When structural rationales fall short: revisiting the immunogenicity of herpesvirus prefusion and postfusion...

The concept of stabilising viral fusion proteins in their prefusion conformation to focus immunogenicity has driven vaccine research across many viruses. However, for herpesviruses, recent findings suggest that this approach may not yield the hoped-for immunological benefits, underscoring the importance of critically assessing the structure of target proteins. This review examines the structural and functional characteristics of herpesvirus glycoprotein B (gB), a key component in herpesvirus entry and fusion, and evaluates recent immunogenicity studies of gB. Despite successes with other viral membrane fusion proteins, multiple studies on herpesvirus gB, including herpes simplex virus 1/2, and human cytomegalovirus, demonstrate that prefusion stabilisation does not increase neutralising antibody responses or improve vaccine efficacy. Factors such as glycan shielding, epitope masking, and structural subtlety between different conformations likely contribute to these outcomes. While for Epstein-Barr virus, there might be a trend towards improved B-cell neutralisation, gB from other herpesviruses is still to be tested. Beyond gB, other glycoproteins like gD and gH/gL complexes show promise as vaccine targets, with some eliciting more neutralising antibodies than gB. The review emphasises that alternative approaches, such as rational immunogen design, oligomerisation, optimised delivery systems, and adjuvants, may improve vaccine effectiveness. Finally, a comprehensive understanding of herpesvirus fusion on a mechanistic and structural level is crucial, as this allows innovative immunogen design, hopefully leading to the development of broad and durable herpesvirus vaccines.