Recombinant vesicular stomatitis virus vector vaccines for WHO blueprint priority pathogens

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

While clinical trials of VSV-EBOV are still ongoing, efforts to create more attenuated second-generation rVSV-EBOV vaccines are already underway with the goal to reduce reactogenicity while maintaining immunogenicity. In one approach, VSV GP was substituted with an EBOV GP exhibiting the mutation F88A which impairs cell entry. VSV*ΔG(EBOV-GP F88A ) induced immunogenicity in guinea pigs comparable to vaccination with rVSV expressing propagation-competent EBOV GP. However, the vaccine construct was found to be genetically unstable and quickly reverted back to a more infectious variant when passaged. Further mutations may, therefore, have to be introduced in order to maintain propagation restriction. 82 N4CT1-EBOVGP1 is another attenuated rVSV-EBOV vaccine candidate. The rVSV vector is attenuated by combining a translocation of the N protein from position 1 to 4 (N4) with a truncation of the VSV-G cytoplasmatic tail (CT), and expresses the EBOV GP from the EBOV-Mayinga strain from the first position of the rVSV genome. 83 The vector has previously been tested as an HIV vaccine candidate in phase I clinical trials and was well tolerated. 19 ,84 N4CT1-EBOVGP1 vaccinated mice developed both humoral and cellular immune responses and guinea pigs and macaques were completely protected from EBOV challenge, mounting antibody responses in the latter by day 14 p.v. 83 Importantly, vaccinated primates were also protected against heterologous challenge with EBOV-Makona. 85 N4CT1-EBOVGP1 is licensed by Profectus BioSciences, a biotech company that has specialized in vaccine development and uses the attenuated rVSV vector in a number of vaccine candidates. N4CT1-EBOVGP1 is now being evaluated in a phase I dose-escalation trial (NCT02718469).