Attenuated recombinant rabies virus mutants and live vaccines thereof

Abstract

The present invention describes recombinant RV mutants comprising a combined mutation in two different parts of the viral genome, involving the P and the G genes. The mutations in the P gene preferably encompass residues 139 to 170, more preferably residues 139 to 149, most preferably residues 143-149. The mutation can be a substitution or deletion of one or more amino acids in the above region, as well as combinations of deletion and substitution. Preferred mutants according to the invention may be obtained by deleting residues 143 to 149 or 139 to 149 of the phosphoprotein (P) of rabies virus and simultaneously replacing the Arg at position 333 of the glycoprotein into another residue, preferably Asp instead of Arg. Surprisingly, when these mutations were introduced into rabies viruses lacking Arg at position 333 of their G protein, a dramatic reduction in pathogenicity for suckling mice was observed. This unexpected finding has a profound advantage in developing more safe live attenuated rabies vaccines. The mutation in the G gene may comprise a mutation of the Arg333 codon into a codon that differs by one, two or three nucleotides from said Arg333 codon. Preferably the mutants are mutants of a RV strain in which all three nucleotides of the Arg333 codon are substituted.

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