Mutations within the S Gene of Hepatitis B Virus Transmitted from Mothers to Babies Immunized with Hepatitis B Immune Globulin and Vaccine

Abstract

ABSTRACT. A variant of hepatitis B virus (HBV) having a specific mutation within the S gene has been found to infect vaccinees. To know whether similar variants were involved in Japan, we analyzed two cases of maternal transmission of HBV in infants immunized with hepatitis B immune globulin and hepatitis B vaccine. DNA clones of HBV S genes were propagated from patients and family members and sequenced. In one family, the DNA clones from the baby patient had a Gly-to-Arg mutation at the 145th codon of the S gene, whereas those from her mother had no such mutations. In the other family, all the DNA clones obtained from the two infected children had the 145th codon intact, but they had a missense mutation at the 126th codon of the S gene, causing an amino acid substitution of Asn for Thr or Ile. This same mutation was observed in 12 of 17 clones of DNA obtained from their mother. In comparison with the wild type HBV-derived hepatitis B surface antigen, the two types of S gene mutations, either at the 145th or the 126th codon, were associated with a significant decrease in the antigenicity of some determinants on the hepatitis B surface antigen, measured by MAb. Amino acid substitution at these sites, therefore, would have induced the escape from conventional vaccines that were S gene products of wild type HBV and also from hepatitis B immune globulin, whose main components were probably also antibodies against the S gene products expressed by wild type HBV. (Pediatr Res 32: [264][265][266][267][268] 1992) Abbreviations HBV, hepatitis B virus HBsAg, hepatitis B surface antigen anti-HBs, antibody to HBsAg HBeAg, hepatitis B e antigen anti-HBc, antibody to hepatitis B core antigen HBIG, hepatitis B immune globulin A492, absorbance at 492 nm in ELISA PHA, passive hemagglutination PCR, polymerase chain reaction

Licensed recombinant hepatitis B vaccines protect chimpanzees against infection with the prototype surface gene mutant of hepatitis B virus

“…Among a number of HBV variants with amino acid mutations in the a determinant, 2-31,72-77 those identified in relation to immunoprophylaxis, 2-27 coexisting anti-HBs, [28][29][30][31] or inability to detect HBsAg by several assays [72][73][74][75][76] may have weak avidity to anti-HBs, and several such variants have been demonstrated in vitro to have a reduced binding affinity for anti-HBs. 5,13,18,26,27,42,73 However, the protective immunity elicited by HB vaccines, which is usually polyclonal in nature, may not be totally lost or severely affected in vivo by the alteration of only a single amino acid in the conformation of the a epitope. The exact sequence recognized by neutralizing antibodies is still unknown.…”

“…This assay could detect a minor population of wild-type virus present at a concentration as low as 0.2% of the total virus population. 32 The heterogeneous nature of the HBV genome 46 as determined by cloning from PCR products 5,9,10,15,17,[25][26][27]30 or by sensitive, PCR-based assays, 17,32,48 strongly suggest that in most instances, mutant viruses coexist with wild-type virus in humans. Therefore, we believe that infecting chimpanzees with serum from patient AS, which contained a small population of wild-type virus, mimicked the mixed infections that occur in nature.…”

“…3, 1999 genetic, or other unknown conditions of hosts may lead to inadequate or restricted immune responses to HBsAg. [68][69][70][71] The large number of reports of S gene mutants associated with unsuccessful perinatal immunoprophylaxis [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] has caused alarm that mutations of amino acids in the a determinant of HBsAg may be a significant cause of vaccine failure. However, molecular epidemiological data from Singapore, 7 Taiwan, 12,16 Indonesia, 14 England and Wales, 17 and the United States 48 have confirmed that, among cases of perinatal vaccine failure, the frequency of infection with S gene mutants is lower than that for infection with wild-type virus.…”

“…In the present study, the protective efficacy of licensed hepatitis B vaccines was evaluated against challenge with this mutant virus. There is evidence for the emergence of hepatitis B virus (HBV) mutants with amino acid substitutions in the a determinant of the surface (S) protein in individuals who received immunoprophylaxis against HBV either at birth [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] or during liver transplantation. [21][22][23][24][25][26][27] Also, such HBV mutants have been identified in chronic HBV carriers who acquired HBV infection naturally.…”

Predictions of the emergence of vaccine-resistant hepatitis B in The Gambia using a mathematical model

“…Hepatitis B virus (HBV) variants have been reported to arise in immunized individuals in three situations : (i) after liver transplantation, despite treatment with monoclonal antibodies against surface antigen (antiHBs) and hyper-immunoglobulin (HBIG) treatment [1][2][3], (ii) neonatal infections, despite HBIG and\or vaccination in the UK [4], Italy [5], Singapore [6], Indonesia [7] and Japan [8], and (iii) horizontal infections in young children despite vaccination in The Gambia [9]. The 22 nm subviral surface antigen peptides (HBsAg) used in the current vaccines (both plasma derived and recombinant) produce a narrower immune response than immunity following infection.…”