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Synthetic Peptides

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Vaccine Protocols

Part of the book series: Methods in Molecular Medicine™ ((MIMM,volume 87))

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Abstract

Efforts to produce more stable and defined vaccines have focused on a detailed analysis of the immune response to many infectious diseases in order to identify the antigenic sites on the pathogens that are involved in stimulating protective immunity. Armed with this knowledge, it is possible to mimic such sites by producing short chains of amino acids (peptides), and to use these as the basis for novel vaccines. The earliest documented work on peptide immunization is actually for a plant virus—the tobacco mosaic virus. In 1963, Anderer (1) demonstrated that rabbit antibodies to an isolated hexapeptide fragment from the virus-coat protein coupled to bovine serum albumin (BSA) would neutralize the infectious virus in culture. Two yr later, he used a synthetically produced copy of the same peptide to confirm this observation. This was pioneering work, and it was more than 10 years before the next example of a peptide that elicited antivirus antibody appeared, following work by Sela and his colleagues (2) on a virus—MS2 bacteriophage—which infects bacteria. The emergence of more accessible techniques for sequencing proteins in 1977, coupled with the ability to readily synthesize peptides already developed in 1963, heralded a decade of intensive research into experimental peptide vaccines. The first demonstration that peptides could elicit protective immunity in vivo, in addition to neutralizing activity in vitro, was obtained using a peptide from the VP1 coat protein of foot-and-mouth-disease virus (FMDV) in 1982, with the guinea pig as a laboratory animal model (3,4). This finding was subsequently supported by the demonstration of protective immunity in cattle and pigs (5,6).

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References

  1. Anderer, F. A. (1963) Versuch zur bestimming der seralogisch terminaten gruppen des tobakmosaik virus. Naturforsch. Tell B. 188, 1010–1014.

    Google Scholar 

  2. Langebeheim, H., Amon, R., and Sela, M. (1976) Antiviral effect of MS-2 coliphage obtained with a synthetic antigen. Proc. Natl. Acad. Sci. USA 73, 4636–4640.

    Article  Google Scholar 

  3. Bittle, J. L., Houghten, R. A., Alexander, H., Schinnick, T. M., Sutcliff, J. G., Lerner, R. A., et al. (1982) Protection against foot-and-mouth disease by immunization with a chemically synthesized peptide predicted from the viral nucleotide sequence. Nature 298, 30–33.

    Article  PubMed  CAS  Google Scholar 

  4. Pfaff, E., Mussgay, M., Bohm, H. O., Schalz, G. E., and Schaller, H. (1982) Antibodies against a preselected peptide recognize and neutralize foot and mouth disease virus. EMBO J. 1, 869–874.

    PubMed  CAS  Google Scholar 

  5. DiMarchi, R., Brooke, G., Gale, C., Crocknell, V., Doel, T., and Mowat, N. (1986) Protection of cattle against foot-and-mouth disease by a synthetic peptide. Science 232, 639–641.

    Article  PubMed  CAS  Google Scholar 

  6. Broekhuijsen, M. P., Van Rijn, J. M. M., Blom, A. J. M., Pouwels, P. H., Enger-Valk, B. E., Brown, F., et al. (1987) Fusion proteins with multiple copies of the major antigenic determinant of foot-and-mouth disease virus protect both the natural host and laboratory animals. J. Gen. Virol. 68, 3137–3143.

    Article  PubMed  Google Scholar 

  7. Langweld, J. P. M., Casal, J. I., Osterhaus, A. D. M. E., Cotes, E., Swart, R. de., Vela, C., et al. (1994) First peptide vaccine providing protection against viral infection in the target animal: studies on canine parvovirus in dogs. J. Virol. 68, 4506–4513.

    Google Scholar 

  8. Loangeveld, J. P. M., Kamstrup, S., Uttenthal, A., Strandbygaard, B., Vela, C., Dalsgaard, K., et al. (1995) Full protection in mink against mink enteritis virus with new generation canine poarvovirus vaccines based on synthetic peptide or recombinant protein. Vaccine 13, 1033–1037.

