The humoral immune response to glycoprotein B of human cytomegalovirus

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Human cytomegalovirus (HCMV) is a ubiquitously distributed pathogen that causes severe disease in immunosuppressed patients and infected newborns. The development of a vaccine has been given high priority and clinical studies using the envelope glycoprotein B (gB) as antigen are ongoing. In the absence of an animal model for HCMV, it is crucial to develop a thorough understanding of the human immune response against the viral gB in order to design optimized vaccines. From repertoire analysis of monclonal antibodies (hMabs), secreted from human memory B cells, we were able to derive an antigenic map of gB. Interestingly, the majority of neutralizing hMabs were found to bind to two previously unknown antigenic domains of gB, increasing the neutralization relevant sites on gB to four. Within the proposed project we will determine the mechanisms of neutralization of hMabs directed to these four sites. In addition, we will establish conditions for the purification of an antibody Fab-fragment in complex with the antigenic domain 4 (AD-4), which induces the highest frequency of neutralizing hMabs during natural infection, to set the ground for future structural analysis. Overall, the proposed project will provide a deeper understanding of the human antibody response against this important HCMV antigen and may identify an “Achilles heel” with respect to neutralization.