Major Areas of Research
- Identification of viral and host factors driving pathogenicity
- Analysis of immune responses to vaccination and challenge to identify important components of protection
- Development of prophylactic and therapeutic strategies against emerging viruses
Highly pathogenic viruses, including filoviruses (Ebola and Marburg virus), continue to pose a significant threat to humans with their potential to cause global public health crises. In 2014, such a crisis occurred and was circumvented to become a pandemic by the global commitment of resources to fight the Ebola virus (EBOV) epidemic that devastated West Africa and spread to Nigeria, the United States and other countries. Since 2018, frequent outbreaks of Ebola virus disease (EVD) have occurred in the Democratic Republic of the Congo.
While EBOV has been extensively studied over the past few decades, we still face gaps in our understanding of the mechanism of pathogenesis. We want to identify and fill these knowledge gaps with the goal to apply the new information to the identification of potential targets for medical intervention. Using our established capacity for in vitro and in vivo experiments in the maximum containment laboratory at RML, we are leveraging molecular approaches including virus reverse genetics systems combined with animal models, and host transcriptome analysis to gain insight into potential mechanisms of pathogenesis.
In 2019, the first EBOV vaccine was approved for human use: a live-attenuated vesicular stomatitis virus (VSV)-based vector expressing the EBOV glycoprotein (VSV-EBOV) as viral antigen. This vaccine was extensively characterized in preclinical studies at RML and deployed during the West African EBOV epidemic in a phase 3 clinical trial highlighting its fast-acting potential as a single dose vaccine ideal for outbreak situations. Filoviruses are genetically distinct and divided into different genera and species making it necessary to develop species-specific vaccines and treatments. Following the successful strategy of the VSV-EBOV, we are developing and characterizing VSV-based vaccines for other human pathogenic filoviruses including Marburg virus. Accompanying these efforts is the development of animal models for novel filoviruses in order to conduct vaccine efficacy studies.
Building upon our existing expertise with the VSV vaccine platform, we used the VSV-EBOV vector as a basis for the development of live-attenuated SARS-CoV-2 vaccines when the Coronavirus disease 2019 (COVID-19) pandemic started in early 2020. Because the VSV-encoded GP determines cellular tropism of the vaccine, we designed and generated vectors without (VSV-SARS2) and with the EBOV GP (VSV-SARS2-EBOV) to allow for ACE2-independent replication. We used the Syrian golden hamster model as well as rhesus macaques to evaluate the protective efficacy of vaccination with VSV-SARS2 or VSV-SARS2-EBOV.
Our long-term goal is to develop approaches that can be applied to any highly pathogenic and emerging virus threatening global public health.
Dr. Marzi received her Ph.D. in virology from the Friedrich-Alexander University Erlangen-Nurnberg, Germany where she studied the glycoprotein-mediated entry of Ebola virus (EBOV) and HIV. After a short first postdoc in Winnipeg, Canada at the National Microbiology Laboratory-Public Health Agency of Canada, Dr. Marzi moved to the NIAID Rocky Mountain Laboratories in Hamilton, MT and continued her BSL4 work on vaccine development for highly pathogenic viruses using primarily the vesicular stomatitis virus (VSV) platform. In 2019, Dr. Marzi was selected as a tenure-track investigator in the NIAID Laboratory of Virology and as an NIH Distinguished Scholar. Her laboratory studies the host-filovirus interactions and develops animal models as well as countermeasures for these pathogens. In addition, her laboratory is expanding the use of the VSV vaccine platform to other emerging pathogens like influenza virus, Zika virus, and SARS-CoV-2.
The German Society of Virology recognized Dr. Marzi with the prestigious Löffler-Frosch Preis (Award) for her research on filoviruses and vaccine development in 2019.
Kyle O'Donnell, Ph.D.
Kyle develops VSV-based vaccines against emerging viruses, and studies how natural killer cell responses and antibody Fc functions contribute to protection.
Paige Fletcher, Ph.D.
Paige investigates the virus-host interactions of filoviruses on early target cells.
Cecilia Prator, Ph.D.
Cecilia is interested in using immune organoids to study immunological responses after vaccination and viral challenge.
J. Fred Rhoderick
Fred is the lab manager and assists with all projects conducted in the lab.
Wakako Furuyama, D.V.M., Ph.D. - Assistant Professor, Nagasaki University, Japan
Tylisha Gourdine, B.Sc. - Contractor, Vaccine Research Center NIAID
Amanda Griffin, Ph.D. - Microbiologist, LV-OOC, NIAID
Benjamin Kaza, B.A. - Graduate Student, Cornell University
Kyle Shifflett, B.Sc. - Graduate Student, University of North Carolina-Chapel Hill
Furuyama W, Shifflett K, Pinski AN, Griffin AJ, Feldmann F, Okumura A, Gourdine T, Jankeel A, Lovaglio J, Hanley PW, Thomas T, Clancy CS, Messaoudi I, O'Donnell KL, Marzi A. Rapid Protection from COVID-19 in Nonhuman Primates Vaccinated Intramuscularly but Not Intranasally with a Single Dose of a Vesicular Stomatitis Virus-Based Vaccine. mBio. 2022 Jan 11;13(1):e0337921.
Marzi A, Jankeel A, Menicucci AR, Callison J, O'Donnell KL, Feldmann F, Pinski AN, Hanley PW, Messaoudi I. Single Dose of a VSV-Based Vaccine Rapidly Protects Macaques From Marburg Virus Disease. Front Immunol. 2021 Oct 27;12:774026.
Furuyama W, Shifflett K, Feldmann H, Marzi A. The Ebola virus soluble glycoprotein contributes to viral pathogenesis by activating the MAP kinase signaling pathway. PLoS Pathog. 2021 Sep 16;17(9):e1009937.
Long CM, Marzi A. Biodefence research two decades on: worth the investment?. Lancet Infect Dis. 2021 Aug 21;(8):e222-e233.
O'Donnell KL, Pinski AN, Clancy CS, Gourdine T, Shifflett K, Fletcher P, Messaoudi I, Marzi A. Pathogenic and transcriptomic differences of emerging SARS-CoV-2 variants in the Syrian golden hamster model. bioRxiv [Preprint]. 2021 Jul 12;2021.07.11.451964.
Marzi A, Robertson SJ, Haddock E, Feldmann F, Hanley PW, Scott DP, Strong JE, Kobinger G, Best SM, Feldmann H. EBOLA VACCINE. VSV-EBOV rapidly protects macaques against infection with the 2014/15 Ebola virus outbreak strain. Science. 2015 Aug 14;349(6249):739-42.