Recombinant vesicular stomatitis virus vector vaccines for WHO blueprint priority pathogens

Fathi, Anahita; Dahlke, Christine; Addo, Marylyn M.

Analogous to its EBOV counterpart, rVSV-MARV vaccine candidates utilize the immunogenic MARV GP and have shown tolerability as well as efficacy in various animal models, including the NHP model. As a preventive vaccine, VSVΔG/ MARVGP, which uses GP strain Musoke as the expressed antigen, was shown to completely protect cynomolgus macaques 28 days p.v. from lethal MARV challenge, and even when challenged almost 4 months after initial vaccination and with a different MARV strain (Popp). 24 A subsequent study further demonstrated that the vaccine was capable to confer cross-protection when NHP were challenged with the more virulent strain Angola, as well as the genetically distant Ravn strain with an amino acid deviation of around 20%. In this study, a dose of 2 × 10 7 PFU was administered; high anti-MARV IgG titers developed and rVSV viremia was detected around 3 days p.v., closely mirroring the observations made for VSV-EBOV. The primates did not develop any signs of clinical illness or abnormalities in hematology or blood chemistry values. 89 Peri-and post-exposure prophylaxis efficacy have been evaluated in animal models. A vaccination 20-30 min p.i. fully protected rhesus macaques from homologous challenge with >10,000 LD 50 doses of MARV, and administration 24 h and 48 h post-exposure protected 5/6 and 2/6 macaques, respectively, suggesting efficacyalbeit limitedas a postexposure treatment, even at high exposure doses. 90, 91 In contrast, when two vaccine candidates expressing MARV-Angola GP were tested for post-exposure efficacy 20-30 min after homologous MARV challenge, survival rates were only 25-75% depending on the challenge dosage and attenuation of the vector used, probably due to the higher pathogenicity as well as shorter incubation period of the MARV-Angola variant, which is of high clinical importance, as the MARV-Angola strain has been responsible for the worst outbreak of Marburg hemorrhagic fever so far. 92 Notably, all surviving animals had mounted anti-MARV specific IgG antibody responses by day 10, indicating that post-exposure treatment may confer protection by delaying disease progression long enough for the infected subject to develop sufficient immunity. 91, 92 The durability of post-vaccination immunity was furthermore assessed by monthly measurements of anti-MARV-GP antibodies in initially VSVΔG/MARVGP vaccinated macaques. All animals developed strong humoral responses that remained overall stable over the course of 13 months. When the macaques were then challenged with homologous MARV-Musoke, no animal developed clinical signs of illness, demonstrating efficacy of the vaccine for at least a year. 93 Taken together with data from other studies, the strong protective capacity of rVSV-MARV seems to be primarily mediated by a strong humoral immune response. 24, 89, 92, 94 Combination of rVSV-vectored filovirus vaccines While the largest EVD outbreaks to date have been caused by EBOV, EVD outbreaks caused by other ebolavirus species have also been described, and MARV and EBOV outbreaks occur in overlapping geographic regions. Cross-protection of VSV-EBOV and -MARV against heterologous strains has been demonstrated as outlined above; 50,89 however, limited or no cross-protection might exist between the more distantly related species and genera. 24, 95, 96 Therefore, a combination of rVSV-vectored filovirus vaccines would be desirable and has been evaluated.