Independent emergence of a vaccine-induced escape mutant of hepatitis B virus

Harrison, Tim J.; Hopes, Elaine; Oon, Chong Jin; Zanetti, Alessandro; Zuckerman, Arie J.

doi:10.1016/0168-8278(91)90037-c

Cited by 135 publications

(104 citation statements)

References 8 publications

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“…Some of the rare or unique changes (144 aspartic acid-alanine and 145 glycine-arginine) have also been found in newborns of carrier mothers who developed HBV infection despite prophylaxis with HBIG and vaccination. 7,[19][20][21] The glycine-to-arginine substitution at codon 145 has been shown to reduce binding to monoclonal as well as polyclonal anti-HBs. 9,11,13,22,23 In addition, synthetic peptides with a proline-to-serine substitution at codon 142, aspartic acid-to-alanine substitution at 144, and glycine-to-arginine substitution at 145 have been shown to have reduced binding to anti-HBs compared with wild-type HBsAg.…”

Section: Discussionmentioning

confidence: 99%

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Hepatitis B virus S mutants in liver transplant recipients who were reinfected despite hepatitis B immune globulin prophylaxis

Ghany¹,

Ayola²,

Villamil³

et al. 1998

Hepatology

307

225

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Early studies found that orthotopic liver transplantation (OLT) for hepatitis B virus (HBV)-related liver failure was associated with a very high rate of reinfection and severe and rapidly progressive liver disease, resulting in a significant decrease in graft and patient survival compared with patients transplanted for other causes of liver disease. 1,2 Various measures have been tried in an attempt to reduce the rate of reinfection. The most promising results have come from the use of long-term (Ն 6 months) high-dose hepatitis B immune globulin (HBIG). 3,4 However, this regimen is expensive, and a significant reduction in the rate of reinfection is mainly seen in patients who have nonreplicative infection pre-OLT. Reinfection despite HBIG immunoprophylaxis may be caused by inadequate neutralization of overwhelming amounts of wildtype HBV, or to breakthrough infection by immune escape mutants.The major B-cell epitopes of hepatitis B surface antigen (HBsAg) have been shown to reside in the 'a' determinant region located at amino acid positions 124-149. 5,6 This region is conformational and is thought to consist of two loops held by disulfide bridges between cysteines 124 and 137, and cysteines 138 and 147. 7 The second loop is more conserved and confers most of the antigenicity of the 'a' determinant; this loop is sometimes referred to as the major hydrophilic region (MHR). HBV can be classified into four major subtypes: adr, adw, ayr, and ayw. Antibodies to the 'a' determinant confer protection against all subtypes of HBV. 8 Mutations in the HBV S gene have been reported in OLT recipients who developed HBV reinfection despite prophylaxis with monoclonal or polyclonal hepatitis B surface antibody (anti-HBs). McMahon et al. found amino acid substitutions in the 'a' determinant in all three patients who were reinfected despite monoclonal anti-HBs prophylaxis, 9 while the incidence of mutations in the 'a' determinant in OLT recipients who were reinfected despite HBIG prophylaxis varied from 0% to 33%. 10-12 Some of these mutations, including the glycine-to-arginine substitution at codon 145, have been shown to decrease binding to monoclonal antiHBs, suggesting that the breakthrough infections were caused by immune escape mutants. 9,11,13 The number of patients cited in the above studies ranged from three to seven patients; therefore, the significance of S escape mutants in HBV reinfection post-OLT remains unclear. It is also possible that additional mutations may be present in the HBV S gene outside the 'a' determinant in patients who received polyclonal anti-HBs (HBIG). Unfortunately, there are very few data on the sequence in the rest of the S gene. In addition, to date, there are no data on the reversibility of these mutations after withdrawal of HBIG therapy.

