Molecular evolution of hepatitis B vaccine escape variants in China, during 2000-2016

Hepatitis B vaccine escape variants are the main threat to hepatitis B virus (HBV) infection in vaccination era worldwide. With 215 genotype B HBV and 313 genotype C HBV vaccine escape variants isolated from China during 2000-2016, we reported that genotype B HBV vaccine escape strains diverged in ∼1997 (95% HPD; 1987-2005), while genotype C HBV vaccine escape strains diverged in ∼1976 (95% HPD; 1955-2003). Additionally, the p-distance of genotype C HBV vaccine escape strains was 0.0291±0.0169, which was significantly higher than that in the genotype B HBV (t=131.02, p<0.05). However, genotype B HBV vaccine escape strains evolved more rapidly than genotype C HBV (2.103×10^-3 vs 1.083×10^-3 substitutions/site/year). Bayesian skyline plot analysis showed that the populations of genotype C HBV vaccine escape strains fluctuated more than those in genotype B HBV. Four sites (A5T/S, L21S, T/A126S and T/N131I/A) and 13 sites (N3S, T5A, G10Q/R/E, L21S, T47K/A/V, L98V/P, I/S126N/V/T, Q129H/R/L, T131P/I/N/A, G145A/R, L175S/F, L213I/S, V224A/G) were found to be under positive selection in genotype B and C HBV vaccine escape strains, respectively. More importantly, N3S, L21S, T47K, L98V, I/S126T and L213I mutations were detected in 1 (2.5%), 1 (2.5%), 1 (2.5%), 3 (7.5%), 1 (2.5%), 1 (2.5%) genotype C HBV infected Chinese younger with neonatal HBV vaccination, respectively. Therefore, our results should be valuable in further understanding the molecular evolution of HBV and providing new ideas for the elimination of HBV infection.