    Article  Google Scholar 

  9. Francis, M. J. (1990) Peptide vaccines for viral diseases. Sci. Prog. 74, 115–130.

    PubMed  CAS  Google Scholar 

  10. Ijaz, M. K., Attah Poku, S. K., Redmond, M. J., Parker, M. I., and Babiuk, L. A. (1991) Heterotypic passive protection induced by synthetic peptides corresponding to VP7 and VP4 of bovine rotavirus. J. Virol. 65, 3106–3113.

    Google Scholar 

  11. Barnett, P. V., Pullen, L., Staple, R. F., Lee, L. J., Butcher, R., Parkinson, D., et al. (1996) A protective anti-peptide antibody against the immunodominant site of the A24 Cruzeiro strain of foot-and-mouth disease virus and its reacitvity with other subtype viruses containing the same minimum binding sequesce. J. Gen. Virol. 77, 1011–1018.

    Article  PubMed  CAS  Google Scholar 

  12. Partidos, C. D., Vohra, P., Jones, D., Farrar, G., and Steward, M. W. (1997) CTL responses induced by a single immunization with peptide encapsulated in biodegradable microparticles. J. Immunol. Methods 206, 143–151.

    Article  PubMed  CAS  Google Scholar 

  13. Delmas, A. and Partidos, C. D. (1996) The binding of chimeric peptides to GM1 gangliotides enables induction of antibody responses after intranasal immunization. Vaccine 14, 1077–1082.

    Article  PubMed  CAS  Google Scholar 

  14. Partidos, C. D., Vohra, P., and Steward, M. W. (1996) Induction of measles virus-specific cytotoxic T-cell response after intranasal immunization with synthetic peptides. Immunology 87, 179–185.

    Article  PubMed  CAS  Google Scholar 

  15. Partidos, C. D., Beignon, A. S., Semetey, V., Briand, J. P., and Muller, S. (2001) The bare skin and the nose as non-invasive routes for administration peptide vaccines. Vaccine 19, 2708–2715.

    Article  PubMed  CAS  Google Scholar 

  16. Jones, D. H., Partidos, C. D., Steward, M. W., and Farrar, G. H. (1997) Oral delivery of poly (lactide-co-glycolide) encapsulated vaccines. Behring. Inst. Mitt 98, 220–228.

    PubMed  CAS  Google Scholar 

  17. Beignon, A. S., Briand, J. P., Muller, S., and Partidos, C. D. (2001) Immunization onto bare skin with heat-labile enterotoxin of Escherichia coli enhances immune responses to coadministered protein and peptide antigens and protects mice against lethal toxin challenge. Immunol. 102, 344–351.

    Article  CAS  Google Scholar 

  18. Merrifield, R. B. (1963) Solid phase peptide synthesis. 1. The synthesis of a tetrapeptide. J. Am. Chem. Soc. 85, 2149–2154.

    Article  CAS  Google Scholar 

  19. Chang, C. D. and Meienhofer, J. (1978) Solid-phase peptide synthesis using mild base cleavage of N-alpha-fluororenylmethyloxycarbonylamino acids, exemplified by a synthesis of dihydrosomatostatin. Int. J. Pept. Protein Res. 11, 246–249.

    Article  PubMed  CAS  Google Scholar 

  20. Houghton, R. A. (1985) General method for the rapid solid-phase synthesis of large numbers of peptides: specificity of antigen-antibody interaction at the level of individual amino acids. Proc. Natl. Acad. Sci. USA 82, 5131–5135.

    Article  Google Scholar 

  21. Partidos, C. D. (2000) Peptide mimotopes as candidate vaccines. Curr. Opin. Mol. Ther. 2, 74–79.

    PubMed  CAS  Google Scholar 

  22. Devlin, J. J., Panganiban, L. C., and Devlin, P. E. (1990) Random peptide libraries: a source of specific protein binding molecules. Science 249, 404–409.

