Disease Modeling of Influenza and Other Emerging Respiratory Viral Pathogens

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

Over the past fiscal year, we have performed studies on four viral pathogens causing respiratory disease in humans, Nipah virus, influenza A virus, Middle East Respiratory Syndrome coronavirus (MERS-CoV), and Sin nombre hantavirus. Work on Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) will be described in a separate annual report. (1) Nipah virus (NiV): Several cell types are targets of NiV, dictated by the expression of the ephrin-B2/3 ligand on the cell's outer membrane, which interact with the NiV surface proteins. Vascular endothelial cells (ECs) are major targets of infection. Cytopathic effects (CPE), characterized by syncytia formation and cell death, and an ensuing vasculitis, are a major feature of the disease. Smooth muscle cells (SMCs) of the tunica media that line small blood vessels are infected in humans and animal models of NiV disease, although pathology or histologic changes associated with antigen-positive SMCs have not been reported. To gain an understanding of the possible contributions that SMCs might have in the development of NiV disease, we investigated the susceptibility and potential cytopathogenic changes of human SMCs to NiV infection in vitro. SMCs were permissive for NiV infection and resulted in high titers and prolonged NiV production, despite a lack of cytopathogenicity, and in the absence of detectable ephrin-B2/3. These results indicate that SMC might be important contributors to disease by producing progeny NiV during an infection, without suffering cytopathogenic consequences. (DeBuysscher et al., Cells 2021) We have developed a VSV-based NiV vaccine expressing the glycoprotein of the Bangladesh genotype. We could demonstrate efficacy of this vaccine in the Syrian hamster and African green monkey model, the key small and large animal disease models, respectively. We are currently studying vaccine dose-finding and time to immunity with this VSV-Based vaccine. (de Wit et al., unpublished data). (2) Influenza virus: The avian influenza virus outbreak in 1997 highlighted the potential of the highly pathogenic H5N1 virus to cause severe disease in humans. Therefore, effective vaccines against H5N1 viruses are needed to counter the potential threat of a global pandemic. In this study, we generated recombinant VSV-based H5N1 influenza virus vectors to demonstrate the feasibility of this platform for a fast-acting pan-H5 influenza virus vaccine. We chose multiple approaches regarding antigen design and genome location to define a more optimized vaccine approach. After the VSV-based H5N1 influenza virus constructs were recovered and characterized in vitro, mice were vaccinated by a single dose or prime/boost regimen followed by challenge with a lethal dose of the homologous H5 clade 1 virus. We found that a single dose of VSV vectors expressing full-length hemagglutinin (HAfl) were sufficient to provide 100% protection. The vaccine vectors were fast-acting as demonstrated by uniform protection when administered 3 days prior to lethal challenge. Moreover, single vaccination induced cross-protective H5-specific antibodies and protected mice against lethal challenge with various H5 clade 2 viruses, highlighting the potential of the VSV-based HAfl as a pan-H5 influenza virus emergency vaccine. (Furuyama et al NPJ Vaccines 2020) (3) Middle East Respiratory Syndrome coronavirus (MERS-CoV): We worked on a therapeutic and vaccine study for MERS-CoV. We tested the efficacy of prophylactic and therapeutic remdesivir treatment in the rhesus macaque model of MERS-CoV infection. Prophylactic remdesivir treatment initiated 24 h prior to inoculation completely prevented MERS-CoV-induced clinical disease, strongly inhibited MERS-CoV replication in respiratory tissues, and prevented the formation of lung lesions. Therapeutic remdesivir treatment initiated 12 h post inoculation also provided a clear clinical benefit, with a reduction in clinical signs, reduced virus replication in the lungs, and decreased presence and severity of lung lesions. The data presented here support testing of the efficacy of remdesivir treatment in the context of a MERS clinical trial. (de Wit et al., Proc Natl Acad Sci 2020) We had previously developed a synthetic DNA-based vaccine encoding a full-length MERS-CoV spike (S) protein. Here, we further developed the approach by studying both intradermal and intramuscular 2-dose delivery regimens of an advanced synthetic DNA vaccine candidate, which induced potent binding and neutralizing antibodies as well as cellular immune responses in rhesus macaques. In a MERS-CoV challenge, all immunized rhesus macaques exhibited reduced clinical symptoms, lowered viral lung load, and decreased severity of pathological signs of disease compared with controls. Intradermal vaccination was dose sparing and more effective in this model at protecting animals from disease. The data support the further study of this vaccine for preventing MERS-CoV infection and transmission, including investigation of such vaccines and simplified delivery routes against emerging coronaviruses. (Patel et al., JCI Insight 2021) (4) Hantaviruses: Sin Nombre orthohantavirus (SNV) is the main causative pathogen for hantavirus pulmonary syndrome (HPS) in the with >800 HPS cases since discovery in 1993, of which 43 were reported from the state of Montana. The reservoir host (Peromyscus maniculatus; deer mouse) covers most of the US, including Montana, where multiple studies found SNV in local deer mouse populations. We studied the prevalence of SNV in the deer mice at popular recreation sites throughout the Bitterroot Valley in Western Montana. We found high prevalence (up to 20%) of deer mice positive for SNV RNA in the lungs. Our findings demonstrate continuing circulation of SNV in western Montana. (Williamson et al., Viruses 2021) Hantavirus cardiopulmonary syndrome (HCPS) is a severe respiratory disease caused by Sin Nombre virus in North America. As of January 1, 2020, SNV has caused 143 laboratory-confirmed cases of HCPS in Canada. We review critical aspects of SNV virus epidemiology and the ecology, biology, and genetics of HCPS in Canada. (Warner et al., Emerg Infect Dis 2020)