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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1989 Dec;86(23):9084–9088. doi: 10.1073/pnas.86.23.9084

Vaccine engineering: enhancement of immunogenicity of synthetic peptide vaccines related to hepatitis in chemically defined models consisting of T- and B-cell epitopes.

J P Tam 1, Y A Lu 1
PMCID: PMC298438  PMID: 2480595

Abstract

We report the development of two models for synthetic hepatitis B vaccines. The models were based on the multiple antigen peptide (MAP) system and contained the relevant B- and T-cell epitopes without any macromolecular carrier. Two peptides, representing the a determinant of the S region (S protein) of hepatitis B surface antigen, a dominant serotype of hepatitis B virus infection found in humans, and residues 12-26 of the pre-S(2) region of the middle protein were incorporated as either monoepitope or diepitope MAP models. Immunizations of outbred rabbits with the monoepitope MAP that contains the pre-S(2) antigen resulted in high-titered antibody response to the middle protein, but the other monoepitope, containing only the a-determinant peptide antigen, resulted in poor immune responses to either the peptide antigens or to the S protein. The diepitope MAPs containing both the a and the pre-S(2) determinants produced high-titer antibodies reactive to the a-synthetic peptide and the S protein, as well as to the middle proteins. Thus, our results show that the diepitope MAP models eliminate the need for a protein carrier and that the pre-S(2) peptide determinant serves as a T-helper cell epitope that enhances the immune response of the S region and overcomes the poor immunogenicity encountered with a single epitope of the S region.

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Selected References

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  1. Benacerraf B., McDevitt H. O. Histocompatibility-linked immune response genes. Science. 1972 Jan 21;175(4019):273–279. doi: 10.1126/science.175.4019.273. [DOI] [PubMed] [Google Scholar]
  2. Bhatnagar P. K., Papas E., Blum H. E., Milich D. R., Nitecki D., Karels M. J., Vyas G. N. Immune response to synthetic peptide analogues of hepatitis B surface antigen specific for the a determinant. Proc Natl Acad Sci U S A. 1982 Jul;79(14):4400–4404. doi: 10.1073/pnas.79.14.4400. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Good M. F., Pombo D., Quakyi I. A., Riley E. M., Houghten R. A., Menon A., Alling D. W., Berzofsky J. A., Miller L. H. Human T-cell recognition of the circumsporozoite protein of Plasmodium falciparum: immunodominant T-cell domains map to the polymorphic regions of the molecule. Proc Natl Acad Sci U S A. 1988 Feb;85(4):1199–1203. doi: 10.1073/pnas.85.4.1199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Itoh Y., Takai E., Ohnuma H., Kitajima K., Tsuda F., Machida A., Mishiro S., Nakamura T., Miyakawa Y., Mayumi M. A synthetic peptide vaccine involving the product of the pre-S(2) region of hepatitis B virus DNA: protective efficacy in chimpanzees. Proc Natl Acad Sci U S A. 1986 Dec;83(23):9174–9178. doi: 10.1073/pnas.83.23.9174. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Lerner R. A. Antibodies of predetermined specificity in biology and medicine. Adv Immunol. 1984;36:1–44. doi: 10.1016/s0065-2776(08)60898-6. [DOI] [PubMed] [Google Scholar]
  6. Merrifield B. Solid phase synthesis. Science. 1986 Apr 18;232(4748):341–347. doi: 10.1126/science.3961484. [DOI] [PubMed] [Google Scholar]
  7. Milich D. R., Chisari F. V. Genetic regulation of the immune response to hepatitis B surface antigen (HBsAg). I. H-2 restriction of the murine humoral immune response to the a and d determinants of HBsAg. J Immunol. 1982 Jul;129(1):320–325. [PubMed] [Google Scholar]
  8. Milich D. R., Thornton G. B., Neurath A. R., Kent S. B., Michel M. L., Tiollais P., Chisari F. V. Enhanced immunogenicity of the pre-S region of hepatitis B surface antigen. Science. 1985 Jun 7;228(4704):1195–1199. doi: 10.1126/science.2408336. [DOI] [PubMed] [Google Scholar]
  9. Mitchell A. R., Erickson B. W., Ryabtsev M. N., Hodges R. S., Merrifield R. B. Tert-butoxycarbonylaminoacyl-4-(oxymethyl)-phenylacetamidomethyl-resin, a more acid-resistant support for solid-phase peptide synthesis. J Am Chem Soc. 1976 Nov 10;98(23):7357–7362. doi: 10.1021/ja00439a041. [DOI] [PubMed] [Google Scholar]
  10. Mitchison N. A. The carrier effect in the secondary response to hapten-protein conjugates. II. Cellular cooperation. Eur J Immunol. 1971 Jan;1(1):18–27. doi: 10.1002/eji.1830010104. [DOI] [PubMed] [Google Scholar]
  11. Neurath A. R., Kent S. B., Strick N. Location and chemical synthesis of a pre-S gene coded immunodominant epitope of hepatitis B virus. Science. 1984 Apr 27;224(4647):392–395. doi: 10.1126/science.6200931. [DOI] [PubMed] [Google Scholar]
  12. Neurath A. R., Kent S. B. The pre-S region of hepadnavirus envelope proteins. Adv Virus Res. 1988;34:65–142. doi: 10.1016/s0065-3527(08)60516-3. [DOI] [PubMed] [Google Scholar]
  13. Posnett D. N., McGrath H., Tam J. P. A novel method for producing anti-peptide antibodies. Production of site-specific antibodies to the T cell antigen receptor beta-chain. J Biol Chem. 1988 Feb 5;263(4):1719–1725. [PubMed] [Google Scholar]
  14. Prince A. M., Ikram H., Hopp T. P. Hepatitis B virus vaccine: identification of HBsAg/a and HBsAg/d but not HBsAg/y subtype antigenic determinants on a synthetic immunogenic peptide. Proc Natl Acad Sci U S A. 1982 Jan;79(2):579–582. doi: 10.1073/pnas.79.2.579. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Shiels M. T., Czaja A. J., Taswell H. F., Gerin J. L., Purcell R. H., Ludwig J., Rakela J., Nelson C. A. Frequency and significance of delta antibody in acute and chronic hepatitis B. A United States experience. Gastroenterology. 1985 Dec;89(6):1230–1234. doi: 10.1016/0016-5085(85)90637-7. [DOI] [PubMed] [Google Scholar]
  16. Stevens C. E., Alter H. J., Taylor P. E., Zang E. A., Harley E. J., Szmuness W. Hepatitis B vaccine in patients receiving hemodialysis. Immunogenicity and efficacy. N Engl J Med. 1984 Aug 23;311(8):496–501. doi: 10.1056/NEJM198408233110803. [DOI] [PubMed] [Google Scholar]
  17. Tam J. P. Synthetic peptide vaccine design: synthesis and properties of a high-density multiple antigenic peptide system. Proc Natl Acad Sci U S A. 1988 Aug;85(15):5409–5413. doi: 10.1073/pnas.85.15.5409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Tiollais P., Pourcel C., Dejean A. The hepatitis B virus. Nature. 1985 Oct 10;317(6037):489–495. doi: 10.1038/317489a0. [DOI] [PubMed] [Google Scholar]
  19. Unanue E. R. Antigen-presenting function of the macrophage. Annu Rev Immunol. 1984;2:395–428. doi: 10.1146/annurev.iy.02.040184.002143. [DOI] [PubMed] [Google Scholar]

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