RP2: Vaccines and antibodies to henipavirus

PROJECT SUMMARY/ABSTRACT - RP2 (Vaccine and Antibodies Against Henipaviruses) Pathogenic RNA viruses represent continuous infectious disease and pandemic threats to public health. Among these are the two emerged zoonotic paramyxoviruses: the ‘prototype’ henipaviruses (HNVs); Nipah virus (NiV) and Hendra virus (HeV), discovered in the mid to late 1990s. The prototype HNVs have a uniquely broad tropism capable of infecting 18 species across 6 orders of mammals using the conserved ephrin-B2 and -B3 ligands as entry receptors. NiV and HeV infection often results in a systemic and fatal respiratory and/or neurological disease in multiple mammalian species including humans. NiV and henipaviral disease are also included in the WHO List of Priority Pathogens, and they are significant biothreats to humans and livestock in South and South East Asia and Australia. HNVs have two membrane glycoproteins: the attachment glycoprotein (G) and the fusion glycoprotein (F) that are the major targets of neutralizing antibodies and the focus of all vaccine and antiviral monoclonal antibody (mAb) strategies. The most extensively studied HNV vaccine is a soluble recombinant form of HeV G (HeV-sG), shown to provide complete protection against lethal challenge by either NiV (both Malaysia (NiV-M) and Bangladesh (NiV-B) or HeV in 4 species including nonhuman primates (NHPs)). With no licensed vaccines or treatments available for human use, this project will use the prototype HNVs as a model to develop, test, and translate a novel vaccination platform (a thermostable, needle-free, adaptable, and widely deployable polyphosphazene (PPZ) adjuvanted dissolvable microneedle patch (MNP)). Preliminary data demonstrates potent immunogenicity of a PPZ-MNP-HeV-sG vaccine in mice, inducing robust antigen-specific HNV cross-neutralizing antibody and cellular immune responses. The MNP vaccines will be used to evaluate HeV-sG and compare stabilized soluble forms of HNV G and F (sGtet and sFstb) and combinations in challenge studies. A reverse genetics system has been developed to generate recombinant, nonpathogenic Cedar virus (rCedV) and rCedV chimeric virus tools by swapping the G and F glycoproteins with those of NiV/HeV as a rapid, surrogate, BSL-2 high-throughput neutralization platform to be used to rapidly evaluate HNV vaccine responses. Also, divergent and pathogenic zoonotic HNVs have been discovered including the related rodent borne Mòjiāng virus and Langya virus (LayV)), and the divergent bat-borne Angavokely virus (AngV). This project will develop and test the rapid, adaptable and readily deployable MNP vaccine platform together with new virological tools to facilitate the translational nature of this pandemic preparedness approach. Specifically, we will: 1) Develop PPZ- MNP-based sGtet and sFstb prototype HNV vaccines; 2) Construct new reporter virus tools; 3) Evaluate vaccine- induced immune responses and HNV-specific mAbs and nabs; and 4) Validate the PPZ-MNP platform with another paramyxovirus antigen.