PROJECT SUMMARY/ABSTRACT Nipah virus (NiV) causes febrile encephalitis and severe respiratory disease in humans with fatality rates as high as 100% in some outbreaks (average ~ 75% for outbreaks over the last decade). There are currently no licensed vaccines or therapies for combating NiV disease. NiV is classified as a Biosafety Level (BSL)-4 pathogen because of the high mortality rates associated with infection, the lack of effective medical countermeasures, and the ease of transmission. In addition to causing morbidity and mortality as a naturally acquired infection, NiV is also categorized as a Category C priority pathogen by several US Government agencies because of the concern for deliberate misuse. Importantly, NiV was recently included on the World Health Organization’s (WHO) 2018 List of Priority Pathogens. As a result of the unprecedented global pandemic of COVID-19 there is heightened concern and awareness regarding respiratory pathogens. Consequently, in March of 2020 the US CDC recommended that NiV be added to the list of Tier 1 Select Agents. Studies to develop effective countermeasures have been hampered by the highly pathogenic nature of NiV and its restriction to BSL-4 containment. An effective prophylactic vaccine would find application with medical personnel and close contacts during outbreaks and with laboratory workers engaged in research. A vaccine based on recombinant G protein deleted (ΔG) vesicular stomatitis virus (rVSVΔG) pseudotyped with the glycoproteins (GP) of a number of high consequence viruses have been shown to completely protect nonhuman primates (NHP) against Ebola, Marburg, and Lassa viruses. In addition, the effectiveness of a rVSV-vectored vaccine in preventing Ebola virus disease was demonstrated in a ring vaccination, open-label, cluster-randomised trial in Guinea during the 2013-16 Ebola epidemic. This vaccine was recently licensed as ERVEBO by the European Union and US FDA. Recently, we developed replication-restricted rVSV NiV vaccine vectors expressing the NiV glycoproteins. Importantly, we showed that these vaccines can completely protect NHPs against high dose lethal NiV Bangladesh strain challenge when used as single injection vaccines. This new data is critically important in the context of containing outbreaks as the most effective vaccine in containing a respiratory pathogen and preventing a pandemic is a vaccine that works rapidly with a single administration. Development of a replication restricted platform that provides improved safety without compromising efficacy is a highly significant advancement and can be applied to other viruses with pandemic potential. The main objective of this proposal is to develop a rVSV-based vaccine against NiV (rVSV-NiVBG) that can provide both rapid protection and long term immunity against the most prevalent and pathogenic Bangladesh strain of NiV and to identify biomarkers that can be used to predict protection. In regard to product development, work will al...