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Section: Discussionmentioning

confidence: 99%

“…Thirteen patients (patients 1-13) became HBsAg-positive again while they were still receiving HBIG; 7 (patients [14][15][16][17][18][19][20] became HBsAg-positive after discontinuation of HBIG. Reinfection occurred after a mean of 8.5 Ϯ 1.5 months (range, 1-20 months) post-OLT.…”

Section: Methodsmentioning

confidence: 99%

Hepatitis B virus S mutants in liver transplant recipients who were reinfected despite hepatitis B immune globulin prophylaxis

Ghany¹,

Ayola²,

Villamil³

et al. 1998

Hepatology

307

225

View full text Add to dashboard Cite

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

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

et al. 1999

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The emergence in vaccinated individuals of hepatitis B virus (HBV) mutants with amino acid substitutions within the a determinant of the surface protein has raised the possibility that such variants represent neutralization escape mutants. We previously demonstrated that one such mutant HBV, strain AS, with an arginine substituted for glycine at surface gene codon 145, was infectious and pathogenic in seronegative chimpanzees. In the present study, the protective efficacy of licensed hepatitis B vaccines was evaluated against challenge with this mutant virus.

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“…(HBV: Carman et al, 1990;Harrison et al, 1991Harrison et al, , 1994Harrison & Zuckerman, 1992. HIV-1 : Albert et al, 1990;Arendrup et al, 1992Arendrup et al, , 1993Nara et al, 1990a, b;Tremblay & Wainberg, 1990;Montefiori et al, 1991;Watkins et al, 1993;Schreiber et al, 1994.…”

Section: Discussionmentioning

confidence: 99%

All rabbits immunized with type A influenza virions have a serum haemagglutination-inhibition antibody response biased to a single epitope in antigenic site B

Lambkin

Dimmock

1995

Journal of General Virology

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Nine rabbits were immunized with type A influenza virions and the epitope specificities of the secondary serum haemagglutination-inhibition (HI) antibody response were analysed with a panel of neutralizing monoclonal (MAb) antibody double escape mutants. Each of the latter was made by sequential selection using a MAb directed to an epitope of a discrete antigenic site, site A, site B or site D, of the haemagglutinin (HA). Thus the epitope reactivity of the escape mutants was represented as A+B-D -, A-B+D and A-B-D +. The HI antibody response of all antisera was biased to the site B epitope. In 9/12 antisera, obtained from seven rabbits immunized with whole virions, the site B epitope was predominant, representing 65-82% of the total HI antibody. The restriction of HI antibody was unaffected by strain of rabbit, route of inoculation (intravenous or subcutaneous), use of Freund's adjuvant, and up to four immunizing injections. In 3/7 rabbits immunized with whole virus, there was a HI antibody response to the HC2 (site A) or HC10 (site D) epitope, but not both, of equal magnitude to the site B epitope. The HI antibody response in one of the rabbits (#40) became more biased to the site B epitope between the third and fourth immunizing doses. Two further rabbits were immunized with virions which had been partially digested with bromelain and then purified from free HA. Both of these made equal HI antibody responses to the site B epitope and the site D epitope, possibly because their remaining HA spikes were better exposed. Overall, these data demonstrate an unexpected degree of restriction in the production of biologically relevant antibody, such that some rabbits (e.g. #45) mount an HI antibody response which is essentially epitope-specific. Implications for epitope specificity of HI antibody stimulated by human influenza vaccines, and also for the generation of antigenic drift variants are discussed. The reason for the non-responsiveness of the immune system to the many other HI epitopes of the HA is not known.

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Independent emergence of a vaccine-induced escape mutant of hepatitis B virus

Cited by 135 publications

References 8 publications

Hepatitis B virus S mutants in liver transplant recipients who were reinfected despite hepatitis B immune globulin prophylaxis

Hepatitis B virus S mutants in liver transplant recipients who were reinfected despite hepatitis B immune globulin prophylaxis

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

All rabbits immunized with type A influenza virions have a serum haemagglutination-inhibition antibody response biased to a single epitope in antigenic site B

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