Disease Modeling of Influenza and Other Emerging Respiratory Viral Pathogens

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

Orthohantavirues 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. Findings: Several studies have shown that neutralizing antibody (Ab) responses strongly correlate with survival from HCPS in humans. Together with our South American collaborator (M. Barria, Universidad de Concepcin, Chile) we used the murine hybridoma technology to generate mAbs that bound different epitopes on the ANDV glycoproteins (Gn, Gc). Four of these mAbs have previously shown potent protection against lethal ANDV challenge in the hamster model. In a subsequent study, we demonstrated protection by a two-mAb cocktail in the ANDV hamster model even when administered at mid-stage or late-stage disease (Williamson et al., Emerg Infect Dis, 2021). A second focus laid on ecology and epidemiology of HCPS in North America. The reservoir for SNV is Peromyscus maniculatus (deer mouse), a rodent that covers most of the US including Montana. We performed a study aimed to determine 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 SNV in deer mice demonstrating continuing circulation of SNV in western Montana (Williamson et al., Viruses 2021). Coronaviruses Introduction: Middle East Respiratory Syndrome coronavirus (MERS-CoV) continues to reemerge in Saudi Arabia. Its ability to spread through human-to-human transmission has prompted the World Health Organization to include MERS on their list of emerging diseases likely to cause major epidemics and for which countermeasures are urgently needed. As MERS-CoV vaccines are advancing through preclinical and clinical trials funded largely through CEPI, a similar initiative does not exist for the development of antivirals for MERS-CoV. The continuous reemergence of MERS in the Middle East coupled with the lack of approved antiviral therapies or vaccines are of major public health concern. Findings: 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). This vaccine is in clinical trials. 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. Findings: 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 the genotypes Bangladesh and 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 (de Wit et al., eBioMed, in revision). We are currently evaluating VSV-NiVG in dosing studies, time-to-immunity and durability studies in preparation for moving this vaccine candidate into clinical trials (CEPI funded). 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. 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) 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. Findings: 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).