Rotavirus Pathogenesis And Vaccine Development

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Abstract

Previously, in studies involving a semi-homologous system of gnotobiotic newborn pigs and a virulent porcine rotavirus strain (SB-1A) and an avirulent human rotavirus strain (DS-1) and their reassortants, we demonstrated that: (i) the third (VP3), fourth (VP4), ninth (VP7), or tenth (NSP4) porcine rotavirus gene each play an important independent role in the virulence of rotavirus infection in piglets; and (ii) all four of the porcine rotavirus virulence-associated genes are required for the induction of diarrhea and the shedding of rotavirus by piglets. These observations suggested a potential new strategy for attenuation of wild-type human rotaviruses of major epidemiologic importance and its application to the development of a safe and effective vaccine. Previously, we developed rhesus (RRV)- or bovine (UK)-based quadrivalent vaccine which was designed to provide antigenic coverage for VP7 (G) serotypes 1-4 of epidemiologic importance. Last year, we reported (i) generation of additional RRV- or UK-based vaccine candidates which are designed to cover G5, G8, G9 or G10 serotypes, (ii) characterization of the VP4 neutralization specificity of the porcine rotavirus Gottfried strain (P2B[6],G4) and (iii) construction of a Gottfried-based reassortant vaccine which incorporates the human rotavirus VP7 (G1, G2 or G3) or VP4 (P1A[8] or P1B[4]) gene of epidemiologic importance. This year, we constructed additional Gottfried-based reassortant candidate vaccines which were designed to provide antigenic coverage for G4, G5, G6, G8, G9 and G10. These vaccines could provide (i) the attenuation phenotype of a porcine rotavirus in humans and (ii) antigenic coverage not only for epidemiologically important VP7 and VP4 serotypes but also for P2A[6] serotype which in some parts of the world appears to be of clinical importance.