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Principal Investigator: Heinrich Feldmann
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2022
Award: $456,404
Funding agency: National Institute of Allergy and Infectious Diseases
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).
Terms: <Acute><Adverse effects><African Green Monkey><Americas><Animal Diseases><Animal Model><Animal Models and Related Studies><Animals><Antibody Response><Antibody titer measurement><Antigenic Determinants><Antigens><Antiviral Agents><Antiviral Drugs><Antiviral Therapy><Antivirals><Avian Influenza><Bangladesh><Binding><Binding Determinants><Bionomics><Bird Flu><Blood Circulation><Blood Vessels><Bloodstream><Borna Disease><Borna disease virus><Borna virus><Brain Inflammation><CNS Nervous System><Cardiopulmonary><Case Fatality Rates><Cell Body><Cells><Central Nervous System><Characteristics><Chile><Chimera Protein><Chimeric Proteins><Chlorocebus aethiops><Chlorocebus sabaeus><Circulation><Clinical><Clinical Treatment Moab><Clinical Trials><CoV S protein><CoV emergence><CoV glycoprotein S><CoV spike glycoprotein><CoV spike protein><Containment><Coronaviridae><Coronaviridae Infections><Coronavirus><Coronavirus Infections><Coronavirus glycoprotein S><Coronavirus spike protein><Coupled><Cricetinae><Data><Deer Mouse><Development><Disease><Disease Outbreaks><Disease model><Disorder><Domestic Horse><Dose><Dysfunction><EBOV><Ebola virus><Ebola-like Viruses><Ecology><Efbn2 Gene Product><Emerging Communicable Diseases><Emerging Infectious Diseases><Encephalitis><Enzootic Encephalomyelitis Virus><Ephrin-B2><Epidemic><Epidemic Hemorrhagic Fever><Epidemiology><Epitopes><Eplg5 Gene Product><Eplg5 Protein><Equine><Equine Morbillivirus><Equine Species><Equus caballus><Equus przewalskii><Europe><Exhibits><Federation of Malaya><Fostering><Fowl Pest><Fowl Plague><Functional disorder><Funding><Fusion Protein><Future><Genotype><Glycoproteins><Goals><Golden Hamsters><Golden Syrian Hamsters><Green Monkey><Grippe><Hamsters><Hamsters Mammals><Hantavirus><Hantavirus Pulmonary Syndrome><Hemorrhagic Fever with Renal Syndrome><Hemorrhagic Nephroso-Nephritis><Hendra><Hendra Virus><Henipavirus><High Prevalence><Histologic><Histologically><Horses><Human><Hybridomas><Immune response><Immunity><Immunize><Immunological response><In Vitro><Individual><Infection><Inflammatory Infiltrate><Influenza><Influenza A><Influenza A virus><Influenza Viruses Type A><Influenzavirus A><International><Intramuscular><Investigation><Korean Hemorrhagic Fever><LERK-5 Gene Product><LERK-5 Protein><Leiomyocyte><Length><Ligands><Lung><Lung Respiratory System><Lymphatic cell><Lymphocyte><Lymphocytic><M mulatta><M. mulatta><MERS><MERS corona virus><MERS coronavirus><MERS coronavirus disease><MERS virus><MERS-CoV><MERS-CoV disease><Macaca mulatta><Malay Federation><Malaya><Malaysia><Membrane><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Meningeal><Mesocricetus auratus><Mice><Mice Mammals><Middle East><Middle East Respiratory Syndrome><Middle East Respiratory Syndrome CoV disease><Middle East Respiratory Syndrome Corona Virus><Middle East Respiratory Syndrome Coronavirus><Middle East Respiratory Syndrome Virus><Middle East Respiratory Syndrome coronavirus disease><Middle East Respiratory Syndrome-CoV><Middle Eastern Respiratory Syndrome><Middle Eastern Respiratory Syndrome CoV disease><Middle Eastern Respiratory Syndrome Corona virus><Middle Eastern Respiratory Syndrome Coronavirus><Middle Eastern Respiratory Syndrome Virus><Middle Eastern Respiratory Syndrome coronavirus disease><Middle Eastern Respiratory Syndrome-CoV><Modeling><Modern Man><Molecular