From Monovalent EV-A71 Vaccines to Multivalent Vaccines Against Hand, Foot and Mouth Disease in China: Development Progress, Evidence Gaps, and Translational Challenges

Hand, foot and mouth disease (HFMD) is caused by several enteroviruses, with enterovirus A71 (EV-A71) most strongly associated with severe disease and death. Licensed monovalent inactivated EV-A71 vaccines in China have a substantial evidence base for safety, immunogenicity, protective efficacy, and real-world effectiveness, together with relatively mature clinical evaluation and quality control systems. Their protection, however, is predominantly type-specific and does not extend reliably to major non-EV-A71 enteroviruses such as coxsackievirus A16 (CVA16), CVA6, or CVA10. As EV-A71-associated disease has declined, these viruses have become more prominent among residual cases and outbreaks, although shifts in etiological proportions should not be equated with vaccine-driven type replacement. This review synthesizes evidence on the developmental basis and limits of monovalent EV-A71 vaccination and evaluates multivalent candidates based on inactivated virus, virus-like particles (VLPs), chimeric antigens, and nucleic acid platforms. Most multivalent evidence remains preclinical, and major translational gaps include the absence of population-validated correlates of protection for non-EV-A71 types, uncertain antigenic coverage, component-specific quality control requirements, immune response imbalance, clinical case accrual, pediatric safety, coadministration, and affordability. We therefore propose a stage-gated framework that separates developmental maturity from public health priority and evaluates each additional antigen according to product objectives, sustained absolute disease burden, antigenic coverage, manufacturing readiness, immune response balance, clinical evaluability, and incremental public health value. Under this framework, higher valency is a conditional development choice rather than an objective in itself, and vaccine composition should be adapted to regional epidemiology and measurable added benefit over lower valency comparators.