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Principal Investigator: Heinrich Feldmann
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2024
Award: $6,531,361
Funding agency: National Institute of Allergy and Infectious Diseases
The mission of the ‘Disease Modeling and Transmission’ (DMT) section is to study emerging and re-emerging viral pathogens that cause hemorrhagic fever, encephalitis and respiratory distress, with an aim of developing diagnostics, treatments, and vaccines. The research objectives are to learn how to interfere with the viral lifecycle and the virus-induced host responses to identify targets of intervention and to develop measures of prevention. Our research activities are targeted towards a better understanding of virus biology and virus-induced host responses to foster the development of vaccines and therapeutics.
Animal modeling plays a pivotal role in all projects and therefore pathology and pathogenesis are key components of DMT’s work. The ABSL3/4 areas of our research facility are suited for work with most rodent species, ferrets, and nonhuman primates (NHPs). In addition, we have included selected livestock species (i.e. pig, sheep and goat) and unconventional animal species such as reservoir species (i.e. rodents and bats). DMT has established breeding colony for the multimammate rat (Mastomys natalensis) to study “Old World” mammarenaviruses in their natural reservoir. Over FY23/24 we have continued to refine mouse and NHP models for Crimean-Congo hemorrhagic fever virus (CCHFV) to study pathogenesis and immune responses to the infection with the aim to ultimately develop countermeasure. We have also modeled CCHFV in livestock species, such as goats and sheep, to study transmission and intervention strategies. We have further developed the Lassa virus reservoir model in Mastomys natalensis for public health prevention measures. The Mastomys model has also been used to study Mpox infection to understand patterns of shedding and transmission. Recently we have started with animal modeling for the emerging H5N1 highly pathogenic avian influenza (HPAI) viruses that have caused outbreaks in wild birds and poultry as well as US cattle herds with rare transmission to humans. The animal health aspect is obvious, but the public health impact needs further evaluation.
DMT’s main vaccine platform is the recombinant vesicular stomatitis virus (VSV) system. The platform was developed to counteract emerging neglected viral pathogens with low worldwide infectious disease impact but of significant local/regional public health concern. The concept is emergency immunization in form of ring vaccination. DMT has continued to utilize and optimize this platform to create vaccines for many known human pathogenic emerging viral pathogens such as bunyaviruses coronaviruses, filoviruses and flaviviruses. Second-generation vectors are being developed based on the licensed VSV-EBOV vaccine vector. The concept is to utilize the favorable immune cell targeting of the Ebola glycoprotein for better foreign antigen presentation. During FY23/24 we have continued to optimize VSV-based filovirus vaccines with focus on Sudan virus. We have also revisited the aspect of postexposure prophylaxis of VSV-based vaccines for Ebola and Andes virus.
Since the COVID pandemic, DMT has included a self-amplifying RNA (repRNA) vaccine platform to its portfolio that is based on an Alphavirus RNA genome replicon and a nanostructured lipid carrier for delivery. During FY23/24 we have continued to refine the repRNA CCHFV vaccine and to understand the mechanisms and correlates of protection in the mouse and NHP models. We have successful generated repRNA vaccines for additional bunyaviruses (Severe Fever with Thrombocytopenia virus (SFTSV), Heartland virus), coronaviruses (SARS-CoV-2), enteroviruses (EV D68) and orthomyxoviruses (H5N1 HPAI). The vaccine platform is easy to manipulate and allows rapid response to emergence.
Another aspect of DMT’s portfolio are antivirals and therapeutics to treat emerging viral infections. We largely focus on repurposing of drugs/compounds that have already been in clinical testing. For efficacy testing we utilize the established animal models. During FY23/24 we have provided efficacy data for ribavirin and favipiravir in the treatment of CCHFV infections. We have tested the efficacy of monoclonal antibodies for SARS-CoV-2. We have also provided important efficacy data for the use of remdesivir in the treatment of Nipah virus infection. Currently, we are looking into antivirals for H5N1 HPAI viruses utilizing the established animal models.
Overall, during FY23/24 we have developed and refined several animal models for emerging viruses, developed and refined several vaccines and treatment options for emerging viruses. The current H5N1 outbreak in cattle in the US will be a focus for FY24/25 at least throughout the first half of that fiscal year.
