Efficacy of rotavirus-like particle vaccines and pathogenesis of human rotavirus evaluated in a gnotobiotic pig model

The main goals of this dissertation were: (1) to identify correlates of protective immunity after vaccination with virus-like particle (VLP) vaccines; (2) to examine the extent of extraintestinal spread of rotavirus and its potential implication for rotavirus protective immunity; and (3) to delineate comprehensively the cytokine profiles induced by virulent (Vir) and attenuated (Att) rotaviruses and the potential role of cytokines in rotavirus pathogenicity or immunity. We evaluated the magnitude of serum and intestinal isotype-specific and virus-neutralizing antibody responses induced by oral priming with AttHRV Wa strain and intranasal boosting with 2/6VLP+mutant E. coli heat labile toxin (mLT) and the correlation of these antibody responses with protection. The serum IgM, IgA and IgG antibody titers and neutralizing antibody titers were all correlated with protection. However, only IgA antibody titers in serum were highly correlated with the corresponding IgA antibody titers in the intestines, indicating that serum IgA antibody titer is a reliable indicator of intestinal antibody responses and protection.; Respiratory symptoms with rotavirus shedding in nasopharyngeal secretions have been reported in children with or without gastrointestinal symptoms. We investigated if AttHRV and VirHRV strains cause upper respiratory tract infections or viremia in gnotobiotic (Gn) pigs. Pigs inoculated orally or intranasally with AttHRV shed virus mainly nasally (79--95%) and to a lesser extent, rectally (5--17%). In contrast, 100% of pigs inoculated with VirHRV (oral, IN or gavage) developed diarrhea, shed virus nasally and rectally and had viremia. The infectivity of sera from the viremic VirHRV-inoculated pigs was confirmed by inoculating Gn pigs orally with pooled HRV-positive serum. Serum-inoculated pigs developed diarrhea, fecal and nasal virus shedding and seroconverted with serum and intestinal HRV antibodies. This study provided new evidence that VirHRV causes transient viremia and upper respiratory tract infection in addition to gastrointestinal infection in Gn pigs.; These findings have improved our understanding of rotavirus pathogenesis, immunogenicity and correlates of protection. This knowledge will facilitate the design of rotavirus vaccines, which are essential for protection against rotavirus diarrhea in human infants and young animals worldwide. (Abstract shortened by UMI.)...