Pan-lyssavirus vaccines against rabies

Abstract

Described herein are recombinant rabies viruses encoding rabies virus glycoprotein and at least one heterologous glycoprotein from another lyssavirus, such as Mokola virus, Lagos bat virus and/or West Caucasian bat virus. In particular embodiments, the recombinant rabies virus includes two or three heterologous lyssavirus glycoproteins. The disclosed recombinant rabies viruses can be used as pan-lyssavirus vaccines to provide protection against lyssaviruses that cause rabies.

1 . A recombinant rabies virus, the genome of which comprises rabies virus nucleoprotein (N), phosphoprotein (P), matrix protein (M), RNA-dependent RNA polymerase (L) and glycoprotein (G) genes and at least two different heterologous lyssavirus G genes, wherein the lyssavirus is selected from the group consisting of Lagos bat virus (LBV), Mokola virus (MOKV), Duvenhage virus (DUVV), European bat lyssavirus-1 (EBLV-1), European bat lyssavirus-2 (EBLV-2), Australian bat lyssavirus (ABLV), Aravan virus (ARAV), Khujand virus (KHUV), Irkut virus (IRKV) and West Caucasian bat virus (WCBV). 
     
     
         2 . The recombinant rabies virus of  claim 1 , comprising two different heterologous lyssavirus G genes and the two heterologous G genes are MOKV and WCBV G genes. 
     
     
         3 . The recombinant rabies virus of  claim 2 , wherein the nucleotide sequence of the MOKV G gene is at least 95% identical to the nucleotide sequence of SEQ ID NO: 47, the nucleotide sequence of the WCBV G gene is at least 95% identical to the nucleotide sequence of SEQ ID NO: 49, or both. 
     
     
         4 . The recombinant rabies virus of  claim 2 , wherein the MOKV G gene comprises the nucleotide sequence of SEQ ID NO: 47, the WCBV G gene comprises the nucleotide sequence of SEQ ID NO: 49, or both. 
     
     
         5 . The recombinant rabies virus of  claim 2 , wherein the two heterologous G genes are located between the rabies virus P and M genes and between the rabies virus G and L genes. 
     
     
         6 . The recombinant rabies virus of  claim 1 , wherein the genome is derived from the rabies virus ERA strain. 
     
     
         7 . The recombinant rabies virus of  claim 1 , wherein the rabies virus glycoprotein comprises a Glu at amino acid position 333 (SEQ ID NO: 5). 
     
     
         8 . A vector comprising a full-length rabies virus antigenomic DNA, wherein the antigenomic DNA comprises rabies virus N, P, M, L and G genes, and at least two different heterologous lyssavirus G genes, wherein the lyssavirus is selected from LBV, MOKV, DUVV, EBLV-1, EBLV-2, ABLV, ARAV, KHUV, IRKV and WCBV. 
     
     
         9 . The vector of  claim 8 , comprising two different heterologous lyssavirus G genes and the two heterologous G genes are MOKV and WCBV G genes. 
     
     
         10 . The vector of  claim 9 , wherein the nucleotide sequence of the MOKV G gene is at least 95% identical to the nucleotide sequence of SEQ ID NO: 47, the nucleotide sequence of the WCBV G gene is at least 95% identical to the nucleotide sequence of SEQ ID NO: 49, or both. 
     
     
         11 . The vector of  claim 9 , wherein the MOKV G gene comprises the nucleotide sequence of SEQ ID NO: 47, the WCBV G gene comprises the nucleotide sequence of SEQ ID NO: 49, or both. 
     
     
         12 . The vector of  claim 9 , wherein the two heterologous G genes are located between the rabies virus P and M genes and between the rabies virus G and L genes. 
     
     
         13 . The vector of  claim 8 , wherein the antigenomic DNA is derived from the rabies virus ERA strain. 
     
     
         14 . A cell comprising the vector of  claim 8 . 
     
     
         15 . A composition comprising the recombinant rabies virus of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         16 . A method of eliciting an immune response in a subject against lyssavirus, comprising administering to the subject the recombinant rabies virus of  claim 1 . 
     
     
         17 . The method of  claim 16 , wherein the immune response in the subject against lyssavirus protects the subject against infection by at least three different genotypes of lyssavirus.