Generation of a live rabies vaccine strain attenuated by multiple mutations and evaluation of its safety and efficacy

Keisuke Nakagawa, Naoto Ito, Tatsunori Masatani, Masako Abe, Satoko Yamaoka, Yuki Ito, Kota Okadera, Makoto Sugiyama

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

An amino acid substitution at position 333 in rabies virus G protein is known to determine the pathogenicity: strains with Arg or Lys at that position kill adult mice after intracerebral inoculation, whereas strains with other amino acids cause non-lethal infection. Based on those findings, attenuated rabies virus strains have been established and used for oral vaccines mainly for wild animals. However, considering the possibility of back-mutation to the virulent phenotype, a strain that is attenuated by multiple mutations not only in the G protein but also in other viral proteins would be more appropriate as a safe live vaccine. We previously demonstrated that the fixed rabies virus Ni-CE strain, which causes only transient body weight loss in adult mice after intracerebral inoculation, is mainly attenuated by mutations in the N, P and M proteins, while this strain has virulent-type Arg at position 333 in the G protein. In this study, to obtain a live vaccine strain that is attenuated by multiple mutations, we generated Ni-CE mutant, Ni-CE(G333Glu) strain, which has an Arg-to-Glu mutation at position 333 in the G protein, and examined its pathogenicity and immunogenicity. We found that, in contrast to Ni-CE strain, Ni-CE(G333Glu) strain did not cause transient body weight loss in adult mice after intracerebral inoculation. The attenuated phenotype of Ni-CE(G333Glu) strain did not change even after 10 serial intracerebral passages in suckling mice. We also demonstrated that inoculation of Ni-CE(G333Glu) strain induced virus-neutralizing antibody in immunized mice and protected the mice from lethal challenge. These results indicate that Ni-CE(G333Glu) strain is a promising candidate for development of a live rabies vaccine with a high safety level.

Original languageEnglish (US)
Pages (from-to)3610-3617
Number of pages8
JournalVaccine
Volume30
Issue number24
DOIs
StatePublished - May 21 2012

Keywords

  • Glycoprotein gene manipulation
  • Live vaccine
  • Rabies virus

ASJC Scopus subject areas

  • Molecular Medicine
  • Immunology and Microbiology(all)
  • veterinary(all)
  • Public Health, Environmental and Occupational Health
  • Infectious Diseases

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  • Cite this

    Nakagawa, K., Ito, N., Masatani, T., Abe, M., Yamaoka, S., Ito, Y., Okadera, K., & Sugiyama, M. (2012). Generation of a live rabies vaccine strain attenuated by multiple mutations and evaluation of its safety and efficacy. Vaccine, 30(24), 3610-3617. https://doi.org/10.1016/j.vaccine.2012.03.044