Recombinant vesicular stomatitis virus vector vaccines for WHO blueprint priority pathogens

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

Experience in use as post-exposure prophylaxis VSV-EBOV is intended for use as a prophylactic vaccine; however, its implementation as a post-exposure prophylaxis is intriguing, as a swift identification and vaccination of EVD-affected individualsif effectivewould contribute to a timely containment of future outbreaks. In NHPs, VSV-EBOV was fully protective when given 7 days before challenge and ameliorated disease when given 3 days pre-exposure. 50 In mice, vaccination with VSV-EBOV 24 h post-infection (p.i.) conferred complete protection, while guinea pigs only showed partial protection from challenge when vaccinated 24 h pre-to 24 h postexposure. Lastly, in NHP, 50% protection was conferred in animals vaccinated 20-30-min post-exposure. 73 In line with this finding, a separate study described an overall 50% protection from EVD when NHP were vaccinated either 1 h or 24 h p.i. or when vaccinated twice, at 1 h and 24 h p.i. with half the vaccine dose, respectively. Surprisingly, however, post-exposure prophylaxis with an rVSV-vectored vaccine against Marburg virus conferred similar protection against EVD, and the authors argued that VSV-driven innate immune activation as well as filovirus-specific immune responses may play a role in protection from EVD. 74 Of note, compared to the disease course in humans, the onset of clinical disease is faster and its manifestation more severe in the NHP model, with a lethality of close to 100%. When NHPs were challenged with Sudan ebolavirus (SUDV), which leads to lethal disease in NHP later than does EBOV, 100% of NHP were protected when vaccinated with rVSV-SUDV 20-30 min p.i. 75 The efficacy of post-exposure prophylaxis may thus well be higher in humans than in the NHP model. 76 In humans, VSV-EBOV was first used as an emergency post-exposure vaccine in 2011, long before entering clinical trials, and has been used in a total of seven individuals with occupational exposure to EBOV. Here, the vaccine was administered 24 h to 3 days post-exposure and none of the individuals developed EVD. [77] [78] [79] It is of course unknown whether, and to what extent, post-exposure prophylaxis prevented the development of EVD, but albeit that these case reports are anecdotal in nature, they are encouraging and provide the basis for current EVD post-exposure recommendations. 76 Vector-specific immunity Although pre-existing anti-VSV immunity is rarely found in humans, 8 anti-vector immunity after vaccination with a VSV vector vaccine might impair vaccine efficacy of future VSV-based vaccines and prime-boost regimens. While data investigating preexisting immunity remain scarce, we recently demonstrated that vaccination with VSV-EBOV induced both vector-specific humoral and cellular immune responses. 80 The VSV-specific antibody responses generated in humans in this study following vaccination with VSV-EBOV were non-neutralizing and correlated with EBOV GP-specific antibody responses. 80 With regard to the potential simultaneous use of VSV-EBOV and VSV-based Lassa virus (LASV) vaccines in West Africa, Marzi et al. vaccinated cynomolgus macaques with VSV-EBOV 90 days after having received a protective dose of the Lassa vaccine VSVΔG/ LASVGPC. Despite having significant anti-VSV antibody titers before vaccination with VSV-EBOV, the vaccination conferred full protection from EBOV challenge, suggesting that a repeated vaccination with VSV-vectored vaccines may be efficacious. 81