Vaccines and molecular tools for the control of the emerging bunyavirus, severe fever with thrombocytopenia syndrome phlebovirus (SFTSV)

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Viruses in the newly formed order Bunyavirales are frequently arthropod-transmitted with many members capable of causing substantial human, animal and disease. The WHO has identified several bunyaviruses as key emerging pathogens, and this call entitled "One health approaches to accelerate vaccine development" also emphasizes interest in this group of viruses. This project focuses on severe fever with thrombocytopenia syndrome phlebovirus (SFTS phlebovirus; SFTSV) of the Phenuiviridae family of bunyaviruses which also includes significant emerging pathogens in both Asia and the USA (Heartland virus, HRTV). To date, over 2500 SFTSV cases have been reported in China, 172 cases in South Korea and 96 cases in Japan, with case fatality rates ranging from 8.2% to 32.6%. The annual incidence of reporting is increasing in all endemic countries, e.g. in China where 53 cases were reported in 2010, compared to 676 in 2013. To address the threat posed by novel, emerging bunyaviruses, scientists at the MRC-University of Glasgow Centre for Virus Research (CVR) have developed a "reverse genetics" system with which SFTSV can be manipulated, and which permit the rational design of rationally attenuated virus vaccine candidates. Such reverse genetics systems enable the rapid recovery of replication competent bunyaviruses from plasmids encoding cDNA copies of the viral genomic RNA. This technology facilitates the mapping of epitopes targeted by the humoral and cellular immune response as well as the identification and manipulation of virally-encoded virulence factors. The NSs proteins of many bunyaviruses are recognised as virulence factors due to their ability to counteract the mammalian innate immune responses. Hence, these reverse genetics-based strategies offer a realistic means to develop rational vaccine candidates for emerging bunyaviral diseases, as well as the development of viruses that help to further elucidate the immune responses mounted to infection and viral pathogenesis. We have now generated a recombinant NSs-deletant SFTSV (called SFTSVdelNSs) which is unable to antagonise type I interferon responses mounted in response to infection. This facilitates the studies into the role of innate immune responses in controlling SFTSV, as well as in vivo tissue tropism and pathogenesis in absence of the virulence factor NSs, leading to the evaluation of such potentially attenuated viruses as vaccine candidates. The strengths of reverse genetics-based approaches to producing recombinant bunyaviruses extends beyond the production of attenuated virus vaccine candidates. The system also allows the development and production of virus-like particles (VLPs). Both recombinant viruses and VLPs can be tested for their ability to induce immune responses in immunised animals as well as protective vaccine candidates. This proposal will bring together CVR and Beijing Institutes of Life Science (BIOLS) researchers to elucidate host immune responses to SFTSV infection and pathogenesis, the development of recombinant virus vaccine candidates and tools to further study SFTSV.Aim 1. To elucidate the contribution of SFTSV NSs to in vivo tissue tropism and pathogenesis. We will also assess a recombinant SFTSV (lacking NSs; SFTSVdelNSs) as vaccine candidate in comparison to VLPs.Aim 2. To produce novel neutralising antibodies against SFTSV for basic research and as potential therapeutic agents. We will investigate antibody responses using a novel SFTS viruses expressing reporter genes to study immune responses in both patient sera and infected animals. This will allow us to define the breadth of the neutralising antibody responses and to map antigenic determinants on the virion. Antigenic variation and escape from neutralisation of the SFTSV Gn structural protein (known target for antibody responses) will be investigated through mutational analysis. The project will also include training in reverse genetics technology for the partner BIOLS.