Interaction><Monkeys><Monoclonal Antibodies><Mononuclear><Montana><Murine><Mus><NIAID><NIH><National Institute of Allergy and Infectious Disease><National Institutes of Health><Near East Equine Encephalomyelitis Virus><Nervous System Diseases><Neuraxis><Neurologic Disorders><Neurologic Signs><Neurological Disorders><Nipah Virus><North America><Orthomyxovirus Type A><Outbreaks><Ovine><Ovis><Pathogenesis><Pathogenicity><Pathologic><Pathology><Peripheral><Peromyscus><Persons><Physiopathology><Predisposition><Preparation><Prevalence><Production><Public Health><Recreation><Regimen><Reporting><Research><Respiratory Disease><Respiratory System Disease><Respiratory System Disorder><Rhesus Macaque><Rhesus Monkey><Rodent><Rodent Model><Rodentia><Rodents Mammals><Route><Saudi Arabia><Severities><Sheep><Site><Smooth Muscle Cells><Smooth Muscle Myocytes><Smooth Muscle Tissue Cell><South American><Spinal Column><Spine><Squirrel><Surface Proteins><Susceptibility><Symptoms><Syndrome><Syrian Hamsters><Technology><Testing><Therapeutic><Time><Transmission><Tunica Media><Type A Influenza><United States National Institutes of Health><Upper respiratory tract><VSV><Vaccination><Vaccines><Vascular Media><Vascular Medias><Vertebral column><Vesicular Stomatitis Virus><Vesicular stomatitis Indiana virus><Viral><Viral Burden><Viral Diseases><Viral Load><Viral Load result><Viral Shedding><Virus><Virus Diseases><Virus Replication><Virus Shedding><Wit><World Health Organization><anti-viral agents><anti-viral compound><anti-viral development><anti-viral drug development><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-viral therapeutic development><anti-viral therapy><anti-viral therapy development><anti-virals><antibody titering><antiviral compound><antiviral development><antiviral drug development><antiviral medication><antiviral therapeutic><antiviral therapeutic development><antiviral therapy development><avian flu><backbone><base><brain tissue><cell type><communicable disease transmission><corona virus><corona virus emergence><coronavirus S protein><coronavirus emergence><coronavirus spike glycoprotein><coronavirus vaccine><deermouse><developing anti-viral agent><developing anti-viral drug><developing anti-viral therapeutic><developing anti-viral therapy><developing antiviral agent><developing antiviral drug><developing antiviral therapeutic><developing antiviral therapy><developmental><disease transmission><disorder model><ebolavirus><emergent CoV><emergent corona virus><emergent coronavirus><emerging CoV><emerging corona virus><emerging coronavirus><epidemiologic><epidemiological><host response><human model><immune system response><immunogen><immunoresponse><infectious disease transmission><influenza in birds><innovate><innovation><innovative><insight><lymph cell><mAbs><medical countermeasure><membrane structure><model of animal><model of human><model organism><nCoV><nervous system disorder><neurological disease><neutralizing antibody><new CoV><new corona virus><new coronavirus><novel CoV><novel corona virus><novel coronavirus><pathogenic virus><pathophysiology><pre-clinical trial><preclinical trial><prevent><preventing><priority pathogen><pulmonary><respiratory><response><subcutaneous><subdermal><synthetic DNA><synthetic construct><tool><transmission process><true squirrel><upper airway tract><vaccination study><vaccination trial><vaccine against coronavirus><vaccine candidate><vaccine study><vaccine trial><vascular><viral infection><viral infectious disease treatment><viral multiplication><viral pathogen><viral replication><virus infection><virus multiplication><virus pathogen><virus-induced disease>