Investigating the functionality and antigenicity of chimeric lyssavirus glycoproteins and their neutralisation profiles

Rabies, the archetypal lyssavirus, is one of the most feared viruses known to man and globally, is the cause of more than 50,000 deaths per year. Alongside rabies virus, numerous related lyssaviruses exist that are also capable of causing fatal clinical disease consistent with that seen following infection with rabies virus. Whilst the human burden of these viruses remains unknown, fatalities have been reported.\n\nThe lyssavirus glycoprotein is the sole target for virus neutralising antibodies and several amino acid epitopes have been linked to virus neutralisation. Lyssaviruses are genetically and antigenically categorised into phylogroups that indicate the level of protection afforded by current vaccines. It is generally accepted that an antibody response to the currently available rabies vaccines affords protection against all viruses that are categorised into phylogroup I. However, this antibody response does not protect against lyssavirus species within phylogroups II and III. Indeed, experimental data has shown that the antibody repertoire induced by rabies virus vaccines is completely unable to neutralise viruses in these phylogroups. In this study we have generated lentivirus pseudotypes containing chimeric lyssavirus glycoproteins that have had their antigenic sites swapped between phylogroup I and II viruses. Using these, we show alteration in both G protein functionality alongside altered neutralisation profiles using a variety of hyperimmune sera. Here we overview results using these chimeric glycoproteins and suggest areas of the G protein responsible for the development of phylogroup specific neutralising responses.