Nancy Sullivan, Ph.D.
Description of Research Program
The research focus of the Biodefense Research Laboratory comprises three areas:
- Development of vaccines and antivirals against hemorrhagic fever viruses such as Ebola, Marburg and Lassa
- Studies of the mechanism of vaccine-induced immune protection
- Basic research to understand the mechanism of virus replication (entry) and neutralization
Ebola and Marburg viruses have been identified as the cause of several highly lethal outbreaks of hemorrhagic fever for which there is no treatment or cure. Therefore, vaccine studies are critically important for protection against infection. We developed a highly effective vaccine strategy for Ebola virus infection in non-human primates (Sullivan et al., Nature, 2000). A combination of primary immunization with plasmid DNA and boosting with adenoviral vectors containing Ebola genes generated protective immunity in cynomolgus macaques. The vaccine yielded 100% protective efficacy against Ebola infection and showed for the first time that protective immune responses could be generated in primates. The DNA vaccine is currently being tested in human trials conducted by the VRC Clinical Trials Core Laboratory. Subsequently, our laboratory has improved on earlier studies by demonstrating that protective immunity can be generated with a single shot of the adenoviral vector vaccine (Sullivan et al., Nature, 2003). Future studies will precisely define the dose and composition of a clinical Ebola vaccine product to be licensed for human use, and will also apply similar strategies to the development of protective vaccines against Marburg and Lassa viruses.
A second area of study in the Biodefense Research Section is the analysis of vaccine-induced immune responses. The mechanism of immune protection against Ebola virus infection is as yet unknown. Studies using knock-out mice have reported that NK-cells, cytolytic T-cells, or antibodies are each necessary for protection in the mouse model of Ebola virus infection. Other studies have shown using adoptive transfer that antibodies alone or T-cells alone are sufficient for protective immunity. Collectively, these investigations suggest that our understanding of immune protection against Ebola remains limited. Moreover, the mouse models of Ebola infection frequently fail to recapitulate important components of pathogenesis and immunity that are observed in primates. Therefore, we are using the studies of vaccine-induced protective immunity in nonhuman primates to help elucidate the precise mechanism(s) of immune protection against Ebola infection. Current studies under investigation are being conducted in nonhuman primates and utilize methods for selective inhibition of specific immunity such as T- and B-cell depletion, inhibition of T-cell help, and passive transfer of immune globulin. Using multicolor flow cytometry we are able to evaluate with high precision the quantity and quality of vaccine induced cellular responses by identifying distinct subsets of lymphocytes that are present in protected animals, and the kinetics with which they appear. Our goal is to combine the methods described to define and characterize the components required for immune protection against Ebola infection.
Our laboratory is also interested the basic biology underlying Ebola virus pathogenesis, virus-host interactions, and inhibition of virus replication. Ebola virus is a non-segmented negative strand RNA virus with a simple genome containing seven open reading frames. The virus replication cycle begins with binding of the envelope glycoprotein, GP, to a putative cell surface receptor(s) and entry into the host cell by fusion of viral and cell membranes. Strategies to interrupt the virus life cycle can be targeted to these early entry events or to later steps in the replication cycle. We are currently investigating the molecular basis for inhibition of virus entry by molecular inhibitors and neutralizing antibodies, and of genome replication and transcription by siRNA technology. We have developed and array of antibodies, both neutralizing and non-neutralizing, that are useful for characterizing GP structural changes and their functional consequences. We are using these tools to dissect the molecular events underlying Ebola GP interactions within the host. Our goal with these studies is to identify points in the Ebola virus replication cycle that are vulnerable antiviral and neutralization targets.
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