971522Pan-filovirus T-cell Vaccine Designed as Bi-valent Conserved Region EpigraphsClosedSmall Business Research InitiativeInnovate UKSince their discovery in 1967, viruses in the Filoviridae family have caused over 50 outbreaks, of which the last one was the devastating epidemic in West Africa during 2013-16. They cause hemorrhagic fevers in humans and non-human primates with 90% fatality rates and there is no licensed drug or vaccine. This family includes 5 distinct species in the Ebolavirus genus: Ebola (EBOV), Sudan (SUDV), Reston (RESTV), Tai Forest (TAFV), and Bundibugyo (BDBV) viruses; 2 viruses in the Marburg-virus genus: Marburg (MARV) and Ravn (RAVV) viruses; and 1 virus species in the Cuevavirus genus: Lloviu virus (LLOV). To date, most vaccine efforts focus on induction of neutralizing antibodies against EBOV, and also SUDV or MARV. While there is a high degree of conservation within one species, so that, for example, antibody responses to EBOV vaccine would likely cross-react with other EBOV outbreaks, protection against other filoviruses will be very low. Furthermore, future outbreaks may result not only from re-emergence of a virus of a rare species, but also of a completely new, as yet unencountered species. We have designed a vaccine designated FILOcepX with the aim to protect against all filoviruses (Theiler et al. Sci Rep 2016, 6:33987). Our vaccine focuses on induction of effective killer T cells targeting the 4 most conserved protein regions among the entire known Filoviridae family. Because there is a remaining diversity even within conserved regions, the vaccine optimizes the match to all known species by employing computed bi-valent epigraphs (a pair of proteins) used as the vaccine immunogens (cep for Conserved EPigraphs). The two epigraphs complement each other, are always used together and are delivered by safe common cold-like adenovirus and smallpox-like vaccines in a simple, in humans proven highly immunogenic regimen. The T-cell strategy is supported by published protection of macaques against challenge with homologous EBOV challenge through vaccine-induced killer T cells. In preliminary experiments in two strains of mice, research-grade FILOcepX vaccines induced killer T cells recognizing many virus regions. Achieving the aims of Stage I will demonstrate the technical feasibility of our solution, provide a proof-of-concept protection against 2 distant viruses EBOV and MARV in macaques and indicate correlates of T-cell protection for future confirmation to inform licensure, and prepare vaccines for manufacture for human use. If invited, Stage II of the Innovation UK will evaluate the vaccine safety and immunogenicity in a small phase 1 clinical trial in Oxford adults. Post Innovation UK, strong and broad immunogenicity in humans supported by protection against two viruses in macaques may lead to a phase 2 trial in most at-risk human populations. Since phase 3 efficacy trial is not likely to be feasible, licensure may proceed through alternative regulatory pathway based on macaque correlates of protection and human phase 2a safety and immunogeni-city. Licenced vaccine would have multiple uses ranging from generation of vaccine stockpiles for containment of future outbreaks, elimination of the 2013 outbreak remnants, provision of long-term protection in high risk popula-tions to saving highly endangered western gorillas. Potential funders would involve international development agen-cies, the World Bank, philanthropies, defense funds, national governments in risk countries or large vaccine Pharmas.