this is a new application from Dr. Dennis Burton to study the anti-viral activity of antibodies to a filovirus. The filoviruses Ebola and Marburg cause severe hemorrhagic fever and high mortality in humans and there are no vaccines or effective treatments available. The induction of a neutralizing antibody response is generally viewed as highly desirable in a vaccine but a formidable challenge is faced in the case of filoviruses because even convalescent patients exposed to large quantities of virus appear to mount very poor neutralizing antibody responses. However a potent neutralizing human monoclonal antibody has been generated to Ebola virus showing that such antibodies do exist and furthermore the antibody has been shown to protect against disease in animal models. A major question is whether a vaccine can be designed that elicits such antibodies. The investigator proposes an approach to this question based on further understanding the properties of the neutralizing human antibody, exploring the reasons for the low humoral neutralizing response to Ebola virus and attempting to enhance this response by immunotargeting strategies. In addition the potential role of a secreted form of the virus envelope in subverting the immune response is to be investigated.
The specific aims are: (1) to further investigate the in vivo anti-viral activity of the human neutralizing monoclonal antibody KZ52; (2) to study the immunogenicity of the envelope glycoprotein GP by using various preparations of GP to immunize mice, rabbits and macaques and to select from human and monkey antibody libraries followed by analysis of the corresponding antibody responses; (3) to attempt to enhance the immunogenicity of GP using immunotargeting strategies; (4) to investigate the role of secreted GP (sGP) in infection in vivo by using anti-sGP antibodies to neutralize sGP in infected monkeys and monitoring the effects on the course of disease.
