New Approaches To Mucosal Immunization

  • Lucía Cárdenas-Freytag
  • Elly Cheng
  • Aysha Mirza
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 473)

Abstract

Every year more than 17 million deaths worldwide are caused by infectious diseases. The great majority of these deaths occur in underdeveloped countries and are attributed to diseases preventable by existing vaccines, or diseases that could potentially be prevented with new vaccines. The fact that most human and veterinary pathogens establish infection in the host by initiating contact at a mucosal surface, provide the rationale for the development of mucosal vaccines. An increasing number of strategies have been proposed to facilitate mucosal immunization. Among the most widely investigated strategies are the use of attenuated microorganisms; the inclusion of immunizing antigens in lipid-based carriers, the genetic creation of transgenic plants and the use of mucosal adjuvants derived from bacterial toxins. This review provides a brief summary of the most recent advances in the field of mucosal immunization with an special emphasis on a promising genetically detoxified mucosal adjuvant, LT(R192G), derived from the heat-labile toxin of enterotoxigenic E. coli. We present evidence regarding the safety, immunogenicity, and efficacy of LT(R192G) for the development of a new generation of mucosal vaccines.

Keywords

Cholera Toxin Tetanus Toxoid Oral Immunization Mucosal Vaccine Intranasal Immunization 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
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References

