Rotavirus capsid VP6 tubular and spherical nanostructures act as local adjuvants when co‐delivered with norovirus VLPs

• Published in: Clinical and experimental immunology 2017-09, Vol.189 (3), p.331-341
• Main Authors: Malm, M., Heinimäki, S., Vesikari, T., Blazevic, V.
• Format: Article
• Language: English
• Subjects: adjuvant; Adjuvants; Adjuvants, Immunologic; Animal models; Animals; Antibodies; Antibodies, Viral - blood; Antibodies, Viral - immunology; Antigens, Viral - administration & dosage; Antigens, Viral - chemistry; Antigens, Viral - immunology; Capsid Proteins - administration & dosage; Capsid Proteins - chemistry; Capsid Proteins - immunology; Children; Gastroenteritis; Immunization - methods; Immunogenicity; Localization; Lymphocytes T; Mice; Mice, Inbred BALB C; Nanospheres; Nanostructures - chemistry; Nanotechnology; Nanotubes; Nanotubes - chemistry; Norovirus - immunology; norovirus VLP; Original; Recombinant Proteins - chemistry; Recombinant Proteins - immunology; Rotavirus; Rotavirus - chemistry; Rotavirus - immunology; Rotavirus Infections - immunology; Rotavirus Infections - prevention & control; Rotavirus Infections - virology; rotavirus VP6; T-Lymphocytes - immunology; Vaccines; Vaccines, Virus-Like Particle - administration & dosage; Vaccines, Virus-Like Particle - chemistry; Vaccines, Virus-Like Particle - immunology; Virus-like particles; Viruses; VP6 protein
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1111/cei.12977

Summary A subunit protein vaccine candidate based on norovirus (NoV) virus‐like particles (VLPs) and rotavirus (RV) VP6 protein against acute childhood gastroenteritis has been proposed recently. RV VP6 forms different oligomeric nanostructures, including tubes and spheres when expressed in vitro, which are highly immunogenic in different animal models. We have shown recently that recombinant VP6 nanotubes have an adjuvant effect on immunogenicity of NoV VLPs in mice. In this study, we investigated if the adjuvant effect is dependent upon a VP6 dose or different VP6 structural assemblies. In addition, local and systemic adjuvant effects as well as requirements for antigen co‐delivery and co‐localization were studied. The magnitude and functionality of NoV GII.4‐specific antibodies and T cell responses were tested in mice immunized with GII.4 VLPs alone or different combinations of VLPs and VP6. A VP6 dose‐dependent adjuvant effect on GII.4‐specific antibody responses was observed. The adjuvant effect was found to be strictly dependent upon co‐administration of NoV GII.4 VLPs and VP6 at the same anatomic site and at the same time. However, the adjuvant effect was not dependent on the types of oligomers used, as both nanotubes and nanospheres exerted adjuvant effect on GII.4‐specific antibody generation and, for the first time, T cell immunity. These findings elucidate the mechanisms of VP6 adjuvant effect in vivo and support its use as an adjuvant in a combination NoV and RV vaccine. Rotavirus VP6 is considered as a next generation rotavirus vaccine candidate. Our results shown that VP6 oligomeric nanotubes and nanospheres also act as adjuvants on norovirus VLP immunogenicity in a rotavirus‐norovirus combination vaccine. The adjuvant effect is local and strictly dependent on co‐delivery of the VP6 and norovirus VLPs. A dual role of the VP6, as a vaccine antigen and an adjuvant make it an excellent vaccine candidate against childhood gastroenteritis.