Location: Foreign Animal Disease Research
Project Number: 3022-32000-064-050-S
Project Type: Non-Assistance Cooperative Agreement
Start Date: Apr 1, 2026
End Date: Mar 31, 2027
Objective:
The overarching goal is to define the molecular and host determinants of attenuation in previously recoded foot-and mouth virus (FMDV) vaccine candidates and to establish an optimal, safe, and translatable recoding strategy for FMDV live-attenuated vaccines (LAVs) in livestock. While codon deoptimization is known to reduce viral protein expression, the precise mechanisms driving this attenuation remain poorly understood. The leading hypothesis is that enrichment of naturally underrepresented codon pairings impairs efficient protein biosynthesis, but direct evidence, specifically FMDV, is lacking. Additionally, FMDV’s broad host range poses challenges for ensuring consistent LAV safety and efficacy across species. Notably, pigs demonstrate increased susceptibility to adverse vaccine effects compared to cattle, but the underlying reasons whether related to differences in translation or innate immune responses, are unknow. Because authentic FMDV work requires BSL-3Ag containment and this work cannot be done at FADRU PIADC due to lack of access to laboratory facilities, a safe surrogate system is essential for iterative vaccine optimization. Senecavirus A (SVA) is a related picornavirus of swine and an ideal platform to evaluate rational attenuation strategies under BSL-2 conditions.
Approach:
1. Define the molecular mechanisms of viral attenuation induced by genetic recoding. We will use a combination of genomic (construction of FMDV codon deoptimized replicon systems) and protein analysis to examine how codon deoptimization impacts protein production from differentially and previously recoded FMDV non-structural regions using a FMDV replicon.
2. Characterize host species specific responses to recoded FMDV sequences. We will compare gene expression and protein production between modified and original FMDV constructs in relevant cell systems from target species. In addition, we will examine host responses to these constructs to understand how different species react at the cellular level.
3. Engineer a BSL-2 surrogate virus to identify optimal attenuation strategies. We will apply different genetic modification strategies to create a range of weakened SVA strains. Laboratory testing will help identify the most promising candidates, which will then be evaluated in vitro.