Relaxation of purifying selection on the SAD lineage of live attenuated oral vaccines for rabies virus

Analysis of patterns of nucleotide sequence diversity in wild-type rabies virus (RABV) genomes and in the SAD live attenuated oral vaccine lineage was used to test for the relaxation of purifying selection in the latter and provide evidence regarding the genomic regions where such relaxation of selection occurs. The wild-type sequences showed evidence of strong past and ongoing purifying selection both on nonsynonymous sites in coding regions and on non-coding regions, particularly the start, end and 5′ UTR regions. SAD vaccine sequences showed a relaxation of purifying selection at nonsynonymous sites in coding regions, resulting a substantial number of amino acid sequence polymorphisms at sites that were invariant in the wild-type sequences. Moreover, SAD vaccine sequences showed high levels of mutation accumulation in the non-coding regions that were most conserved in the wild-type sequences. Understanding the biological effects of the unique mutations accumulated in the vaccine lineage is important because of their potential effects on antigenicity and effectiveness of the vaccine.