Norovirus immunobiology and vaccine design Public Deposited

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Last Modified
  • March 21, 2019
Creator
  • LoBue, Anna Deirdre
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Noroviruses are a genus of 40+ diverse positive polarity RNA viruses that cause approximately 23 million cases of gastroenteritis annually in the United States alone. The lack of a cell culture system or small animal model in which to study these human pathogens has hindered development of norovirus vaccines since their discovery in 1972. Because noroviruses have a very low infectious dose and high transmissibility, vaccines would be beneficial for employees and patrons of institutionalized settings such as hospitals, nursing homes, and schools, where outbreaks frequently occur. To begin to unravel how norovirus exposure affects the adaptive immune response, we utilized Venezuelan equine encephalitis virus replicons as immune adjuvants and delivery vectors for norovirus antigens to demonstrate induction of B cell and T cell responses in protective immunity to noroviruses in mice. Norovirus-like particle (VLP) vaccination induces robust IgG and IgA responses in serum, feces, and tissues that can block norovirus binding to ABH histo-blood group antigen receptors in a strain-specific manner but have little cross-reactivity to additional norovirus strains. CD4+ T cells are also activated following vaccination to produce large amounts of the anti-viral compound IFN-[gamma] upon stimulation with homologous norovirus VLPs or peptides in vitro. To effect a broader immune response, we vaccinated mice with a cocktail of VLPs from multiple norovirus strains simultaneously resulting in cross-reactive receptor-blocking antibody responses to heterologous strains not included in the vaccine composition. Furthermore, multivalent vaccination did not diminish specificity or quantity of antibody or T cell responses to individual vaccinating strains. Studies with the newly discovered murine norovirus (MNV) revealed that MNV VLP vaccination protects against MNV infection, and both humoral and cellular immunity are involved in clearance of the virus. Furthermore, adoptive transfer of serum but not CD4+ or CD8+ T cells from vaccinated mice completely protected immunodeficient mice from MNV infection, suggesting pre-existing antibodies can prevent establishment of acute infection. Vaccination with multiple human VLPs also provided significant protection against MNV infection in mice, advocating the development of multivalent human norovirus vaccines for cumulative protection against norovirus challenge.
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  • In Copyright
Advisor
  • Baric, Ralph S.
Degree granting institution
  • University of North Carolina at Chapel Hill
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  • Open access
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