Viral Hemorrhagic Fevers: Disease Modeling and Transmission

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

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 and Pathogenesis. Animal modeling continues to play a key 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 Mastomys natalensis (rodent) and certain bats. DMT has established breeding colony for the multimammate rat (Mastomys natalensis) to study “Old World” mammarenaviruses, especially Lassa virus (LASV) in their natural reservoir. Using the colony, we have recently demonstrated the potential for sexual transmission of LASV in this rodent reservoir species (Prevost et al. J Infect Dis 2025; Staliunaite et al J Virol 2025). We have also utilized the colony to assess the feasibility of a disseminating vaccine designed to block LASV spillover from the Mastomys into the human population (Streicker et al. Science 2024). The vaccine platform is a Mastomys specific Cytomegalovirus (CMV) that was isolated from samples collected at our field site in Mali (Hansen et al. J Gen Virol 2023) and modified to carry a LASV antigen (Staliunaite et al. J of Virol 2025). We are currently assessing the vaccine’s potential for transmission in the Mastomys and the protection it affords against the transmission of LASV in these animals. During FY24/25 we have continued to refine mouse models for Crimean-Congo hemorrhagic fever virus (CCHFV) and found that host genetic diversity contributes to disease outcome (Rao et al. Npj Viruses 2025). We have also modeled CCHFV in livestock species, such as goats and sheep, to study transmission and intervention strategies (Hawman et al. manuscript in preparation). We also have continued to refine small animal disease models for SARS-CoV-2 (Fischer et al J Infect Dis 2024). More recently, we have performed animal modeling for the emerged 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. We have established mouse and NHP disease models for HPAIV H5N1 and shown that severe disease outcome is dependent on inoculation route (Tipih et al. Nat Commun, 2025; Rosenke et al. Nature 2025). In FY 24/25 DMT has started with in vitro replacement models. Different primary cell cultures derived from mammalian species have been established for in vitro work. In addition, lung and brain organoids derived from human and other mammalian species are currently being investigated as a substitute or to support animal modeling. Vaccines and Immune Responses. DMT’s main vaccine platform remains the recombinant vesicular stomatitis virus (VSV) system. The attenuated, replication-competent VSV platform was developed to counteract the emergence of viral pathogens of significant local/regional and potential global 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 more 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. In collaboration with Dr. A. Marzi (LV, DIR, NIAID), we have continued in FY24/25 to optimize VSV-based filovirus vaccines with focus on Sudan virus that has recently caused disease outbreaks in Uganda (Marzi & Feldmann Npj Vaccines 2024; Fletcher et al. bioRxiv 2025). We have created a new VSV-based vaccine for CCHFV based on the nucleoproteins and demonstrated its efficacy in the CCHFV mouse disease model (Tipih et al. Npj Vaccines 2025). DMT now also uses a second vaccine platform based on a self-amplifying RNA (repRNA) vaccine platform that is based on an alphavirus RNA genome replicon and a nanostructured lipid carrier for delivery. This vaccine platform benefits from a prime-boost strategy and is prone to generate a more durable protective immunity. During FY24/25 we have continued to refine the repRNA CCHFV vaccine and studied the mechanisms and correlates of protection in the mouse and NHP models (Hawman et al. EBioMedicine 2025; Leventhal et al Npj vaccines). We have successful generated repRNA vaccines for other human pathogenic bunyaviruses (severe fever with thrombocytopenia syndrome virus (SFTSV) and Heartland virus (HRTV) (Stamper et al. in revision), enteroviruses (enterovirus D68 (Warner et al Sci Transl Med 2024), and orthomyxoviruses (HPAI H5N1), pathogens that all are of potential national/international public health concern (Hawman et al. Nat Commun 2025). The vaccine platform is easy to manipulate and allows rapid and durable response to emergence. Furthermore, in collaboration with USAMRIID, we have shown durable protective efficacy of a DNA-based vaccine for LASV in NHPs (Andrade et al Commun Med 2024). Treatments. 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 in vitro tissue culture, organoid, and animal models. During FY24/25 we have provided mechanistic and efficacy data for antibodies and drug compounds directed to CCHFV (Monteil et al Nat Microbiol 2024; Leventhal et al Nat Commun 2024), Nipah virus (Johnston et al Cell Rep 2025), and SARS-CoV-2 (Patel et al Emerg Microbes Infect 2024; Zhou et al J Infect Dis 2024). Currently, we are looking into antivirals for HPAI H5N1 viruses utilizing the established models. Overall, during FY24/25 we have developed and refined several animal models for emerging viruses such as arenaviruses, bunyaviruses, filoviruses, flaviviruses, orthomyxoviruses and poxviruses. Using these models, we have studied the pathogenesis of and developed and refined several vaccines and treatment options for these viral pathogens. In an intensified effort, we have started to develop primary tissue culture and organoid models as replacement systems for animal studies. We plan to use those systems for basic mechanistic work and as prescreening tools. This will drastically reduce animal use in future.