부산대학교 도서관

Cytomegalovirus (CMV) is a leading cause of infant hearing loss and neurodevelopmental delay, but there are no clinically licensed vaccines to prevent infection, in part due to challenges eliciting neutralizing antibodies. One of the most well-studied targets for CMV vaccines is the viral fusogen glycoprotein B (gB), which is required for viral entry into host cells. Within gB, antigenic domain 2 site 1 (AD-2S1) is a target of potently neutralizing antibodies, but gB-based candidate vaccines have yet to elicit robust responses against this region. We mapped the genealogy of B cells encoding potently neutralizing anti-gB AD-2S1 antibodies from their inferred unmutated common ancestor (UCA) and characterized the binding and function of early lineage ancestors. Surprisingly, we found that a single amino acid heavy chain mutation A33N, which was an improbable mutation rarely generated by somatic hypermutation machinery, conferred broad CMV neutralization to the non-neutralizing UCA antibody. Structural studies revealed that this mutation mediated key contacts with the gB AD-2S1 epitope. Collectively, these results provide insight into potently neutralizing gB-directed antibody evolution in a single donor and lay a foundation for using this B cell-lineage directed approach for the design of next-generation CMV vaccines. Author summary: Despite over 50 years of research, CMV vaccine candidates have achieved only up to 50% efficacy in clinical trials, in part due to challenges generating neutralizing antibody responses. One of the most promising targets is CMV gB, which mediates viral entry into host cells, and specifically the gB AD-2S1 epitope, which is a target of neutralizing antibodies in natural infection that have not yet been successfully elicited by vaccination. Utilizing B cell lineage analysis of a neutralizing gB AD-2S1-specific monoclonal antibody lineage, we identified a single, improbable heavy chain mutation that conferred neutralizing function and mediated a key contact within the epitope. Our study suggests that lineage-based vaccine design may be used to target induction of CMV gB AD-2S1-specific potently neutralizing antibodies. [ABSTRACT FROM AUTHOR]