Genetic Studies Of Rotavirus Pathogenesis And Developmen

Hoshino, Yasutaka

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 epidemiological 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. This year, we reported additional RRV- or UK-based vaccine canididates which are designed to cover G5, G8, G9 or G10 serotypes. Last year, we characterized the VP4 neutralization specificity of the porcine rotavirus Gottfried strain (P1B[6],G4) and showed that it was related in a one-way fashion to human rotavirus P[6] VP4s (see AI000339-22 LID). This finding gave us a rationale to develop 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 vaccine can 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 significance. Thus, we developed last year Gott x G1, Gott x G2 and Gott x G3 reassortant candidate vaccines. This year, we constructed Gott x G5, Gott x G8 and Gott x G9 reassortant vaccine candidates. Additional candidate vaccines are being constructed.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Allergy and Infectious Diseases (NIAID)
• Type: Intramural Research (Z01)
• Project #: 1Z01AI000340-22
• Application #: 6807907
• Study Section: (LID)
• Support Year: 22
• Fiscal Year: 2003

Institution

• Name: Niaid Extramural Activities
• Country: United States

Publications

Feng, N; Sen, A; Nguyen, H et al. (2009) Variation in antagonism of the interferon response to rotavirus NSP1 results in differential infectivity in mouse embryonic fibroblasts. J Virol 83:6987-94

Ross, Jerri; Ostlund, Eileen N; Cao, Dianjun et al. (2008) Acrylamide concentration affects the relative position of VP7 gene of serotype G2 strains as determined by polyacrylamide gel electrophoresis. J Clin Virol 42:374-80

Kapikian, Albert Z; Hoshino, Yasutaka (2007) To serotype or not to serotype: that is still the question. J Infect Dis 195:611-4

Vesikari, Timo; Karvonen, Aino V; Majuri, Jukka et al. (2006) Safety, Efficacy, and Immunogenicity of 2 Doses of Bovine-Human (UK) and Rhesus-Rhesus-Human Rotavirus Reassortant Tetravalent Vaccines in Finnish Children. J Infect Dis 194:370-6

Vesikari, Timo; Karvonen, Aino; Forrest, Bruce D et al. (2006) Neonatal administration of rhesus rotavirus tetravalent vaccine. Pediatr Infect Dis J 25:118-22

Hoshino, Yasutaka; Honma, Shinjiro; Jones, Ronald W et al. (2005) A porcine G9 rotavirus strain shares neutralization and VP7 phylogenetic sequence lineage 3 characteristics with contemporary human G9 rotavirus strains. Virology 332:177-88

Hoshino, Yasutaka; Jones, Ronald W; Ross, Jerri et al. (2005) Porcine rotavirus strain Gottfried-based human rotavirus candidate vaccines: construction and characterization. Vaccine 23:3791-9

Kapikian, Albert Z; Simonsen, Lone; Vesikari, Timo et al. (2005) A hexavalent human rotavirus-bovine rotavirus (UK) reassortant vaccine designed for use in developing countries and delivered in a schedule with the potential to eliminate the risk of intussusception. J Infect Dis 192 Suppl 1:S22-9

Yuan, Lijuan; Ishida, Shin-Ichi; Honma, Shinjiro et al. (2004) Homotypic and heterotypic serum isotype-specific antibody responses to rotavirus nonstructural protein 4 and viral protein (VP) 4, VP6, and VP7 in infants who received selected live oral rotavirus vaccines. J Infect Dis 189:1833-45

Hoshino, Yasutaka; Jones, Ronald W; Ross, Jerri et al. (2004) Rotavirus serotype G9 strains belonging to VP7 gene phylogenetic sequence lineage 1 may be more suitable for serotype G9 vaccine candidates than those belonging to lineage 2 or 3. J Virol 78:7795-802