Synergistic attenuation of vesicular stomatitis virus, vectors thereof and immunogenic compositions thereof

1. A genetically modified vesicular stomatitis virus (VSV) vector comprising at least two different classes of mutations in the same VSV genome, wherein the VSV vector comprises:

(a) a truncated G gene mutation, wherein the G protein encoded by the truncated G gene has a cytoplasmic tail domain consisting of one amino acid and,

(b) a non-cytopathic M gene (M (ncp) ) mutation, wherein the M (ncp) mutation is a mutation at methionine 33 and a mutation at methionine 51 of the M gene, and optionally

(c) at least one foreign RNA sequence inserted into or replacing a region of the VSV genome non-essential for replication,

wherein the at least two mutations synergistically attenuate VSV pathogenicity.

2. The VSV of claim 1 , wherein the pathogenicity is further defined as neurovirulence.

3. The VSV of claim 1 , wherein the VSV injected intracranially in 4-week old female Swiss-Webster mice has a LD 50 100-fold, 1,000-fold, 10,000-fold, or 100,000-fold greater than wild-type VSV injected intracranially in 4-week old female Swiss-Webster mice.

4. The VSV of claim 1 , comprising a mutated genome of 3′-NPM (ncp) G (ct-1) L-5′.

5. The vector of claim 1 , wherein the foreign RNA is further defined as an open reading frame (ORF).

6. The vector of claim 1 , wherein the foreign RNA is selected from the group consisting of an HIV gene, an HTLV gene, an SIV gene, an RSV gene, a PIV gene, an HSV gene, a CMV gene, an Epstein-Barr virus gene, a Varicella-Zoster virus gene, a mumps virus gene, a measles virus gene, an influenza virus gene, a poliovirus gene, a rhinovirus gene, a hepatitis A virus gene, a hepatitis B virus gene, a hepatitis C virus gene, a Norwalk virus gene, a togavirus gene, an alphavirus gene, a rubella virus gene, a rabies virus gene, a Marburg virus gene, an Ebola virus gene, a papilloma virus gene, a polyoma virus gene, a metapneumovirus gene, a coronavirus gene, a Vibrio cholerae gene, a Streptococcus pneumoniae gene, Streptococcus pyogenes gene, a Helicobacter pylori gene, a Streptococcus agalactiae gene, a Neisseria meningitidis gene, a Neisseria gonorrheae gene, a Corynebacteria diphtheriae gene, a Clostridium tetani gene, a Bordetella pertussis gene, a Haemophilus gene, a Chlamydia gene, an Escherichia coli gene, a gene encoding a cytokine, a gene encoding T-helper epitope, a gene encoding a CTL epitope, a gene encoding an adjuvant and a gene encoding a co-factor.

7. The vector of claim 6 , wherein the foreign RNA is an HIV gene is selected from the group consisting of gag, env, pol, vif, nef, tat, vpr, rev and vpu.

8. An immunogenic composition comprising an immunogenic dose of the VSV vector of claim 1 comprising (a), (b), and (c).