Cross-herpesvirus immunity of the cytomegalovirus gB/MF59 vaccine response

Vaccination against human cytomegalovirus (HCMV) to protect transplant recipients and prevent congenital infection remains highest priority. Follow-up analyses of a vaccine directed against the fusion protein glycoprotein B (gB/MF59) identified a vaccine-specific response (AD-6) that correlated with protection. Subsequently, it was demonstrated that AD-6 antibodies are anti-viral by preventing cell-associated spread. Here we now demonstrate AD-6 antibodies limit HCMV reactivation - an event critical for pathogenesis via hematogenic spread in vivo. To better understand the AD-6 immunogen, we use structural homology to identify putative AD-6 regions in related herpesviruses and show, despite limited sequence similarity, they share key physico-chemical properties. Of note was that AD-6 mapped to a region under high molecular frustration within gB - arguing AD-6 antibodies inhibit gB function by targeting activity dependent on conserved conformational changes. Consistent with structural conformation being crucial, we observe that both rabbit and human HCMV AD-6 antibodies recognise other herpesvirus AD-6s and that AD-6 antibodies are potently antiviral against HSV-1. Thus, a combinatorial in silico, biochemical and immunological approach reveals conformational epitopes within AD-6 are critical components of the gB/MF59 vaccine, represent crucial conserved elements of AD-6 in gB structure and function which makes it an attractive target of multiple herpesviruses.