Change in hepatitis B virus large surface antigen variant prevalence 13 years after implementation of a universal vaccination program in China

Abstract

A nationwide hepatitis B virus (HBV) vaccination program was implemented in China starting in 1992. To study the change in HBV variant prevalence with massive immunization, large HBV surface protein (LHBs) genes from HBV surface antigen (HBsAg)-positive sera were amplified and sequenced. The prevalences of LHBs mutants were compared between the 1992 and 2005 surveys in child and adult groups. The prevalence of "α" determinant mutants in the children increased from 6.5% in 1992 to 14.8% in 2005, where the G145R mutant occurred most frequently. In contrast, mutation frequencies showed little difference between 1992 (9.4%) and 2005 (9.9%) in adults. Moreover, compared to the 1992 survey, the child group surface (S) protein mutation frequency specifically increased (P = 0.005) in the 2005 survey, but the pre-S region mutation frequency did not show a significant difference (P > 0.05). However, the mutation frequency in the adult group increased in both the pre-S and S regions. Furthermore, the frequencies of the disease-related pre-S2 deletion and start codon mutations were significantly higher in the adult groups than in the child groups in both the 1992 and 2005 surveys (P < 0.01). Massive immunization enhances the HBV S protein mutation; the prevalence of LHBs mutants, particularly disease-related mutants, tends to increase with patient age.

Fig 1

Phylogenetic analysis of children from the 1992 survey. The first two letters represent the name of the province.

Fig 2

Phylogenetic analysis of children from the 2005 survey. The first two letters represent the name of the province.

Fig 3

Phylogenetic analysis of adults from the 1992 survey. The first two letters represent the name of the province.

Fig 4

Phylogenetic analysis of adults from the 2005 survey. The first two letters represent the name of the province.

Fig 5

Mutations in the α determinant. (A) Schematic representation showing LHBs and amplified sequences. The start and end residues of the pre-S1, pre-S2, and S proteins and the α determinant of HBsAg are indicated. The bottom rectangle represents the amplified sequence, with the start and end positions labeled. (B) Mutations in the α determinant of child groups. (C) Mutations in the α determinant of adult groups. The y axis represents the mutation ratio (number of mutations/number of all indicated sequences). The x axis represents the amino acid site of the S protein where the indicated mutations occurred.

Fig 6

Distribution of LHBs substitution mutations. (A) Mutation of genotype B in child groups (1992 survey, n = 46; 2005 survey, n = 25). (B) Mutation of genotype B in adult groups (1992 survey, n = 14; 2005 survey, n = 11). (C) Mutation of genotype C in child groups (1992 survey, n = 81; 2005 survey, n = 59). (D) Mutation of genotype C in adult groups (1992 survey, n = 18; 2005 survey, n = 62). The y axis represents the mutation ratio (number of mutations/number of all indicated sequences). The x axis represents the amino acid site of the LHBs protein where the indicated mutations occurred. The yellow line represents the pre-S1 region. The blue line represents the pre-S2 region. The black line represents the S region.