Live-attenuated foot-and-mouth disease virus vaccine engineered by codon deoptimization induces a strong protective immune response in cattle

Foot-and-mouth disease (FMD) is a fast-spreading, economically devastating veterinary viral disease. While inactivated vaccines have contributed to FMD control worldwide, recent outbreaks in Europe and Asia highlight the need for new control strategies. Live-attenuated virus (LAV) vaccines provide strong and long-lasting protection. We previously demonstrated that deoptimization of various viral coding regions results in attenuated foot-and-mouth disease virus (FMDV). Here, an FMDV A24Cruzeiro LAV with codon deoptimized P2/P3 regions (A24-P2/P3Deopt) and markers differentiating infected from vaccinated animals (DIVA) was tested for safety/efficacy in cattle. Animals inoculated intradermolingually (IDL) with 10⁶ or 10⁷ pfu of A24-P2/P3Deopt for safety testing exhibited no clinical signs, viremia or viral shedding for 28 days post inoculation (DPI). To assess efficacy, cattle were subcutaneously inoculated either once with 10⁵ pfu or twice (0- and 14-dpi) with 10⁴, 10⁵ or 10⁶ pfu A24-P2/P3Deopt. No animal developed signs of disease post-inoculation. All prime-boost vaccinated animals developed strong neutralizing antibody responses that were protective against challenge with WT FMDV A24. Moreover, vaccinated sera showed strong cross-reactivity against several A strains and serotype Asia1. Our work demonstrates that codon deoptimization is a viable technology to derive novel LAV candidates that are safe, immunogenic and efficacious against FMD in cattle.