Foot-and-mouth disease (FMD) is globally recognized as a highly economically devastating and prioritized viral disease affecting livestock. Vaccination remains a crucial preventive measure against FMD. The improvement of current vaccine platforms could help control outbreaks, leading to the potential eradication of the disease. In this review, we describe the variances in virulence and immune responses among FMD-susceptible host species, specifically bovines and pigs, highlighting the details of host–pathogen interactions and their impact on the severity of the disease. This knowledge serves as an important foundation for translating our insights into the rational design of vaccines and countermeasure strategies, including the use of interferon as a biotherapeutic agent. Ultimately, in this review, we aim to bridge the gap between our understanding of FMDV biology and the practical approaches to control and potentially eradicate FMD.

Foot-and-mouth disease (FMD), caused by the FMD virus (FMDV), is a highly contagious disease of cloven-hoofed livestock that can have severe economic impacts. Control and prevention strategies, including the development of improved vaccines, are urgently needed to effectively control FMD outbreaks in endemic settings. Previously, we employed two distinct strategies (codon pair bias deoptimization (CPD) and codon bias deoptimization (CD)) to deoptimize various regions of the FMDV serotype A subtype A12 genome, which resulted in the development of an attenuated virus in vitro and in vivo, inducing varying levels of humoral responses. In the current study, we examined the versatility of the system by using CPD applied to the P1 capsid coding region of FMDV serotype A subtype, A24, and another serotype, Asia1. Viruses carrying recoded P1 (A24-P1Deopt or Asia1-P1Deopt) exhibited different degrees of attenuation (i.e., delayed viral growth kinetics and replication) in cultured cells. Studies in vivo using a mouse model of FMD demonstrated that inoculation with the A24-P1Deopt and Asia1-P1Deopt strains elicited a strong humoral immune response capable of offering protection against challenge with homologous wildtype (WT) viruses. However, different results were obtained in pigs. While clear attenuation was detected for both the A24-P1Deopt and Asia1-P1Deopt strains, only a limited induction of adaptive immunity and protection against challenge was detected, depending on the inoculated dose and serotype deoptimized. Our work demonstrates that while CPD of the P1 coding region attenuates viral strains of multiple FMDV serotypes/subtypes, a thorough assessment of virulence and induction of adaptive immunity in the natural host is required in each case in order to finely adjust the degree of deoptimization required for attenuation without affecting the induction of protective adaptive immune responses.

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 10 ⁶ or 10 ⁷ 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 10 ⁵ pfu or twice (0- and 14-dpi) with 10 ⁴ , 10 ⁵ or 10 ⁶ 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.