Variola virus, the etiologic agent of smallpox, and the closely related vaccinia virus, which is the basis for the smallpox vaccine, have evolved a complex strategy to evade host defenses in the individual and to permit rapid and devastating spread of infection across a population. The viruses exist in multiple forms distinguished by the size and constitution of their envelope. In order to develop an effective means of passive immunization against smallpox that can be protective for both infected individuals and their contacts, it will be necessary to select high affinity humanized or fully human neutralizing antibodies against these different viral forms. The challenge is profound because most neutralizing antibodies that can prevent infection cannot prevent cell-to-cell spread of the virus after infection has occurred. We have developed a novel and proprietary human monoclonal antibody discovery platform that permits fully human antibodies to be selected from immunoglobulin gene libraries expressed in mammalian cells. The goals of this Phase I proposal are to discover fully human antibodies against vaccinia virus that block the spread of infection in individuals and in the population. We propose to select human antibodies against antigens of the two most relevant infectious forms of vaccinia virus. Selected antibodies will be tested in vitro for virus neutralization. Human/mouse chimeric forms of these antibodies will be tested in vivo for protection of mice from lethal infection. These human monoclonal antibodies may provide a substitute for vaccinia immunoglobulin, which is in short supply, and may prove efficacious in prophylactic and therapeutic treatment of acute exposure to smallpox in the event of a variola virus bioterrorist attack.
