Addresing Efficacy of a Dengue vaccine candidate in a macaque challenge model

Dengue virus (DENV) infects 400 million people a year. It is a leading cause of illness and death in the tropics and subtropics and its incidence is geographically expanding. Dengue and Dengue Haemorrhagic Fever are caused by any one of four DENV serotypes transmitted by mosquitoes and no licensed vaccines to prevent infection have become available worldwide to tackle all DENV at once. A major challenge in developing a DENV vaccine is to overcome virus variability because immune responses mounted to one serotype are not relevant to protect against the other 3 DENV serotypes. Furthermore, patients that previously suffered from dengue are in high risk to develop a more aggressive form of the disease if they come into contact with a different DENV serotype, as they have non-neutralising DENV antibodies -a process known as Antibody Dependent Enhancement (ADE) that promote DENV infection in a second exposure. Top-leading vaccines (B-cell vaccines) focus on the production of neutralising antibodies (humoral immune response) but pose a great risk to induce ADE in vaccinees and require multiple doses of complex polyvalent vaccines, becoming expensive and difficult to deploy in low-income settings. Importantly, those vaccines disregard the capacity of the T-Cell cytotoxicity to clear viral-infected cells (cellular immunity) in which ADE is not a concern. To date, a DENV T-cell vaccine has not been developed yet. After three years of R&D activities, we have designed and filed a patent (with Isis Innovation) of a set of T-Cell dengue vaccines, with the ability to recognise and mount strong cellular responses against highly conserved non-structural proteins across all four DENV serotypes. These DENV universal vaccines are contained in viral-vectored platforms such as Chimpanzee Adenovirus (ChAdOx1) and Poxvirus (MVA), which are highly immunogenic and safe in humans (i.e. they have been used in the latest Ebola Vaccine Trial in Oxford). The innovation of our development consists on the use of only one universal antigen to tackle all dengue serotypes and genotypes, using only two vaccine components and no adjuvant. This will contribute to the development of an affordable vaccine suitable for all endemic countries. Recently, we have assessed safety and T-cell immunogenicity elicited by one of our vaccines in Non Human Primates (NHP) at the Biomedical Primate Research Centre in the Netherlands. To date, NHP data have been essential for vaccines advancing to clinical trials, based on neutralizing activity in serum and/ or reduction of post-challenge viremia, which indicates to vaccine developers and regulatory agencies of the potential for efficacy in humans. Our goal now is to take forward our DENV vaccine development to explore its ability to confer efficacy protection against a reproducible DENV challenge model in macaques at the Caribbean Primate Reseach Center in Puerto Rico, where this DENV challenge is widely used to test DENV vaccine developments. Accomplishment of this goal will allow us to apply for a streamline funding to support a Phase-I clinical trial.