An oral norovirus vaccine generates mucosal immunity and reduces viral shedding in a phase 2 placebo-controlled challenge study
Becca A. Flitter, Joshua Gillard, Susan N. Greco, Maria Apkarian, Nick P. D’Amato, Lam Nguyen, Elena D. Neuhaus, Darreann Carmela M. Hailey, Marcela F. Pasetti, Mallory Shriver, Christina Quigley, Robert W. Frenck, Lisa C. Lindesmith, Ralph S. Baric, Lee‐Jen Wei, Sean N. Tucker, James F. Cummings
Abstract
There are currently no licensed vaccines for norovirus, a leading cause of epidemic and endemic gastroenteritis worldwide. Clinical advancement of promising vaccine candidates from phase 2 studies to phase 3 field trials has been hampered by the lack of robust immunological correlates of protection. Here, we conducted a phase 2b randomized, placebo-controlled vaccination and challenge study to assess the safety, efficacy, immunogenicity, and correlates of protection of VXA-G1.1-NN, an oral tablet norovirus vaccine. VXA-G1.1-NN was safe and well tolerated, conferred protection against norovirus GI.1 challenge, and reduced viral shedding in stool and emesis. Norovirus VP1-specific serum immunoglobulin A (IgA), IgG, and functional blocking antibody titers increased substantially after oral vaccination. Moreover, oral immunization stimulated VP1-specific IgA antibodies in nasal lining fluid, saliva, and fecal samples. Serum and mucosal antibody responses 7 days after vaccination were correlated with the induction of antibody-secreting, α4β7 + mucosal-homing B cells. Machine learning analyses of vaccine-stimulated immune components identified serum functional blocking antibody and fecal IgA as robust correlates of protection. These results demonstrate the potential of VXA-G1.1-NN as a safe and effective oral norovirus vaccine and reveal critical immunological features underpinning vaccine efficacy.