Targeting the Gut: Oral Norovirus Vaccine Generates Protective Mucosal Immunity and Reduces Viral Shedding Following GI.1 Challenge

Becca Flitter, Vaxart

Authors: Becca A. Flitter 1, Joshua Gillard 2, Susan N. Greco 1, Maria D. Apkarian 1, Nick P. D’Amato 1, Lam Quynh Nguyen 1, Elena D. Neuhaus 1, Darreann Carmela M. Hailey 1, Marcela F. Pasetti 3, Mallory Shriver 3, Christina Quigley 4, Robert W. Frenck, Jr. 4, Lisa C. Lindesmith 5, Ralph S. Baric 5, Lee-Jen Wei 6, Sean N. Tucker 1, James F. Cummings 1 Affiliations: 1. Vaxart, Inc.; South San Francisco, CA 94080, USA 2. Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine; Stanford, CA 94305, USA 3. Center for Vaccine Development, University of Maryland Baltimore School of Medicine; Baltimore, MD 21201, USA 4. Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center; Cincinnati, OH, 45229, USA 5. Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27599, USA 6. Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA 02115, USA

Vaccines and immunity

There are no licensed vaccines for norovirus, a highly transmissible pathogen and leading cause of viral gastroenteritis worldwide. We conducted a phase 2b randomized, placebo-controlled vaccination and challenge study, to assess the safety, immunogenicity, and efficacy of the oral norovirus vaccine VXA-G1.1-NN. One month after receiving oral administration of VXA-G1.1-NN or placebo, participants were challenged with 1x106 genomic copies of GI.1 norovirus, and monitored for acute gastroenteritis (AGE) using a modified Vesikari Score. Norovirus infection and viral burden were quantified in stool and emesis samples by qPCR. Vaccine-induced immune correlates were identified using machine learning.VXA-G1.1-NN immunization was safe, well-tolerated, and elicited both systemic and mucosal immunogenicity. Significant increases in GI.1 VP1-specific serum IgA, IgG, and functional blocking antibody titers (NBAA) were observed in the VXA-G1.1-NN vaccinated cohort, as well as mucosal IgA in nasal lining fluid, saliva, and fecal samples. Upon challenge, VXA-G1.1-NN significantly reduced norovirus infection rates compared to placebo (57.8% vs. 81.5%, p=0.003), lowered viral shedding (p=0.0009), and increased the proportion of individuals protected from both illness and infection (p=0.012). Vaccination also reduced the incidence of Norovirus AGE compared to placebo (44.7% vs. 56.9%), though this difference did not reach statistical significance (p=0.178). Machine learning analyses of vaccine-stimulated immune responses identified NBAA and fecal IgA as robust immune correlates of protection against infection. These results demonstrate the potential of VXA-G1.1-NN as a safe and an effective mucosal norovirus vaccine that reduces infection, viral shedding, and provide insights into immunological mechanisms underlying vaccine-mediated protection.