Use of synonymous deoptimization for the development of modified live attenuated strains of foot and mouth disease virus

Authors: Diaz San Segundo, Fayna; MEDINA, GISSELLE - University Of Kansas; SPINARD, EDWARD - Oak Ridge Institute For Science And Education (ORISE); KLOC, ANNA - Oak Ridge Institute For Science And Education (ORISE); RAMIREZ-MEDINA, ELIZABETH - University Of Connecticut; Azzinaro, Paul; MUELLER, STEFFEN - Codagenix, Inc; Rieder, Aida - Elizabeth; De Los Santos, Teresa

Submitted to: Frontiers in Microbiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/23/2020
Publication Date: 1/21/2021
Citation: Diaz San Segundo, F.C., Medina, G., Spinard, E., Kloc, A., Ramirez-Medina, E., Azzinaro, P.A., Mueller, S., Rieder, A.E., De Los Santos, T.B. 2021. Use of synonymous deoptimization for the development of modified live attenuated strains of foot and mouth disease virus. Frontiers in Microbiology. https://doi.org/10.3389/fmicb.2020.610286.
DOI: https://doi.org/10.3389/fmicb.2020.610286

Interpretive Summary: Despite the big efforts of FAO, OIE and GFRA, FMD eradication remains a challenge. Novel vaccines and biotherapeutics might be required to achieve such goal. In collaboration with Codagenix Inc, ARS has now applied a novel technology to derive multiple strains of FMDV with genomes that have been recoded without affecting their antigenic landscape. These strains grow to high titers in tissue culture and induce an antibody response in the natural host without causing disease when used at low doses. These novel strains can potentially be used as the basis of novel live attenuated or safer inactivated vaccine platforms that ultimately could lead to FMD eradication.

Technical Abstract: Foot-and-mouth disease (FMD) is one of the most feared viral diseases that can affect livestock. The use of an inactivated whole antigen vaccine and the enforcement of strong sanitary policies appeared to contain the disease in vast areas of the world but mostly in developed countries. Unfortunately, FMD remains endemic in the most populated areas of our planet and sporadically, outbreaks occured in previously disease-free countries including the UK, Japan, Taiwan, and South Korea, clearly demonstrating that infection can vastly spread causing devastating economic and social consequences. In proof of concept studies, we had previously demonstrated that “synonymous codon deoptimization” could be applied to the P1 coding region of the viral genome to derive attenuated FMDV strains able to induce protective immune responses after inoculation of the natural host. Here we demonstrate that a similar approach can be extended to the P2 and P3 coding regions of the FMDV genome. Engineered codon deoptimized P2, P3 or P2 and P3 combined RNA 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 swine, a natural host. Derived strains were thoroughly characterized in vitro and in vivo. Our work demonstrates that codon deoptimization technologies can basically be applied to the entire FMDV genome highlighting the potential of this technology to derive for further development into novel improved FMD vaccine candidates.