust estimates of protection against norovirus clinical outcomes in all settings. Immune markers beyond serum antibody titers should be evaluated to identify more robust correlates of protection for norovirus.