Abstract
Foot-and-mouth disease (FMD) is one of the most economically important viral diseases that can affect livestock. In the last 70 years, use of an inactivated whole antigen vaccine has contributed to the eradication of disease from many developed nations. However, recent outbreaks in Europe and Eastern Asia demonstrated that infection can spread as wildfire causing economic and social devastation. Therefore, it is essential to develop new control strategies that could confer early protection and rapidly stop disease spread. Live attenuated vaccines (LAV) are one of the best choices to obtain a strong early and long-lasting protection against viral diseases. In proof of concept studies, we previously demonstrated that “synonymous codon deoptimization” could be applied to the P1 capsid coding region of the viral genome to derive attenuated FMDV serotype A12 strains. Here, we demonstrate that a similar approach can be extended to the highly conserved non-structural P2 and P3 coding regions, providing a backbone for multiple serotype FMDV LAV development. Engineered codon deoptimized P2, P3 or P2, and P3 combined regions were included into the A24Cruzeiro infectious clone optimized for vaccine production, resulting in viable progeny that exhibited different degrees of attenuation in cell culture, in mice, and in the natural host (swine). Derived strains were thoroughly characterized in vitro and in vivo. Our work demonstrates that overall, the entire FMDV genome tolerates codon deoptimization, highlighting the potential of using this technology to derive novel improved LAV candidates.
Highlights
Foot-and-mouth disease (FMD) is a highly contagious viral disease that affects cloven-hoofed animals
In order to test if deoptimization would work for the highly conserved P2 and/or P3 regions of FMD virus (FMDV), we designed viral genomes in which codon usage was deoptimized by replacement with a non-preferred codon (Burns et al, 2006)
Modified sequences were synthetically obtained from a commercial supplier and subsequently replaced into the pA24-wild type (WT) FMDV infectious cDNA clone (Rieder et al, 2005; Supplementary Figures 2A,B)
Summary
Foot-and-mouth disease (FMD) is a highly contagious viral disease that affects cloven-hoofed animals. Its etiologic agent is the FMD virus (FMDV), a member of the Picornaviridae family (Grubman and Baxt, 2004). FMDV can infect over 70 animal species including domestic and wild animals, mostly cattle, swine, sheep, goat, and deer (Grubman and Baxt, 2004). FMD is listed by the International Organization of Animal Health (OIE) as a reportable disease and upon disclosure of an outbreak, severe limitation of movement, and trading are imposed (OIE, 2018). Control of disease in FMD-free countries usually involves culling of infected and in-contact animals, animal movement restrictions, thorough disinfection of affected premises and, sometimes, vaccination with an inactivated virus vaccine (Pluimers et al, 2002). The 2001 United Kingdom outbreak carried an economic burden that exceeded US$12B and impacted the economy of affected areas and the nation as a whole (Mahy, 2004)
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