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21th VHPB Meeting on “Prevention of viral hepatitis in Italy: lessons learnt and the way forward” Catania, 7-8 novembe

21th VHPB Meeting on “Prevention of viral hepatitis in Italy: lessons learnt and the way forward” Catania, 7-8 november 2002. Impact of HBV S-gene mutants on the efficacy of vaccination A. Zanetti Institute of Virology, University of Milan (Italy) . HEPATITIS B GENOME . HBV mutants .

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21th VHPB Meeting on “Prevention of viral hepatitis in Italy: lessons learnt and the way forward” Catania, 7-8 novembe

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  1. 21th VHPB Meeting on “Prevention of viral hepatitis in Italy: lessons learnt and the way forward” Catania, 7-8 november 2002 Impact of HBV S-gene mutants on the efficacy of vaccination A. Zanetti Institute of Virology, University of Milan (Italy)

  2. HEPATITIS B GENOME

  3. HBV mutants • Many mutations which occur during replication • are highly detrimental or lethal and are not • mantained in the virus population. • A proportion of mutants may survive but only • if they confer some advantage over pre-existing • strains. • The immune responses of the host as well as • prophylactic and therapeutic interventions may • select variants which arise during the process • of replication.

  4. Hepatitis B virus • 7 genotypes (A – G) • 9 serotypes (ayw1, ayw2, • ayw3, ayw4, ayr, adw2, adw4, • adrq+, adrq-)

  5. HBsAg mutants 145 Zuckerman AJ, Lancet 2001; 355:1382-4

  6. HBV S-gene mutants (1) • Neutralizing (protective) antibodies induced • by vaccines are mainly targeted towards a • determinant. • Evidence indicates that aasubstitution within • this region of HBsAg can lead to conformational • changes which allows mutated HBV to escape the • vaccine-induced antibodies.

  7. HBV S-gene mutants (2) • The emergence of a HBV variant possibly able • to escape the vaccine-induced response was • first suggested in Italy some 15 years ago • (Zanetti et al, Lancet 1988) • 44 of 1590 (2.8%) vaccinated people, including • babies born to HBsAg carrier mothers, became • HBV infected despite immunisation. All cases • showed co-existence of HBsAg and anti-HBs.

  8. HBV S-gene mutants (3) • Sequence analysis from one of these cases • revealed substitution from Gly to Arg at position • 145 of the a determinant (Carman et al, Lancet 1990) • The same mutation (G145R) was observed in • a patient who underwent transplantation for • end-stage HBV induced hepatitis and who was • subsequently treated with monoclonal anti-a • to prevent reinfection of the homograft • (McMahon et al, 1991)

  9. HBV S-gene mutants (4) • G145R mutation as well as other less frequent • mutations within the HBsAg a determinant were • also found in succesfully vaccinated babies in • Singapore, Thailand, China, Japan, Brazil, the • Gambia and in the USA.

  10. Singapore study (Oon et al, 1995) • 41 breakthrough infections occurred in 345 • (11.9%) infants born to HBsAg/HBeAg carrier • mothers and who were given HBIG + vaccine • at birth (the most frequent variant was G145R). • No evidence of infection was seen in 670 • children born to mothers with HBsAg and • anti-HBe or in any of 107 immunized babies • born to mothers HBsAg -ve.

  11. Taiwan study (Hsu et al, 1999) • An increase in the prevalence (7.8% in 1984, • 19.6% in 1989, 28.1% in 1994) of HBV mutants • (mostly G145R) was reported in Taiwan over • 10 years after the introduction of universal • vaccination. • The rate of mutations was higher among • fully immunised children than among those • unvaccinated.

  12. Emergence of HBV S-gene mutants secondary to vaccination • Based on the assumption that current vaccines • containing S protein do not cross-protect against • S-gene mutants, a mathematical model predicted • the disappearance of wt HBV and the emergence • of G145R in approx 100 years.

  13. Ability of licensed vaccines to protect chimpanzees against infection with G145R • A study carried out at NIH on 4 chimpanzees • vaccinated with licensed recombinant vaccines, • showed that immunised animals were protected • when challenged with G145R(Ogata, 1999)

  14. HBV S-gene mutants in Italy • Studies designed to the detection of HBV S-gene • in vaccinees as well in chronic HBsAg carriers, are • scanty in Italy. • Occasional breakthrough HBV infections due to • G145R or to the less frequent S gene mutants, have • been described both in liver transplant recipients • (Cariani et al, 1995) and in children born to HBsAg • mothers (Mele et al, 2001).

  15. Effectiveness of HB vaccination in babies born to HBsAg+ mothers in Italy • 522 babies were given at birth HBIG + vaccine • At 5-14 years after immunization: • 97% of children had protective anti-HBs • 14 children (2.7%) seroconverted to anti-HBc • 3 children became HBsAg carriers • 1 child carrier had a double mutation with substitution of proline to serine at codons 120 (P120S) and 127 (P127S) within the a determinant

  16. HBsAg + anti-HBe+ Grand mother Grand father HBsAg + anti-HBe+ anti-HBs+ (V) anti-HBs+ (V) HBsAg+ anti-HBc+ anti-HBe+ anti-HBs+ anti-HBc+ HBsAg+ anti-HBc+ anti-HBs+ (V) HBsAg + anti-HBe+ HBV wt anti-HBs + anti-HBc+ mother father Birth: 10/01/1999 Treated with HBIG + vaccine April 2001 ALT 80IU/l June 2001 ALT 60IU/l July 2001 ALT 124IU/l HBsAg+ HBeAg+ anti-HBS + (21mIU/ml) HBV sequence G145R Case AMS

  17. HBV S-gene mutants: a mere curiosity or a potential public health problem? (1) • HBV S-gene mutants have been identified in • successfully immunised people worldwide. • There is evidence that such mutants may escape • detection by assays based on mAbs. • G145R is replication competent, stable and may • persist in the host for years. • S-gene mutants appear to have a greater • chance to emerge after post-exposure prophylaxis • with HBIG and vaccine.

  18. HBV S-gene mutants: a mere curiosity or a potential public health problem? (2) • At present, in Italy there is no evidence that • S-gene mutants may pose a threat to the • established program of vaccination. • Epidemiological monitoring of viral mutations, • documentation of the natural history and disease • progression caused by mutants and their • person-to-person trasmissibility in both susceptible • and immunised individuals, deserve further studies.

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