T cell responses to nonstructural proteins promote cross-serotype immunity to foot-and-mouth disease virus

T-cell responses and significantly enhanced humoral immunity induced by the FMDV GH-Loop peptide, which provided more effective broad-spectrum protection against FMDV serotypes A and O. The underlying mechanisms involved Th1 response activation, memory T-cell differentiation, germinal center formation, and high-level NAb production. The synergy between epitope-specific T cells and humoral immunity is key to protective immune responses. This study presents a novel strategy for the development of broad-spectrum vaccines against FMDV. IMPORTANCE: T-cell epitopes of the nonstructural proteins 2B and 2C of foot-and-mouth disease virus (FMDV) were systematically characterized using FMDV-infected swine combined with intracellular cytokine staining and IFN-γ ELISpot assays. The highly conserved epitopes 2C 157-174 and 2C 109-126, identified across seven FMDV serotypes, were recognized by both swine and cattle T cells. This discovery will aid in the development of universal FMDV vaccines capable of eliciting cross-serotype and cross-species immunity. Unlike conventional FMDV vaccines that rely on humoral responses, the trimeric vaccine Trimer-CD40L-TB, integrating CD40L-enhanced T cells, was engineered with conserved B-/T-cell epitopes. This design not only induced broad-spectrum Th1/cytotoxic T-cell responses but also improved germinal center formation and neutralizing antibody production, leading to cross-protection against serotypes O and A. This approach demonstrated that T-cell-mediated immunity is essential for durable and cross-serotype protection, thereby offering a blueprint for next-generation vaccines.