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.