Neonatal infections by herpes simplex viruses (HSV) still claim a significant toll in terms of morbidity and mortality. It is widely recognized that current approaches are inadequate in preventing most cases of neonatal HSV infections, which occur in the absence of overt active HSV infection. For these reasons, it would be highly desirable to establish affordable, low impact prophylactic measures to prevent cases of neonatal HSV infection due to asymptomatic virus shedding. Transplacental antibodies to HSV are believed to greatly influence both the severity of neonatal HSV infection and the likelihood of transmission. Therefore, passive immunization with selected human monoclonal antibodies could be beneficial in reducing vertical transmission due to asymptomatic viral shedding. Passive immunization of neonates against hepatitis B virus (HBV) combined with active immunization has proven effective in reducing vertical HBV transmission. The present application is aimed at the establishment of novel human recombinant antibodies to HSV of potential utility in the prophylaxis and therapy of HSV infections. Two type-common determinants of HSV glycoprotein D (gD), the group I and VII gD antigenic clusters eliciting protective antibody responses in experimental animals. The investigators have previously established and characterized a very potent human recombinant antibody to the group I antigenic cluster and have shown that group I and group VII murine antibodies are synergistic in virus neutralization, a property that could to be highly beneficial in the prophylactic setting. In the present application it is proposed to establish human recombinant monoclonal antibodies to the group VII antigenic determinant. Because of the low immunogenicity of this antigenic determinant in humans, it is proposed to isolate group VII-specific murine recombinant Fabs and to employ a phage-display strategy for the rapid humanization of the most promising antibodies isolated. Passive immunization with combinations of synergistic human monoclonal antibodies of exceptional efficacy could be useful in the prophylaxis of neonatal HSV infections as well as in the prophylaxis and management of other HSV infections such as opportunistic infections in the immunocompromised and herpetic keratitis. ? ? ?
