Major Areas of Research
- Development of vaccines and antivirals against hemorrhagic fever viruses such as Ebola, Marburg, and Lassa
- Studies of the mechanism of vaccine-induced immune protection and host immunity to natural infection
- 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. The Biodefense Research Section (BRS) has developed highly effective vaccine strategies for Ebola virus infection in non-human primates. The vaccines are currently being tested in human trials conducted by the VRC Clinical Trials Core Laboratory in Bethesda, Maryland, and Makerere University in Uganda.
A second area of study is the analysis of vaccine-induced immune responses to better understand the mechanisms of immune protection against natural Ebola virus infection. We are using the nonhuman primate model for this study. 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. We have shown that CD8+ cells are required for rAd Ebola vaccine protection and that the level of vaccine-induced antibodies correlates with protection but does not mediate protective responses when delivered by passive transfer. We are currently expanding these studies to define the relative or cooperative roles of antibodies and T lymphocytes for immune protection against Ebola.
Our laboratory is also interested the basic biology underlying Ebola virus pathogenesis, virus-host interactions, and inhibition of virus replication. Evaluation of immune responses in survivors of natural Ebola infection will help to elucidate immune mechanisms of protection, especially memory responses that are critical in a prophylactic vaccine. We have initiated a prospective study of more than 200 subjects in an Ebola-endemic region of West Africa to determine genetic and immunological factors mediating protection against Ebola infection. We have also obtained blood samples from individuals who survived the 1995 Ebola outbreak in Kikwit and are conducting a cross-sectional study to define antibody and T-lymphocyte responses associated with survival from infection. We identified durable antigen-specific T-cell responses in these subjects and also isolated and purified monoclonal antibodies from the B cells of these subjects. We are currently defining their critical characteristics for efficient clearance of virus by neutralization or antibody-dependent cytotoxicity. We have developed an 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.
Dr. Sullivan is a tenured Senior Investigator and Chief of the Biodefense Research Section at the Vaccine Research Center, a division of the National Institute of Allergy and Infectious Diseases (NIAID) at the NIH. She conducted her doctoral thesis in the laboratory of Dr. Joe Sodroski, where her work demonstrated that primary HIV isolates exhibit resistance to antibody neutralization due to occlusion of the coreceptor binding site on gp120. Following her work on HIV, Dr. Sullivan pursued postdoctoral training under the guidance of Dr. Gary Nabel, studying the mechanisms of Ebola virus pathogenesis and immune protection.
Dr. Sullivan’s current research is on the immunologic correlates and mechanisms of protection against infection by hemorrhagic fever viruses. Ebola virus infection is a highly lethal disease for which there are currently no effective therapeutic or preventive treatments. Dr. Sullivan is a leader in the field and has personally conducted many of the most critical experiments. Her work on filovirus immunology and vaccine development is widely considered as one of the very best in the field despite the difficulties of conducting research under highly specialized BSL-4 containment conditions. Dr. Sullivan’s innovative and specialized work on filovirus immunology is recognized worldwide and has consistently been the source of novel observations that have contributed to critical advancements in the field.
Dr. Sullivan’s long-term commitment to Ebola research has resulted in discovery of both vaccines and therapies. By using a novel gene-based prime boost vaccine, Dr. Sullivan and her team were the first to demonstrate vaccine protection against Ebola infection in primates. This was followed by her discovery of a single shot vaccine that provided more immediate protection, making it a very practical vaccine that could be used in the face of an acute Ebola epidemic. As a result, this vaccination schedule is now standard in the field of Ebola vaccine research, where one of the lead Ebola vaccine candidates, ChAd3-EBOV, has been advanced to Phase I/II and III human clinical trials. More recently, Dr. Sullivan and her team discovered a potently protective monoclonal antibody, mAb114, from a human Ebola survivor that completely rescues Ebola-infected primates, even when given as a monotherapy several days after their Ebola exposure. Studies with the antibody demonstrated that the most potent mechanism of antibody protection is through high affinity, low pH-stable binding that blocks a critical Ebola interaction with its intracellular receptor, Neimann-Pick C1. This antibody will undergo Phase I clinical trials in 2017 to support stockpiling in preparation for use in future Ebola outbreaks.
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Sullivan NJ, Geisbert TW, Geisbert JB, Xu L, Yang ZY, Roederer M, Koup RA, Jahrling PB, Nabel GJ. Accelerated vaccination for Ebola virus haemorrhagic fever in non-human primates. Nature. 2003 Aug 7;424(6949):681-4.
Sullivan NJ, Sanchez A, Rollin PE, Yang ZY, Nabel GJ. Development of a preventive vaccine for Ebola virus infection in primates. Nature. 2000 Nov 30;408(6812):605-9.