Serotype-specific differences in antigenic regions of foot-and-mouth disease virus (FMDV): a comprehensive statistical analysis.

Although vaccines are available for prophylaxis of foot-and-mouth disease virus (FMDV), few cases of escape mutants have been reported. To develop serotype-specific FMDV vaccination strategies it is imperative to understand how host selection has influenced evolution of FMDV. This study identified several possible targets for serotype-specific FMDV vaccines using a novel statistical approach. Pairs of closely related FMDV genomes identified in a phylogenetic analysis representing all seven serotypes were examined in order to understand the long term effects of host selection on well-characterized and predicted antigenic regions of importance (B, T(H), and T(C)). Estimates of synonymous and non-synonymous substitution rates for antigenic and non-antigenic regions were calculated for individual pairs of FMDV genomes. We found that on average, both antigenic and non-antigenic regions were subject to purifying selection acting at non-synonymous sites and that several antigenic sites showed a pattern of nucleotide substitution suggesting repeated positive selection across the population. In addition, we found that antigenic regions from the individual FMDV serotypes differed with respect to the extent of amino acid conservation. For a capsid T(H) epitope currently used in one synthetic vaccine, we found that serotypes SAT1-3 had significantly greater non-synonymous nucleotide substitutions than the other serotypes. In contrast, in a second well-studied B-cell epitope, there were no serotype-dependent differences in synonymous or non-synonymous nucleotide substitutions. These results support the hypothesis that host selection acting on individual serotypes has been an important factor in the long-term evolution FMDV and needs to be considered for vaccine design.