    Article  PubMed  CAS  Google Scholar 

  23. Lam, K. S., Salmon, S. E., Hersh, E. M., Hruby, V. J., Kazmierski, W., and Knapp, R. J. (1991) A new type of synthetic peptide library for ligand-binding activity. Nature 354, 82–84.

    Article  PubMed  CAS  Google Scholar 

  24. Geysen, H. M., Rodda, S. J., and Mason, T. J. (1986) A priori deliniation of a peptide which mimics a discontinuous antigenic determinant. Mol. Immunol. 23, 709–715.

    Article  PubMed  CAS  Google Scholar 

  25. Arnon, R., Tarrab-Hazdai, R., and Steward, M. (2000) A mimotope peptide based vaccine against Schistosoma mansoni: synthesis and characterization. Immunology 4, 555–562.

    Article  Google Scholar 

  26. Francis, M. J., Hastings, G. Z., Clarke, B. E., Brown, A. L., Beddell, C. R., Rowlands, D. J., et al. (1990) Neutralizing antibodies to all seven serotypes of foot-and-mouth disease virus elicited by synthetic peptides. Immunology 69, 171–176.

    PubMed  CAS  Google Scholar 

  27. Dewey, M. E., Bleasdale-Barr, K. M., Bird, P., and Amlot, P. L. (1990) Antibodies of different human IgG subclasses show distinct patterns of affinity maturation after immunisation with keyhole limpet haemocyanin. Immunology 70, 168–174.

    Google Scholar 

  28. Davies, D., Chardhri, B., Stephens, M. D., Carne, C. A., Willers, C., and Lachmann, P. J. (1990) The immunodominance of epitopes within the transmembrane protein (gp4l) of human immunodeficiency virus type 1 may be determined by the host’s previous exposure to similar epitopes on unrelated antigens. J. Gen. Virol. 71, 1975–1983.

    Article  Google Scholar 

  29. Katz, D. H., Paul, W. E., Goidl, E. A., and Benacerraf, B. (1970) Carrier function in anti-hapten immune responses. 1. Enhancement of primary and secondary anti-hapten antibody responses by tamer pre-immunisation. J. Exp. Med. 132, 261–282.

    Article  PubMed  CAS  Google Scholar 

  30. Gupta, S. G., Hengartner, H., and Zinkernagel, R. M. (1986) Primary antibody responses to a well-defined and unique hapten are not enhanced by pre-immunisation with carrier: analysis in a viral model. Proc. Natl. Acad. Sci. USA 83, 2604–2608.

    Article  PubMed  CAS  Google Scholar 

  31. Herzenberg, L. A., Tokuhisa, T., and Herzenberg, L. A. (1980) Carrier-priming leads to hapten-specific suppression. Nature 285, 664, 667.

    Article  PubMed  CAS  Google Scholar 

  32. Dyrberg, T. and Oldstone, M. B. (1986) Peptides as antigens, importance of orientation. J. Exp. Med. 164, 1344–1349.

    Article  PubMed  CAS  Google Scholar 

  33. Zeng, W., Ghosh, S., Macris, M., Pagnon, J., and Jackson, D. C. (2000) Assembly of synthetic peptide vaccines by chemoselective ligation of epitopes: influence of different chemical linkages and epitope orientation on biological activity. Immunology 19, 3843–3852.

    Google Scholar 

  34. Palfreyman, J. W., Aitcheson, T. C., and Taylor, P. (1984) Guidelines for the production of polypeptide specific antisera using small synthetic oligopeptides as immunogens. J. Immunol. Methods 75, 383–393.

    Article  PubMed  CAS  Google Scholar 

  35. Francis, M. J., Fry, C. M., Rowlands, D. J., Brown, F., Bittle, J. L., Houghton, R. A., et al. (1985) Immunological priming with synthetic peptides of foot-and-mouth disease virus. J. Gen. Virol. 66, 2347–2354.

    Article  PubMed  CAS  Google Scholar 

  36. Francis, M. J., Fry, C. M., Rowlands, D. J., Bittle, J. L., Houghton, R. A., Lerner, R. A., and Brown, F. (1987) Immune response to uncoupled peptides of foot-and-mouth disease virus. Immunology 61, 1–6.

