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Significance Recoding viral genomes by numerous synonymous substitutions provided live attenuated vaccine candidates predicted to have a low risk of reversion. However, their stability under selective pressure was largely unknown. We evaluated the phenotypic reversion of representative genome-scale deoptimized human respiratory syncytial virus (RSV) vaccine candidates in the context of strong selective pressure. We found that a virus bearing a deoptimized L-polymerase ORF evolved to escape temperature sensitivity restriction by mutations in L and multiple other proteins. Additional analysis revealed that single mutations in the M2-1 ORF were able to substantially escape the restriction imposed by the deoptimized polymerase. Based on this information, we generated a stable deoptimized RSV vaccine candidate with improved attenuation and immunogenicity suitable for additional development.

Genetic stability of genome-scale deoptimized RNA virus vaccine candidates under selective pressure