RP1: Antigen design and testing of arenavirus and nairovirus

PROJECT SUMMARY/ABSTRACT - RP1 (Antigen Design and Testing Of Arenavirus And Nairovirus Vaccines) The viral order Bunyavirales contains several high priority human pathogens. Notably, Arenaviridae and Nairoviridae families contain viruses which cause severe hemorrhagic diseases in humans across the world with mortality rates up to 60% and some are associated with significant, long-term sequelae in survivors. Of these, rodent borne arenaviruses - Lassa (LASV), Lujo, Chapare, Guanarito, Junin and Machupo viruses and one tickborne Nairovirus-Crimean-Congo Hemorrhagic Fever Virus- are identified as NIAID Category A pathogens due to ease of dissemination or transmission person-to-person, production of significant morbidity and mortality, the potential for major public health impact, and due to the requirement for special action for public health preparedness. Threats to public health are further heightened by the lack of internationally approved vaccines to address threats of natural epidemics as well as the potential bio-weaponization of these viruses. To address this unmet need, PABVAX RP1 will leverage combined expertise in high-containment virology, immunology, and biological product development, to develop arenavirus and nairovirus research tools and vaccine approaches using prototype members of each viral group which can be adapted across each viral family using a "plug-and-play" approach. Much of the work developing vaccines for these viruses has relied on isolates derived over 40 years ago, recent advances in viral reverse for these viral families is making vaccine testing of emerging isolates more feasible by improving access. Vaccine development for most arenaviruses and nairoviruses has centered on the understanding of the critical role for viral glycoproteins (GP) and nucleoproteins (NP) to drive natural immunity. We have recently successfully engineered a recombinant, stabilized prefusion LASV GPe to act as an antigenic mimic of viral surface displayed GP and found this trimeric GPe alone, co- delivered with NP, or NP subunits alone, can protect guinea pigs against lethal challenge by LASV underscoring the value of these antigens as vaccine components. Subunit vaccines are prime candidates for alternative vaccination approaches like microneedle patches (MNP). MNP coupled antigens and adjuvants directly interact with the potently immunoresponsive cutaneous microenvironments using dissolvable MNPs to elicit robust and long-lasting protective immunity against the target pathogen. The importance of humoral immunity for affording potent protection or treatment against viral infections cannot be understated as evidenced by the recent success using monoclonal antibody therapies to treat Ebola virus disease or COVID-19, yet little is known for the potential for pre-exposure prophylactic (PREP) administration of antibody therapies and what kind of prophylactic windows are possible. In this proposal, we will develop protective protein-based subunit-MNP vaccines, PREP treatment strategies, and recombinant virus tools using prototyped arenaviruses and nairoviruses which will template development of countermeasures against other related Bunyaviridae members.