    PubMed  CAS  Google Scholar 

  37. DeLisi, C. and Berzofsky, J. A. (1987) T-cell antigenic sites tend to be amphipathic structures. Proc. Natl. Acad. Sci. USA 82, 7048–7052.

    Article  Google Scholar 

  38. Rothbard, J. B. (1986) Peptides and the cellular immune response. Ann. Inst. Pasteur 137E, 518–526.

    Article  CAS  Google Scholar 

  39. Rothbard, J. B. and Taylor, W. R. (1988) A sequence pattern common to T cell epitopes. EMBO J. 7, 93–100.

    PubMed  CAS  Google Scholar 

  40. Berzofsky, J. A. (1993) Epitope selection and design of synthetic vaccines. Molecular approaches to enhancing immunogenicity and cross-reactivity of engineered vaccines. Ann NY Acad. Sci. 12, 256–264.

    Article  Google Scholar 

  41. Partidos, C. D. and Steward, M. W. (1990) Prediction and identification of a T cell determinant in the fusion protein molecule of measles virus immunodominant in mice and humans. J. Gen. Virol. 71, 2099–2105.

    Article  PubMed  CAS  Google Scholar 

  42. Falk, K., Rotzschke, O., Stevanovic, S., Jung, G., and Rammensee, H.-G. (1991) Allele-specific motifs revealed by sequencing of self-peptides eluted form MHC molecules. Nature 351, 290–296.

    Article  PubMed  CAS  Google Scholar 

  43. Schadeck, E. B., Partidos, C. D., Fooks, A. R., Obeid, O. E., Wilkinson, G. E., Stephenson, J. R, et al. (1999) CLT epitopes identified with a defective recombinant adenovirus expressing measles virus nucleoprotein and evaluation of their protective capacity in mice. Virus Res. 65, 75–86.

    Article  PubMed  CAS  Google Scholar 

  44. Partidos, C. D., Delmas, A., and Steward, M. W. (1996) Structural requirements for synthetic immunogens to induce measles virus specific CLT responses. Mol. Immunol. 33, 1223–1229.

    Article  PubMed  CAS  Google Scholar 

  45. Partidos, C. D., Vohra, P., and Steward, M. W. (1996) Priming of measles virus-specific CTL responses after immunization with a CTL epitope linked to a fusogenic peptide. Virology 215, 107–110.

    Article  PubMed  CAS  Google Scholar 

  46. Partidos, C. D., Vohra, P., Jones, H. H., Farrar, G., and Steward, M. W. (1999) Induction of cytotoxic T-cell responses following oral immunization with synthetic peptides encapsulated in PLG microparticles. J. Control Release 62, 325–332.

    Article  PubMed  CAS  Google Scholar 

  47. Shaw, D. M., Stanley, C. M., Partidos, C. D., and Steward, M. W. (1993) Influence of the T-helper epitope on the titre and affinity of antibodies to B-cell epitopes after co-immunization. Mol. Immunol. 30, 961–968.

    Article  PubMed  CAS  Google Scholar 

  48. Leclerc, C., Przewlocki, G., Schutze, M., and Chedid, L. (1987) A synthetic vaccine constructed by co-polymerization of B and T cell determinants. Eur. J. Immunol. 17, 269–273.

    Article  PubMed  CAS  Google Scholar 

  49. Good, M. F., Malay, W. F., Lunde, M. N., Margalit, H., Cornette, J. L., Smith, G. L., et al. (1987) Construction of synthetic immunogen: use of new T-helper epitope on malaria circumsporozoite protein. Science 235, 1059–1062.

    Article  PubMed  CAS  Google Scholar 

  50. Borras-Cuesta, F., Petit-Camurdan, A., and Fedon, Y. (1987) Engineering of immunogenic peptides by co-linear synthesis of determinants recognised by B and T cells. Eur. J. Immunol. 17, 1213–1215.

