Prevention of CMV infection with a viral IL-10 neutralizing antibody - the goal of this work is to prevent primary CMV infection through prophylactic passive vaccination with a highly potent CMV IL-10…

Prevention of CMV infection with a viral IL-10 neutralizing antibody - the goal of this work is to prevent primary CMV infection through prophylactic passive vaccination with a highly potent CMV IL-10 neutralizing monoclonal antibody. The greatest risk of congenital cytomegalovirus (CMV) infection, in terms of both numbers of infections and severity of disease, follows from primary maternal infection during the first trimester of pregnancy. There is no vaccine to prevent congenital CMV disease, and treatment options are limited due to risk to the fetus. Previous CMV vaccine approaches have focused on eliciting neutralizing antibody responses against viral glycoproteins, similar to those observed following infection. Glycoprotein b (GB) has shown some efficacy in CMV seronegative women and is considered a leading vaccine antigen, as are members of the pentameric complex. However, IT is not clear whether targeting CMV glycoproteins can ever be sufficient to prevent or reduce CMV transmission since natural immunity to CMV in immune-competent people appears only to protect against clinical disease-not against (super)infection. We propose to protect against CMV infection by instead targeting the CMV-encoded IL-10 (cmvil-10) immunomodulatory gene using a highly potent neutralizing monoclonal antibody. We hypothesize that a highly potent CMV IL-10 neutralizing monoclonal antibody will provide significant protection from horizontal primary infection in a rhesus macaque model for CMV. Aim 1. Characterize and purify highly potent viral IL-10 neutralizing monoclonal antibodies. Our preliminary data using active vaccination showed that macaques with strong rhcmvil-10 neutralizing antibody responses were significantly protected from horizontal rhcmv infection. We will use pbmc isolated from those protected macaques to select for b cell clones and use them to produce highly potent VIL-10 neutralizing antibodies. Aim 2. Test if viral IL-10 neutralization protects against primary rhcmv infection. Our previous work demonstrated that rhcmvil-10 neutralizing antibodies elicited following vaccination with recombinant protein provided significant protection from horizontal transmission of rhcmv. In this aim, we will determine whether highly potent rhcmvil-10 neutralizing monoclonal antibodies provide similar protection, either alone or in combination with anti-GB antibodies. Significance. Host immune evasion and modulation by CMV have hindered development of a vaccine to prevent infection. Targeting cmvil-10, a key viral immunomodulatory protein, with neutralizing monoclonal antibodies will open a novel approach to preventing CMV disease that also has potential to impact our understanding of how to control other pathogens that manipulate host immunity.