Emerging and zoonotic viruses pose an increasingly serious threat to both human and animal health. Many of the most highly pathogenic viral zoonoses are caused by RNA viruses. With antivirals against RNA viruses scarce, the impact of these viruses is most often mitigated through the development of vaccines that confer protection against infection. However, vaccines are only as good as the antigen(s) incorporated in the preparation. While it is known that upon infection with such viruses a strong humoral immune response is normally stimulated against the viral envelope protein(s; VEP), the antigens that dictate potent neutralising antibody production are often ill defined. Further, virus vaccines are routinely generated from serially passaged virus strains that are lab adapted and may have generated mutations that alter the neutralising antibody response to the protein in question. Finally, antigens are frequently chosen based on availability of virus strains strain rather than by informed design. Together these factors can dramatically reduce the public health relevance of these vaccines.

One example of this is with the existing rabies virus (RABV) vaccines that are based on classical rabies isolates. Rabies is caused by a number of antigenically divergent viruses within the lyssavirus genus. Whilst the existing vaccines protect against the prototypic lyssavirus, rabies virus, these vaccines are unable to confer robust protection against other lyssavirus species. Therefore, a better understanding of the antigenicity of these VEP will aid the development of more broadly neutralising and potent vaccines.

This PhD aims to address this requirement by undertaking serological and structural studies of VEP using pseudotyped viruses (PV), which are replication defective recombinant virus-like particles. The first part will extend the work we are currently undertaking on filoviruses and arenaviruses, by bringing together cutting edge in silico and in vitro technologies to achieve dramatic improvements in vaccine efficacy against all lyssavirus species. Digitally designed VEP sequences for ancestral viral isolates will be synthesised and characterised using our PV system. Promising antigens will be taken forward for in vivo analysis. Secondly, we will study the composition of the PV produced bearing the ancestral VEP. Cryo-electron tomography will be used to assess the density of VEP on the virus surface and the high resolution structure of the VEP. This information will be fed into our vaccine-antigen platform and used to guide further VEP optimisation.

The majority of the work will be carried out within the School of Life Sciences at the University of Sussex, with the live lyssaviruses work undertaken at APHA in bespoke SAPO4/ACDP3 laboratories.