Disease Modeling of Influenza and Other Emerging Respiratory Viral Pathogens

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

Orthohantavirus Introduction: Orthohantaviruses are largely rodent-borne viruses causing two clinical syndromes, hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardio-pulmonary syndrome (HCPS). Currently there are no approved vaccines or therapeutics available. The individual rodent hosts of orthohantaviruses are thought to be persistently infected, without conspicuous adverse effects. Sin nombre orthohantavirus (SNV) and Andes orthohantavirus (ANDV) are the two most relevant HCPS causing orthohantaviruses in the Americas. Only ANDV infections have been associated with human-to-human transmission, an important characteristic when it comes to epidemic potential and public health. The only HCPS rodent model currently available is the Syrian hamster, in which ANDV causes HCPS-like disease but SNV is apathogenic. For SNV there is a NHP model closely mimicking human HCPS. During FY23 we have been working on refining animal models. We have started to test additional monoclonal antibodies as a therapy for orthohantavirus infection. In addition, we have continued trapping rodents in Montana for ecological studies. All studies are ongoing. Henipaviruses Introduction: Nipah virus (NiV) causes severe respiratory and neurological disease with a high case-fatality rate in infected individuals. Based on its lethality, ability to transmit between people, and the lack of medical countermeasures, the World Health Organization has listed NiV as a priority pathogen for which more research is urgently needed. Although no approved vaccines to prevent NiV disease and transmission currently exists, they would be essential tools to prevent NiV outbreaks or to limit their spread. Several NiV vaccine candidates are currently in different stages of development; all are based on the induction of neutralizing antibodies against the NiV glycoprotein (G) or fusion protein. We continued our work on developing treatment options for henipavirus infections. Remdesivir is a nucleotide prodrug with preclinical efficacy against lethal Nipah virus infection in African green monkeys when administered 1 day post inoculation (dpi) (Lo et al., 2019). Here, we determined whether remdesivir treatment was still effective in the African green monkey model when treatment administration initiation was delayed. Remdesivir treatment initiation on 3 dpi provided partial protection from severe Nipah virus disease that was dose dependent, with 67% of animals in the high dose group surviving the challenge. However, remdesivir treatment did not prevent clinical disease, and surviving animals showed histologic lesions in the brain. Thus, early administration seems critical for effective remdesivir treatment during Nipah virus infection. (de Wit et al., Antiviral res 2023) We produced two NiV vaccine candidates using the licensed VSV-EBOV vaccine as a backbone and tested its efficacy against lethal homologous and heterologous NiV challenge with Nipah virus Bangladesh and Nipah virus Malaysia, respectively, in the African green monkey model. The VSV-EBOV vaccine expressing NiV glycoprotein G (VSV-NiVG) induced high neutralizing antibody titers and afforded complete protection from homologous and heterologous challenge. The VSV-EBOV vaccine expressing NiV fusion protein F (VSV-NiVF) induced a lower humoral response and afforded complete homologous protection, but only partial heterologous protection. Both vaccines reduced virus shedding from the upper respiratory tract, and virus replication in the lungs and central nervous system. None of the protected animals vaccinated with VSV-NiVG or VSV-NiVF showed histological lesions in the CNS, but one VSV-NiVF-vaccinated animal that was not protected developed severe meningoencephalitis. VSV-NiVG vaccine offers broad protection against NiV disease. This vaccine is funded through CEPI and has entered clinical trials. (de Wit et al., EBioMedicine 2023) Bornaviruses Introduction: Until the variegated squirrel bornavirus 1 (VSBV-1) was detected in 2015, it was assumed that no bornavirus could infect humans. VSBV-1 was discovered as the causative agent of severe and fatal encephalitis in three squirrel breeders. The closest relative, classical Borna disease virus 1 (BoDV-1), is the causative agent of fatal Borna disease in horses and sheep in Europe. It has recently become clear, that also BoDV-1 causes severe encephalitis in humans. To establish animal models reflecting the pathogenesis in humans, we infected twelve rhesus macaques either with VSBV-1 or with BoDV-1. For each virus, three monkeys each were inoculated by the intracerebral route or by multiple peripheral routes (intranasal, conjunctival, intramuscular and subcutaneous). All BoDV-1 and VSBV-1 intracerebrally infected monkeys developed severe neurological signs around 6 or 12-weeks post infection, respectively. Only one BoDV-1 peripherally infected animal developed similar disease manifestations. All animals with severe clinical disease showed high viral loads in brain tissues and displayed perivascular mononuclear cuffs with a predominance of lymphocytes and similar meningeal inflammatory infiltrates. Thus, intracerebral infection of rhesus macaques may serve as future surrogate model for human bornavirus infection. (Schlottau et al., PNAS Nexus 2022) Note, this working project will be discontinued and the orthohantavirus and henipavirus work will be integrated into Viral hemorrhagic fevers in the future.