    Article  PubMed  CAS  Google Scholar 

  51. Francis, M. J., Hastings, G. Z., Syred, A. D., McGinn, B., Brown, F., and Rowlands, D. J. (1987) Nonresponsiveness to a foot-and-mouth disease virus synthetic peptide overcome by addition of foreign helper T-cell determinants. Nature 330, 168–169.

    Article  PubMed  CAS  Google Scholar 

  52. Milich, D. R., Hughes, J. L,, McLachlan, A., Thornton, G. B., and Moriarty, A. (1988) Hepatitis B synthetic immunogen comprised of nucleocapsid T-cell sites and an envelope B-cell epitope. Proc. Natl. Acad. Sci. USA 85, 1610–1614.

    Article  PubMed  CAS  Google Scholar 

  53. Partidos, C. D., Stanley, C. M., and Steward, M. W. (1991) Immune response in mice following immunization with chimeric synthetic peptides representing B and T cell epitopes of measles virus protein. J. Gen. Virol. 72, 1293–1299.

    Article  PubMed  CAS  Google Scholar 

  54. Patarroyo, M. E., Romero, P., Torres, M. L., Clavijo, P., Moreno, A., Martinez, A., et al. (1987) Induction of protective immunity against experimental infection with malaria using synthetic peptides. Nature 328, 629–632.

    Article  PubMed  CAS  Google Scholar 

  55. Partidos, C. D., and Steward, M. W. (1992) The effects of a flanking sequence on the immune response to a B and a T cell epitope from the fusion protein of measles virus. J. Gen. Virol. 73, 1987–1994.

    Article  PubMed  CAS  Google Scholar 

  56. Fernandez, I. M., Snijders, A., Benaissa-Trouw, B. J., Harmsen, M., Snippe, H., and Kraaijeveld, C. A. (1993) Influence of epitope polarity and adjuvants on the immunogenicity and efficacy os a synthetic peptide vaccine against Semliki Forest virus. J. Virol. 67, 5843–5848.

    PubMed  CAS  Google Scholar 

  57. Bittle, J. L., Worrell, P., Houghten, R. A., Lerner, R. A., Rowlands, D. J., and Brown, F. (1984) Immunization against foot-and-mouth disease with a chemically synthesized peptide, in Modern Approaches to Vaccines (Chanock, R. M. and Lerner, R. A., eds.), Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, pp. 103–108.

    Google Scholar 

  58. Francis, M. J. (1991) Enhanced immunogenicity of recombinant and synthetic peptide vaccines, in Vaccines: Recent Trends and Progress. NATO ASI Series: Vaccines, vol. 215, pp. 13–23.

    CAS  Google Scholar 

  59. Tam, J. P. (1988) Synthetic peptide vaccine design: synthesis and properties of a high-density multiple antigenic peptide system. Proc. Natl. Acad. Sci. USA 85, 5409–5413.

    Article  PubMed  CAS  Google Scholar 

  60. Posnett, D. N., McGrath, H., and Tam, J. P. (1988) A novel method for producing anti-peptide antibodies: production of site specific antibodies to the T cell antigen receptor β-chain. J. Biol. Chem. 263, 1719–1725.

    PubMed  CAS  Google Scholar 

  61. Tam, J. P. (1989) Multiple antigen peptide system: a novel design for peptide-based antibody and vaccine, in Vaccines 90: Modern Approaches to New Vaccines Including Prevention of AIDS (Lerner, R. A., Ginsberg, H., Chanock, R. M., and Brown, F., eds.), Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, pp. 21–25.

    Google Scholar 

  62. Francis, M. J., Fry, C. M., Rowlands, D. J., and Brown, F. (1988) Qualitative and quantitative differences in the immune response to foot-and-mouth disease virus antigens and synthetic peptide. J. Gen. Virol. 69, 2483–2491.

    Article  PubMed  CAS  Google Scholar 

  63. Francis, M. J., Hastings, G. Z., Brown, F., McDermed, J., Lu, Y. A., and Tam, J. P. (1991) Immunological evaluation of the multiple antigen peptide (MAP) system using a major immunogenic site of foot-and-mouth disease virus. Immunology 73, 249–254.

