Trivalent Lassa, Ebola and Marburg viral vaccine (Tri-LEMvac)

African haemorrhagic fever viruses have a significant impact on human health in low income countries and developing economies (Heeney, J Internal Med, 2006). Lassa fever is endemic to Western Africa with estimates ranging between 300,000 to a million infections, with 5,000 deaths per year. It’s overlapping geographic distribution with other Viral Haemorrhagic Fevers (VHFs) caused by Filoviruses such as Ebola virus (EBOV), complicated the early clinical diagnosis of Ebola virus disease in the 2014/2015 West African outbreak. A combined Old World Arenavirus and Filovirus vaccine eliciting protection against Lassa Fever virus (LASV), Ebola (EBOV) and Marburg (MARV) viruses, the most important haemorrhagic fevers in West and Central Africa, would be of great benefit in the control of spread of these notorious pathogens. Currently there are no licensed vaccines for these infections. A single vaccine to protect against all three of these regionally important VHFs that was economic, easy to produce, readily deployable and temperature stable in the absence of continuous cold chain storage would be highly desirable.
The Modified Vaccinia Ankara (MVA) vaccine platform is a non-replicating strain third generation smallpox vaccine and one of the most advanced recombinant poxviral vaccine vectors in human clinical trials (Cottingham & Carroll, Vaccine, 2013). MVA is a robust vector system capable of co-expressing up to four transgenes facilitating potent promoters and stable insertion sites (Orubu et al, Pone, 2012). We will bring synergistic new platform technologies together from EVAC and LassaVacc (Innovate UK). Using EVAC’s DIOS synthetic immune optimised vaccine inserts to give the broadest possible vaccine protection, together with LassaVacc's MVA based LASV (NP/GPC T & B-cell antigens) we will develop a single trivalent vaccine (Tri-LEMvac) that will generate combined vaccine efficacy against future outbreaks of variants of the haemorrhagic fever Lassa, Ebola and Marburg viruses.

Towards this goal we propose two stages:
Stage 1) Proof of concept (this application). Within 12 months, we will demonstrate proof of concept by constructing trivalent MVAs expressing conserved Lassa, Ebola and Marburg antigen inserts in a single MVA, confirming optimal expression, demonstrating immunogenicity in small animals and efficacy by live virus challenges with these pathogens. MVA is a clinically trialled vaccine vector which we will use to compare improvements in immune responses, the breadth of protection, durability and efficacy. This new trivalent LEMvac MVA vaccine will allow direct comparison in head to head clinical trials in stage 2.
Stage 2) follow-up proposal; refine preclinical work, including GLP manufacturing toxicology/manufacturing. To perform first in human phase I trials of Tri-LEMvac to establish dose, durability of one shot versus prime boost and safety.