Nebulization of anti-viral peptides to fight against Nipah virus infection – NebuNipaStop

Nipah virus (NiV) is a zoonotic virus of Henipavirus genus, capable of causing severe encephalitis and respiratory illness in humans. Since its emergence in 1998 in Malaysia, NiV reappeared in 2001 in India and Bangladesh, where epidemics, with an average mortality rate of 70%, are occurring almost every year. The ability NiV to be transmitted from human-to-human, and the discovery of Henipavirus in bats in West Africa, highlights the threat these viruses pose to human health. There is to date neither prophylaxis nor therapeutic treatment to fight against outbreaks of NiV humans. Due to their high pathogenicity, the wide host range distribution, the interspecies transmission and absence of prophylactic and therapeutic approaches, Henipavirus are classified as class 4 pathogens and considered to be the potential agents of bioterrorism. The prevention and/or containment of present and future outbreaks, irrespective of their natural or bioterrorism origin, will depend on our ability and to design efficient strategies to combat these viruses. The objective of this project is to contribute to the development of antiviral strategies against Nipah virus by developing a new approach to administrate aerosolized peptides capable of inhibiting respiratory NiV infection. To achieve this goal, we will target the virus entry into the host using peptides that inhibit fusion between the virus and the cell. Our work previously funded by ANR Astrid, demonstrated the efficacy of intranasal administration of peptides blocking viral fusion, in preventing NiV infection in hamsters and identified the lead candidates with the best antiviral activity in vivo. We propose in this project to go further and develop a new approach based on aerosolization (nebulization) of peptides, for their distribution in the respiratory system and test the ability to prevent infection in the non-human primate model, African green monkeys, highly susceptible to NiV infection. This approach presents a conceptually new strategy to protect the population at risk against infection by respiratory viruses, including NiV. It is a non-invasive needle-free approach, which may be used when antiviral protection is required, without any medical assistance. As part of the project we will analyze pharmacokinetics, biodistribution, possible toxicity and antiviral efficacy of fusion inhibitor peptides in monkeys. The validation of the approach would consequently provide a solid basis for its rational application in humans.

To achieve the objectives of the project, two academic teams and one company join their complementary skills. The academic partners have the excellent expertise in the immunovirological characterization (CIRI) and the primate models of infection (P4 Jean Mérieux) by class 4 viruses. In addition, the Partner 1 (CIRI) is a leading world expert in the field of immunopathogenesis of infections by Henipavirus. The industrial partner (DTF) has a solid expertise in development of drug nebulization approaches and aerosoltherapy. The results that will be obtained during this project will provide the critical set up of a novel prophylactic and therapeutic strategy against the NiV and thus open up new prospects for preventing and treating this highly lethal infectious disease. In addition, the validation of this antiviral approach based on the nebulization of anti-fusion peptides may allow the development of new strategies against other respiratory viruses.