    PubMed  CAS  Google Scholar 

  64. Riley, E. M., Young, S. C., and Secombes, C. J. (1996) Immunisation of rainbow trout Oncorhynchus mykiss with a multiple antigen peptide system (MAPS), Vet. Immunol. Immunopathol. 55, 243–253.

    Article  PubMed  CAS  Google Scholar 

  65. Kennedy, R. C., Dressman, G. R., Sparrow, J. T., Culwell, A. R., Sanchez, Y., Ionescu-Matiu, E., et al. (1983) Inhibition of a common human anti hepatitis B surface antigen idiotype by a cyclic synthetic peptide. J. Virol. 46, 653–655.

    PubMed  CAS  Google Scholar 

  66. Schultz-Gahmen, U., Klenk, H. D., and Beyreuther, K. (1986) Immunogenicity of loop structured short synthetic peptides mimicking the antigen site A of influenza virus haemagglutinin. Eur. J. Biochem. 159, 283–289.

    Article  Google Scholar 

  67. Fergusen, M., Evans, D. M. A., Magrath, D. I., Minor, P. D., Almond, J. W., and Schild, G. C. (1985) Induction by synthetic peptides of broadly reactive, type specific neutralizing antibody to poliovirus type 3. Virology 143, 505–515.

    Article  Google Scholar 

  68. Satterthwait, A. C., Arrhenius, T., Hagopian, R. A., Zavala, F., Nussenzweig, V., and Lerner, R. A. (1988) Conformational restriction of peptidyl immunogens with covalent replacements for the hydrogen bond. Vaccine 6, 99–103.

    Article  PubMed  CAS  Google Scholar 

  69. Arnon, R. and Van Regenmortal, M. H. V. (1992) Structural basis of antigenic specificity and design of new vaccines. FASEB J. 6, 3265–3274.

    PubMed  CAS  Google Scholar 

  70. Spitzer, N., Jardin, A., Lippert, D., and Olafson, R. W. (1999) Long-term protection in mice against Leishmania major with a synthetic peptide vaccine. Vaccine 17, 1298–1300.

    Article  PubMed  CAS  Google Scholar 

  71. Minev, B. R., Chavez, F. I., and Mitchell, M. S. (1998) New trends in the development of cancer vaccines. In Vivo 12, 629–638.

    PubMed  CAS  Google Scholar 

  72. Hipp, J. D., Hipp, J. A., Lyday, B. W., and Minev, B. R. (2000) Cancer vaccines: an update. In Vivo 14, 571–585.

    PubMed  CAS  Google Scholar 

  73. Stanworth, D. R., Jones, V. M., Lewin, I. V., and Nayyar, S. (1990) Allergy treatment with a peptide vaccine. The Lancet 336, 1279–1281.

    Article  CAS  Google Scholar 

  74. Francis, M. J. (1991) Enhanced immunogenicity of recombinant and synthetic peptide vaccines, in Vaccines: Recent Trends and Progress. NATO ASI Series: Vaccines, vol. 215, pp. 13–24.

    CAS  Google Scholar 

  75. Francis, M. J. (1992) Use of hepatitis B core as a vehicle for presenting viral antigens. Rev. Med. Virol. 2, 225–231.

    Article  Google Scholar 

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  1. Schering Plough Animal Health, Harefield, Uxbridge, UK

    Michael J. Francis

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  1. Michael J. Francis
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  1. Centre for Applied Microbiology and Research, Health Protection Agency, Porton Down, Salisbury, Wiltshire, UK

    Andrew Robinson  & Michael J. Hudson  & 

  2. Department of Cellular and Molecular Medicine, St. George’s Hospital Medical School, London, UK

    Martin P. Cranage

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Francis, M.J. (2003). Synthetic Peptides. In: Robinson, A., Hudson, M.J., Cranage, M.P. (eds) Vaccine Protocols. Methods in Molecular Medicine™, vol 87. Humana Press. https://doi.org/10.1385/1-59259-399-2:115

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  • DOI: https://doi.org/10.1385/1-59259-399-2:115

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