Recombinant vesicular stomatitis virus vector vaccines for WHO blueprint priority pathogens

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

The Henipavirus Nipah virus (NiV) is a zoonotic pathogen that can cause severe pulmonary and neurologic disease with a high case-fatality rate and has been responsible for almost yearly outbreaks on the Indian subcontinent. The NiV vaccine portfolio currently under development includes rVSVvectored Nipah vaccines, which utilize rVSV expressing two different structural proteins as antigens, the NiV fusion (F) and attachment (G) glycoproteinstwo surface proteins that together are required for viral cell entry. The rVSV vector expressing either antigen has been described in two different models, one with the insertion of either protein after VSV-G (VSV-G/F(NiV)), the other in place of the VSV glycoprotein (rVSVΔG-G/F(NiV)). In mice, intranasal (i.n.) administration of rVSV-G(NiV) and/or -F(NiV) induced neutralizing Ab (nAb) formation, and highest nAb formation was observed when rVSV-G(NiV) alone or in combination with rVSV-F(NiV) was given. The rVSVΔG vector was evaluated using i.m. vaccination and likewise induced nAb, especially when rVSVΔG-G-and -F(NiV) were used in combination. 109 Of note, the combined administration of rVSVΔG-G/F(NiV) was found to be lethal when given intranasally in 5/8 postnatal mice in a later study, while the individual administration of either vaccine candidate did not cause any symptoms, even when directly injected into the brain. 110 Vaccination with rVSVΔG-G-or -F(NiV) was demonstrated to be fully protective against NiV challenge in a Syrian hamster model, where none of the animals developed disease. 111 Similarly, the vector VSV-EBOV, complemented with NiV F or G protein downstream of EBOV-GP, was assessed in the hamster model and conferred the same level of protection from disease. 112 Importantly, while the vaccine was administered 28 days prior to challenge in this study, a follow-up study additionally demonstrated peri-exposure protection. Full protection was achieved until one day before vaccination and decreased to 17% until one day after challenge, while administration three days after challenge did not show protection. 113 Interestingly, similarly to observations made by Marzi et al. in an EBOV post-exposure vaccine model, 74 an rVSV vector vaccine control also mediated partial protection when given one day pre-challenge. 113 Antibody generation was associated with protection 113 and a serumtransfer experiment confirmed that protection was antibodydependent. 112 A simultaneously assessed rVSV-ΔG-EBOV vector expressing NiV nucleocapsid protein (N) was shown to be inferior to the F and G variants. 112 The more immunogenic rVSV-ΔG-EBOV-G(NiV) was subsequently demonstrated to be completely protective in African Green Monkeys, described as the most appropriate animal model for NiV infection. 114, 115 MERS-and SARS-coronaviruses SARS as well as MERS constitute severe pulmonary infections that are caused by SARS-and MERS-coronaviruses (CoV), respectively. A severe outbreak of SARS-CoV, which originated in China in 2002, spread swiftly and ultimately affected over 8000 humans within a few months. 116 While the virus has been contained, its potential to reemerge and cause new outbreaks remains high, and the rVSV platform has been employed to create SARS-CoV vaccine candidates for such a future scenario. VSV-S expresses the immunogenic spike protein (S) of SARS-CoV between the G and the L gene of VSV. In a mouse model, vaccination with VSV-S induced higher levels of neutralizing antibodies than immunization wi