Neutralizing antibody responses to GII.4 vaccination from early childhood through old age: harnessing the power of immune imprinting to drive breadth.

Lisa Lindesmith, University of North Carolina-Chapel Hill

Lisa C. Lindesmith1, Mark R. Zweigart1, Paul D. Brewer-Jensen, Yaoska I. Reyes, Cameron Nguyen1, Michael L. Mallory1, Samantha R. May1, Lily M. Parsons1, Astrid Borkowski2, Michael E. Abram, and Ralph S. Baric1 1Department of Epidemiology, CB7435, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA 2 Clinical Development, HilleVax GmbH, Glattpark-Zurich, Switzerland 3 Clinical Development, HilleVax, Inc., Boston, MA, USA

Vaccines and immunity

Globally, the burden of severe norovirus disease is primarily among young children and older aged adults. Norovirus neutralizing antibodies (nAb), a correlation of protection from severe disease, are biased by immune imprinting from previous exposures. The factors that determine when an imprint is established are unknown. Likewise, how imprinting effects vaccine induced nAb responses in populations with varying imprinted patterns is also unknown. Here, utilizing a surrogate neutralization assay and sera collected during three clinical trials evaluating the immunogenicity of a bivalent (GI.1/GII.4) virus-like particle norovirus vaccine candidate, we compared nAb responses to the GII.4 immunogen and divergent GII.4 variants in subjects aged 5 months-4 years and 60-85 years of age. In infants, both infection and vaccination yielded exposure-specific nAb. In contrast to non-vaccinated infants, vaccinated young children nAb profiles broadened post first symptomatic GII.4 infection. Furthermore, in children ≥2 years, vaccination boosted GII.4 broadly nAb (bnAb). Cross-neutralization patterns indicated that bnAb are derived from previous exposures, suggesting that the nAb imprint had been established and subsequently provided the underlying memory that supported boosting of bnAb post-vaccination. Similarly, in older adults with an nAb imprint already set, vaccination boosted GII.4 bnAb potent across a divergent array of GII.4 variants. NAb cross-reactivity patterns before and after vaccination visualized by antigenic cartography defined antigenic clusters within bnAb responses predicting potential immunogen combinations that could improve vaccine breadth. Multiple exposures prime GII.4 bnAb in young children and older adults, supporting further norovirus vaccine development in populations most at risk of severe norovirus illness.