T-cell immunity in human herpesvirus vaccine development: research advances and translational challenges

Human herpesviruses are widespread, establish lifelong latency, undergo intermittent or context-dependent reactivation, and cause diverse clinical manifestations. These features distinguish herpesvirus vaccine development from that for most acute infections. For indications involving latency, reactivation, or virus-associated disease, assessments based solely on the prevention of primary infection or on neutralizing-antibody responses do not capture all relevant mechanisms of immune control. Depending on the virus and indication, T cells may recognize infected or transformed cells, maintain immune surveillance, and limit viral replication, shedding, tissue injury, or disease progression. T-cell-directed strategies are therefore being investigated for therapeutic vaccination, protection of high-risk populations, prevention of reactivation-associated disease, and immunotherapy of virus-associated tumors. Using an indication-to-endpoint framework, this review compares preventive and therapeutic strategies and examines how antigen accessibility, tissue localization, host context, and endpoint selection influence whether measurable cellular immunogenicity translates into virological or clinical benefit across viruses and disease settings.