The broad species tropisms and the ability to cause fatal disease in both animals and humans have distinguished the Henipaviruses;Nipah virus and Hendra virus from all other paramyxoviruses. They can be amplified and cause disease in animals and be transmitted to humans where infection presents as a severe respiratory illness and/or febrile encephalitis. Hendra appeared in Australia in 1994 and was transmitted to humans from infected horses;Nipah appeared in1998 in Malaysia and was passed from infected pigs to humans, but several animal species were also infected. Since their initial discovery, five additional Hendra spill-over events have been reported from 1995 to 2007 and Nipah outbreaks have occurred on a regular basis in Bangladesh and India. We have been extensively studying Hendra and Nipah for several years and have characterized the envelope glycoproteins (F and G), developed animal models of virus infection and pathogenesis. We have identified the cellular receptor for both viruses (ephrinB2), developed a soluble G (sG) subunit vaccine and the first and only potent neutralizing and cross-reactive, fully-human monoclonal antibodies (mAbs). Most recently, we have conducted a series of preliminary virus challenge experiments in nonhuman primates (NHPs). There are presently no approved active or passive therapeutic modalities for Nipah or Hendra infection and there is a critical need for a NHP model for Nipah and Hendra infection. This proposal will bring together the expertise to fully develop and evaluate an African Green Monkey model and test several pre- and post-exposure therapeutic modalities for Nipah virus infection. The main objectives of this proposal will be to: fully characterize a NHP model of Nipah virus infection and evaluate several existing and develop new potential therapeutics for Nipah and Hendra virus infection. Specifically, we will: 1. Establish virus infection, lethal dose, and detection parameters of Nipah and Hendra virus in a nonhuman primate model. 2. Evaluate the protective efficacy of recombinant sG and sF as subunit vaccines for Nipah and Hendra virus in the AGM. 3. Determine the passive protective efficacy of a neutralizing, anti-G, fully-human mAb therapy for Nipah and Hendra virus infection in the AGM. 4. Determine the passive protective efficacy of fusion inhibitor peptide and small interfering RNA (siRNA) therapy for Nipah and Hendra virus infection in the AGM.
Nipah and Hendra are NIAID Priority Pathogens and classified as BSL4 select agents and possess several characteristics which make them highly adaptable for their use as a deliberate release for malicious intent. Recent Nipah outbreaks have involved significant numbers of humans with high fatality >75% and documented person-to-person transmission. The development of therapeutics and vaccine strategies is now important.
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