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Research Project: Intervention Strategies to Respond, Control, and Eradicate Foot-and-Mouth Disease Virus (FMDV)

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Title: Deoptimization of FMDV P1 region results in robust serotype-independent viral attenuation

item Medina, Gisselle
item DIAZ-SAN SEGUNDO, FAYNA - National Institutes Of Health (NIH)
item Spinard Iii, Edward
item Azzinaro, Paul
item RODRIGUEZ-CALZADA, MONICA - Oak Ridge Institute For Science And Education (ORISE)
item Gutkoska, Joseph
item KLOC, ANNA - University Of New Haven
item Rieder, Aida - Elizabeth
item MUELLER, STEPHEN - Codagenix, Inc
item De Los Santos, Teresa

Submitted to: Viruses
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/30/2023
Publication Date: 6/6/2023
Citation: Medina, G.N., Diaz-San Segundo, F., Spinard III, E.J., Azzinaro, P.A., Rodriguez-Calzada, M., Gutkoska, J.R., Kloc, A., Rieder, A.E., Mueller, S., De Los Santos, T.B. 2023. Deoptimization of FMDV P1 region results in robust serotype-independent viral attenuation. Viruses. 15(6).

Interpretive Summary: Foot-and-mouth disease (FMD) is the most contagious animal viral disease known. Use of live attenuated vaccines (LAVs) has been proposed as a strategy to control FMD because such vaccines can stimulate a strong and long-lasting immune response. Recoding the genome of FMDV by codon pair bias deoptimization has resulted in viable attenuated viral strains that offer various distinct levels of protection. In this study we expand the recoding to other FMDV serotypes (A24 and Asia1) and evaluate virulence in vitro and in vivo.

Technical Abstract: Foot-and-mouth disease (FMD), caused by the FMD virus (FMDV), is a highly contagious disease of cloven-hooved livestock that can cause severe economic impact in affected regions. Control and prevention strategies, including development of improved vaccines are urgently needed to effectively control FMD outbreaks in endemic settings. By using reverse genetics, we had previously demonstrated that codon pair bias deoptimization (CPD) could be applied to the P1 region of FMDV serotype A12, rendering a viable virus severely attenuated in mice and swine that was able to mount a strong humoral immune response. In this study, we examined the versatility of the system by using CPD applied to the P1 capsid coding region of other FMDV A subtype, A24 or another serotype, Asia1. Viruses carrying recoded P1 (A24 or Asia1) exhibited different degrees of attenuation (i.e., delayed viral growth kinetics and replication) in cultured cells. Studies in vivo using the mouse model of FMD, demonstrated that inoculation with A24-P1Deopt and Asia1-P1Deopt strains elicited a strong humoral immune response capable of offering protection against challenge with wildtype (WT) homologous strains in this species. However, different results were obtained in pigs. While clear attenuation was detected for both, A24-P1Deopt and Asia1-P1Deopt strains, only a limited induction of adaptive immunity and protection against challenge was detected depending on the inoculated dose. Our work demonstrates that although CPD of the P1 coding region allows for the derivatization of multiple FMDV serotypes/subtypes attenuated viral strains, a detailed evaluation of virulence and induction of immunity in the relevant hosts should be evaluated in each case. Extending CPD to other regions of the FMDV might offer an alternative for derivatization of effective live attenuated FMD vaccine candidates.