and objectives: Noroviruses (NoVs) are major causative agents of non-bacterial acute gastroenteritis in people of all ages worldwide. NoV capsid VP1 derived virus-like particles (VLPs) produced in various expression systems are main vaccine candidates against NoV. The aim of this study was to investigate and compare systemic and mucosal delivery and a combination of both deliveries of NoV VLPs for induction of immune responses in BALB/c mice. Materials and methods: BALB/c mice were immunized

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... ramuscularly (IM), Intranasally (IN) or sequentially (IM followed by IN) with a candidate NoV GII-4 VLP vaccine developed by our laboratory. NoV GII-4-specific serum and mucosal IgG and IgA antibodies were analyzed by ELISA. GII-4-specific T cell immune responses were investigated using an ELISPOT assay measuring production of interferon-γ (IFN-γ) at a single cell level. Results: IM immunized mice developed a strong systemic and mucosal NoV-specific IgG antibody response but completely lacked IgA response. In contrast, mice immunized IN had strong systemic and mucosal IgG and IgA production but lacked CD8 + T cell responses. Sequential immunization compensated for the deficient IgA and CD8 + T cell responses induced by each delivery alone. Conclusion: Our results show that sequential IM+IN immunization should be considered for NoV VLP vaccine delivery to activate broad immune responses.