A single residue in domain II of envelope protein of yellow fever virus is critical for neutralization sensitivity

The YF-17D vaccine has been used to prevent YF disease. However, recent strains belonging to the SAI displayed reduced sensitivity to the antibodies produced by vaccination, raising concerns about potential future outbreaks. To identify potential amino acid residues responsible for the decreased neutralizing activity of YF-17D-vaccinated sera, we conducted a screening and generated recombinant viruses with amino acid changes specific to the SAI in EDII using the YF-17D genome as a genetic backbone. We found the A83E mutation played a key role in reducing neutralizing sensitivity to YF-17D-vaccinated mouse sera. Importantly, the A83E mutant maintained a comparable attenuation phenotype to YF-17D but elicited enhanced neutralization activity and conferred protection in mice. Together, we identify a key amino acid residue responsible for the neutralization escape of SAI YFV isolates. We propose that this substitution could act as a target for developing an updated YF-17D vaccine.