Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Full Paper
  • Published:

Family study of non-responsiveness to hepatitis B vaccine confirms the importance of HLA class III C4A locus

Abstract

Non-responsiveness to hepatitis B virus (HBV) vaccine in adults is strongly associated with HLA-C4AQ0,DRB1*0301,DQB1*02 haplotype. This association was also demonstrated in neonates who failed to mount a humoral response to challenge with HBV vaccine. About 4% of vaccinated newborns do not reach a protective antibody level (10 mIU/ml) at seroconversion and 0.4% is a non-responder even after receiving a fourth dose of vaccine (true non-responders (TNR)); while 3.6% achieved an antibody level 10 mIU/ml (slow responders (SR)) only when reboostered with the fourth dose. In the present study we extend the vaccination and HLA typing to 91 family members of probands to understand better the possible parent-to-child transmission of this trait. A transmission disequilibrium test (TDT), performed in 27 families, showed that the C4AQ0 allele was almost always transmitted to probands, both TNRs and SRs. Although not statistically significant, the highest LOD score was obtained with C4A locus: 1.58. These results suggest the presence of a region regulating immune response against HBV vaccination near to or coincident with the C4A locus.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Mcdermott AB, Zuckerman JN, Sabin CA, Marsh SGE, Madrigal JA Contribution of human leukocyte antigens to the antibody response to hepatitis B vaccination Tissue Antigens 1997 50 8–14

    Article  CAS  PubMed  Google Scholar 

  2. Desombere I, Willems A, Leroux-Roels G Response to hepatitis B vaccine: multiple HLA genes are involved Tissue Antigens 1998 51 593–604

    Article  CAS  PubMed  Google Scholar 

  3. Martinetti M, Cuccia M, Daielli C et al Anti-HBV neonatal immunization with recombinant vaccine. Part II. Molecular basis of the impaired alloreactivity Vaccine 1995 13 555–560

    Article  CAS  PubMed  Google Scholar 

  4. Belloni C, Tinelli C, Orsolini P et al Revaccination against hepatitis B virus of non-responding and low-responding infants immunised at birth. A parallel evaluation of rubella and tetanus vaccine Vaccine 1998 16 399–402

    Article  CAS  PubMed  Google Scholar 

  5. Martinetti M, De Silvestri A, Belloni C et al Humoral response to recombinant hepatitis B virus vaccine at birth: role of HLA and beyond Clin Immunol 2000 97 234–240

    Article  CAS  PubMed  Google Scholar 

  6. Svejgaard A, Ryder P HLA and disease association: detecting the strongest association Tissue Antigens 1994 43 18–27

    Article  CAS  PubMed  Google Scholar 

  7. Fisher MB, Ma M, Goerg S et al Regulation of the B cell response to T-dependent antigens by classical pathway complement J Immunol 1996 157 549–556

    Google Scholar 

  8. Carrol MC, Fisher MB Complement and the immune response Curr Opin Immunol 1997 9 64–69

    Article  Google Scholar 

  9. Finco O, Li S, Cuccia M, Rosen FS, Carrol MC Structural differences between the two human complement C4 isotypes affect the humoral immune response J Exp Med 1992 175 537–543

    Article  CAS  PubMed  Google Scholar 

  10. Spielman RS, McGinnis RE, Ewens WJ Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM) Am J Hum Genet 1993 52 506–516

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Kruskall MS, Alper CA, Awdeh Z, Yunis EJ, Marcus-Bagley D The immune response to hepatitis B vaccine in humans: inheritance patterns in families J Exp Med 1992 175 495–502

    Article  CAS  PubMed  Google Scholar 

  12. Olerup O, Zetterquist H HLA-DR typing by PCR amplification with sequence-specific primers (PCR-SSP) in 2 hours: an alternative to serological DR typing in clinical practice including donor recipient matching in cadaveric transplantation Tissue Antigens 1992 39 225–235

    Article  CAS  PubMed  Google Scholar 

  13. Mauff G, Luther B, Schneider P et al Reference typing report for complement component C4 Exp Clin Immunogenet 1998 15 249–260

    Article  CAS  PubMed  Google Scholar 

  14. Spielman RS, Ewens WJ The TDT and other family-based tests for linkage-disequilibrium and association Am J Hum Genet 1996 59 983–989

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Lathrop GM, Lalouel JM, Julier C, Ott J Strategies for multilocus linkage analysis in humans Proc Nat Acad Sci USA 1984 81 3433–3446

    Article  Google Scholar 

Download references

Acknowledgements

Special thanks are due to Mr Adriano Cortelazzo for his invaluable technical work.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to A De Silvestri.

Additional information

This work was supported by a grant, “Ricerca finalizzata” N.620RFM967/01, from the Ministero Italiano della Sanità.

Rights and permissions

Reprints and permissions

About this article

Cite this article

De Silvestri, A., Pasi, A., Martinetti, M. et al. Family study of non-responsiveness to hepatitis B vaccine confirms the importance of HLA class III C4A locus . Genes Immun 2, 367–372 (2001). https://doi.org/10.1038/sj.gene.6363792

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gene.6363792

Keywords

This article is cited by

Search

Quick links