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Title: Synonymous deoptimization of the foot-and-mouth disease virus P1 coding region causes attenuation in vivo while inducing a strong neutralizing antibody response

item DIAZ-SAN SEGUNDO, FAYNA - University Of Connecticut
item Koster, Marla
item RAMIREZ-MEDINA, ELIZABETH - Oak Ridge Institute For Science And Education (ORISE)
item Medina, Gisselle
item VELAZQUEZ-SALINAS, LAURO - Oak Ridge Institute For Science And Education (ORISE)
item Grubman, Marvin
item De Los Santos, Teresa

Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/4/2015
Publication Date: 11/18/2015
Citation: Diaz-San Segundo, F., Koster, M.J., Ramirez-Medina, E., Medina, G.N., Velazquez-Salinas, L., Grubman, M.J., De Los Santos, T.B. 2015. Synonymous deoptimization of the foot-and-mouth disease virus P1 coding region causes attenuation in vivo while inducing a strong neutralizing antibody response. Journal of Virology. 90:1298-1310. doi:10.1128/JVI.02167-15.

Interpretive Summary: Foot-and-mouth disease (FMD) is one of the most feared viral diseases that can affect cloven-hoofed livestock and wild species. Although by the end of the last century this disease appeared to be contained in developed nations, recent outbreaks in Europe, Japan, Taiwan, South Korea, etc, have demonstrated that infection can spread like wild-fire causing devastating economic and social consequences. One of ARS goals is to be at the vanguard of developing next generation control measures such as novel vaccines and biotherapeutics that could induce rapid, broad and long term protection. Recently it has been demonstrated that in some viruses such as those causing polio or influenza, the genetic code that the virus uses to make proteins can be changed without affecting the intrinsic protein composition. Such viruses became less infectious causing reduced or no disease in animals in comparison to the parental virus. We have applied a similar approach to create a foot and mouth disease virus (FMDV) and evaluated its pathogenic properties in mice and swine. Our results indicate that this technology is feasible and resulted in weakened FMDV without affecting its properties to induce immunity in the host. These results highlight the potential of this technology for further development into novel vaccines that may aid in the control of FMD in a more rapid manner than currently available vaccines.

Technical Abstract: Codon bias deoptimization has been previously used to successfully attenuate human pathogens including polio, respiratory syncytial and influenza viruses. We have applied a similar technology to deoptimize the capsid coding region (P1 region) of the cDNA infectious clone of foot-and-mouth disease virus (FMDV). Despite the presence of 489 nucleotide changes (19 percent), synonymous deoptimization of the P1 region rendered FMDV viable progeny. The resulting strain was stable and reached cell culture titers similar to those obtained for wild type (WT) virus albeit there was a slight reduction of specific infectivity. Studies in mice showed that 100 percent of animals inoculated subcutaneously with the FMDV A12 P1 deoptimized mutant (A12-P1 deopt) survived even when infected at doses 100 times higher than those required to cause death by WT FMDV A12. Interestingly, all mice inoculated with FMDV A12-P1 deopt mutant developed a strong antibody response and were protected against subsequent lethal challenge with WT FMDV at 21 days post inoculation. Remarkably, the safety vaccine margin in mice was at least 1000 fold higher for the A12-P1 deopt as compared to the WT virus. Similar patterns of attenuation were observed in swine, a natural host, in which animals inoculated with FMDV A12-P1 deopt virus did not develop clinical disease until doses reached 1,000-10,000 times the dose required to cause disease with FMDV A12 WT. Consistently, high levels of antibody titers were induced, even at the lowest dose tested. These results highlight the potential use of synonymous codon pair deoptimization as a strategy to safely attenuate FMDV and further develop live attenuated vaccine candidates to control such a feared livestock disease.