Terms: <1-Beta-D-ribofuranosyl-1,2,4-triazolo-3-carboxamide><1-Beta-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide><Alpha Virus><Andes Virus><Animal Model><Animal Models and Related Studies><Animals><Anti-viral Agents><Antigen Presentation><Area><Arenaviridae><Arenavirus><Arenavirus group><Avian Influenza><Avian Influenza A Virus><Avian Influenza Virus><Avian Orthomyxovirus Type A><Bats><Biology><Bionomics><Bird Flu><Bovine Species><Brain Inflammation><Breeding><Bunyavirus><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 antibody><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><Caprine Species><Cattle><Cell Body><Cells><Chiroptera><Clinical Evaluation><Clinical Testing><Clinical Treatment Moab><Common Rat Strains><Communicable Diseases><Congo Virus><Congo hemorrhagic fever virus><Containment><Coronaviridae><Coronavirus><Crimean Hemorrhagic Fever Virus><Crimean-Congo Hemorrhagic Fever Virus><Crimean-Congo hemorrhagic fever orthonairovirus><Data><Diagnostic><Diagnostic tests><Disease Outbreaks><Domestic Fowls><Dysfunction><EBOV><EV-68><EV-D68><Ebola><Ebola Vaccines><Ebola Virus Vaccines><Ebola virus><Ebola-like Viruses><Ecology><Emergencies><Emergency Situation><Encephalitis><Enterovirus><Enterovirus 68><Enterovirus D68><Epidemiologic Research><Epidemiologic Studies><Epidemiological Studies><Epidemiology Research><Evaluation><Family suidae><Farm Animal><Ferrets><Filoviridae><Filovirus><Flavivirus><Fostering><Fowl Pest><Fowl Plague><Fowl Plague Virus><Functional disorder><GS-5734><Generations><Genome><Glycoproteins><Goat><Goats Mammals><Group A Arboviruses><Group B Arbovirus><H5N1><H5N1 virus><Health><Heartland virus><Human><Immune><Immune response><Immunes><Immunization><Immunological response><In Vitro><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Influenza A H5N1><Influenza A Virus, H5N1 Subtype><Intervention><Intervention Strategies><Lassa fever virus><Lassa virus><Learning><Licensing><Life Cycle><Life Cycle Stages><Livestock><Mastomys><Mice><Mice Mammals><Mission><Modeling><Modern Man><Molecular><Monkey Pox><Monkeypox><Monoclonal Antibodies><Murine><Mus><Myxovirus pestis galli><Nanostructures><Nipah Virus><Nipah henipavirus><Non-Polyadenylated RNA><Orthobunyavirus><Orthoflavivirus><Orthomyxoviridae><Orthomyxoviruses><Outbreaks><Ovine><Ovis><Pathogenesis><Pathogenicity><Pathology><Pattern><Physiopathology><Pigs><Play><Poultry><Prevention Measures><Prophylactic treatment><Prophylaxis><Public Health><RNA><RNA Gene Products><RNA amplification><Rat><Rats Mammals><Rattus><Recombinants><Replication Unit><Replicon><Research><Research Activity><Respiratory distress><Ribavirin><Ribonucleic Acid><Ribovirin><Rodent><Rodentia><Rodents Mammals><Role><SARS-CoV-2 antibody><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SUDV><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Fever and Thrombocytopenia Syndrome Virus><Severe Fever with Thrombocytopenia Syndrome Virus><Severe Fever with Thrombocytopenia virus><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Sheep><Sudan Ebola virus><Sudan ebolavirus><Sudan virus><Suidae><Swine><System><Technology><Therapeutic><Transmission><Tribavirin><VSV><Vaccination><Vaccine against ebola><Vaccines><Veklury><Vesicular Stomatitis Virus><Vesicular stomatitis Indiana virus><Viral><Viral Diseases><Viral Hemorrhagic Fevers><Viral reservoir><Virus><Virus Diseases><Virus reservoir><Visit><Work><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><antibody against COVID-19><antibody against SARS-CoV-2><antibody against coronavirus disease 2019><antibody against severe acute respiratory syndrome coronavirus 2><antibody to COVID-19><antibody to SARS-CoV-2><antibody to coronavirus disease 2019><antibody to severe acute respiratory syndrome coronavirus 2><avian flu><avian flu virus><avian influenza H5N1><avian influenza H5N1 virus><avian strains of influenza><bird flu virus><bovid><bovine><clinical test><communicable disease transmission><corona virus><coronavirus disease 2019 antibody><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><cow><develop a vaccine><develop vaccines><development of a vaccine><disease model><disease transmission><disorder model><drug repositioning><drug repurposing><efficacy testing><emergent virus><emerging virus><epidemiologic investigation><epidemiology study><hemorrhagic fever><host response><immune system response><immunoresponse><in vivo><infectious disease transmission><influenza in birds><innovate><innovation><innovative><interventional strategy><life course><mAbs><model of animal><monoclonal Abs><mpox><nano-sized structures><nano-structures><neglect><new vaccines><next generation vaccines><non-human primate><nonhuman primate><novel vaccines><pathogen><pathogenic virus><pathophysiology><plasmid vaccine><porcine><remdesivir><repurposing agent><repurposing medication><research clinical testing><research facility><response><reverse genetics><severe acute respiratory syndrome coronavirus 2 antibody><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><social role><structured lipid><suid><transmission process><vaccine candidate><vaccine development><vaccine platform><vector><vector vaccine><viral emergence><viral infection><viral pathogen><virus infection><virus pathogen><virus-induced disease><wild bird>