  1. Belyakov, I.M., Ahlers, J.D., Brandwein, B.Y., Earl, P., Kelsall, B.L., Moss, B., Strober, W., and Berzofsky, J.A., 1998, The importance of local mucosal HIV-specific CD8(+) cytotoxic T lymphocytes for resistance to mucosal viral transmission in mice and enhancement of resistance by local administration of IL-12, J Clin Invest. 102(12):2072–2081.PubMedCrossRefGoogle Scholar
  2. Boyaka, P.N., Marinaro, M., Jackson, R.J., Menon, S., Kiyono, H., Jirillo, E., and McGhee, J.R., 1999, IL-12 is an effective adjuvant for induction of mucosal immunity, J Immunol. 162(1):122–128.PubMedGoogle Scholar
  3. Bruhl, P., Kerschbaum, A., Eibl, M.M., and Mannhalter, J.W., 1998, An experimental prime-boost regimen leading to HIV type 1-specific mucosal and systemic immunity in BALB/c mice, AIDS Res Hum Retroviruses. 14(5):401–407.PubMedCrossRefGoogle Scholar
  4. Buge, S.L., Richardson, E., Alipanah, S., Markham, P., Cheng, S., Kalyan, N., Miller, C.J., Lubeck, M., Udem, S., and Eldridge, J., et al., 1997, An adenovirus-simian immunodeficiency virus env vaccine elicits humoral, cellular, and mucosal immune responses in rhesus macaques and decreases viral burden following vaginal challenge, J Virol. 71(11):8531–8541.PubMedGoogle Scholar
  5. Burnette, W.N., Mar, V.L., Platler, B.W., Schlotterbeck, J.D., McGinley, M.D., Stoney, K.S., Rhode, M.F., and Kaslow, H.R., 1991, Site-specific mutagenesis of the catalytic subunit of cholera toxin: substituting lysine for arginine 7 causes loss of activity, Infection and Immunity. 59:4266–4270.PubMedGoogle Scholar
  6. Cardenas, L. and Clements, J.D., 1993, Development of mucosal protection against the heat-stable enterotoxin (ST) of Escherichia coli by oral immunization with a genetic fusion delivered by a bacterial vector, Infect Immun. 61(11):4629–4636.PubMedGoogle Scholar
  7. Cardenas-Freytag, L., Cheng, E., Mayeux, P., Domer, IE., and Clements, J.D., 1999, Effectiveness of a vaccine composed of heat-killed Candida albicans and a novel mucosal adjuvant, LT(R192G), against systemic candidiasis [In Process Citation], Infect Immun. 67(2):826–833.PubMedGoogle Scholar
  8. Cheng, E., Cardenas-Freytag, L., and Clements, J., 1999, The role of cAMP in mucosal adjuvanticity of Escherichia coli heat-labile enterotoxin (LT), Vaccine. In press.Google Scholar
  9. Chong, C., Frieberg, M., and Clements, J.D., 1998, LT(R192G), a non-toxic mutant of the heat-labile enterotoxin of Escherichia coli elicits enhanced humoral and cellular immune responses associated with protection against lethal oral challenge with Salmonella spp., Vaccine. 16(7):732–740.PubMedCrossRefGoogle Scholar
  10. Clements, J.D., Hartzog, N.M., and Lyon, F.L., 1988, Adjuvant activity of Escherichia coli heat-labile enterotoxin and effect on the induction of oral tolerance in mice to unrelated protein antigens, Vaccine. 6:269–277.PubMedCrossRefGoogle Scholar
  11. de Haan, L., Verweij, W.R., Feil, I.K., Holtrop, M., Hol, W.G., Agsteribbe, E., and Wilschut, J., 1998, Role of GMl binding in the mucosal immunogenicity and adjuvant activity of the Escherichia coli heat-labile enterotoxin and its B subunit, Immunology. 94(3):424–430.PubMedCrossRefGoogle Scholar
  12. Di Tommaso, A., Saletti, G, Pizza, M., Rappuoli, R., Dougan, G, Abrignani, S., Douce, G., and De Magistris, M.T., 1996, Induction of antigen-specific antibodies in vaginal secretions by using a nontoxic mutant of heat-labile enterotoxin as a mucosal adjuvant, Infect Immun. 64(3):974–979.PubMedGoogle Scholar
  13. Dickinson, B.L. and Clements, J.D., 1995, Dissociation of Escherichia coli heat-labile enterotoxin adjuvanticity from ADP-ribosyltransferase activity, Infection and Immunity. 63:1617–1623.PubMedGoogle Scholar
  14. Dickinson, B.L. and Clements, J.D., 1996, Use of Escherichia coli Heat-labile Enterotoxin as an Oral Adjuvant. In: Mucosal Vaccines. H. Kiyono, PL. Ogra, and J.R. McGhee. San Diego, Academic Press: 73–87.CrossRefGoogle Scholar
  15. Dietrich, G., Bubert, A., Gentschev, I., Sokolovic, Z., Simm, A., Catic, A., Kaufmann, S.H., Hess, J., Szalay, A.A., and Goebel, W., 1998, Delivery of antigen-encoding plasmid DNA into the cytosol of macrophages by attenuated suicide Listeria monocytogenes, Nat Biotechnol. 16(2):181–185.Google Scholar
  16. Domenighini, M.C.M., Pizza, M., and Rappuoli, R., 1994, Common features of the NAD-binding and catalytic site of ADP-ribosylating toxins, Molecular Microbiology. 14:41–50.PubMedCrossRefGoogle Scholar
  17. Duncan, J.D., Gilley, R.M., Schäfer, D.P, Moldoveanu, Z., and Mestecky, JF, 1996, Poly(lactide-co-glycolide) microencapsulation of vaccines for mucosal immunization. In: Mucosal vaccines. K. Hiroshi, PL. Ogra, and J.R. McGhee. New York, Academic Press: 159–173.CrossRefGoogle Scholar
  18. Elson, CO., 1989, Cholera toxin and its subunits as potential oral adjuvants, Immunology Today. 146:29–33.Google Scholar
  19. Field, M., 1980, Regulation of small intestinal ion transport by cyclic nucleotides and calcium. In: Secretory diarrhea. M. Field, J.S. Fordtran, and S.G Schultz. Baltimore, Md., Waverly Press: 21–30.Google Scholar
  20. Fischetti, V.A., Medaglini, D., and Pozzi, G, 1996, Gram-positive commensal bacteria for mucosal vaccine delivery, Curr Opin Biotechnol. 7(6):659–666.PubMedCrossRefGoogle Scholar
  21. Fontana, M.R., Manetti, R., Giannelli, V, Magagnoli, C., Marchini, A., Olivieri, R., Domenighini, M., Rappuoli, R., and Pizza, M., 1995, Construction of nontoxic derivatives of cholera toxin and characterization of the immunological response against the A subunit, Infection and Immunity. 63:2356–2360.PubMedGoogle Scholar
  22. Freytag, L.C. and Clements, J.D., 1999, Bacterial toxins as mucosal adjuvants, Curr Top Microbiol Immunol. 236:215–236.PubMedCrossRefGoogle Scholar
  23. Ghazi, H.O., Potter, C.W., Smith, TL., and Jennings, R., 1995, Comparative antibody responses and protection in mice immunized by oral or parenteral routes with influenza virus subunit antigens in aqueous form or incorporated into ISCOMs, J Med Microbiol. 42(1):53–61.PubMedCrossRefGoogle Scholar
  24. Giuliani, M.M., Del Giudice, G, Giannelli, V, Dougan, G, Douce, G, Rappuoli, R., and Pizza, M., 1998, Mucosal adjuvanticity and immunogenicity of LTR72, a novel mutant of Escherichia coli heat-labile enterotoxin with partial knockout of ADP-ribosyltransferase activity, J Exp Med. 187(7):1123–1132.PubMedCrossRefGoogle Scholar
  25. Haq, TA., Mason, H.S., Clements, J.D., and Arntzen, C.X, 1995, Oral immunization with a recombinant bacterial antigen produced in transgenic plants [see comments], Science. 268(5211):714–716.PubMedCrossRefGoogle Scholar
  26. Harford, S., Dykes, C.W., Hobden, A.N., Read, M.X, and Halliday, I.X, 1989, Inactivation of the Escherichia coli heat-labile enterotoxin by in vitro mutagenesis of the A-subunit gene, European Journal of Biochemistry. 183:311–316.PubMedCrossRefGoogle Scholar
  27. Hase, C.C., Thai, L.S., Boesman-Finkelstein, M., Mar, V.L., Burnette,W.N, Kaslow, H.R., Stevens, L.A., Moss, J., and Finkelstein, R.A., 1994, Construction and characterization of recombinant Vibrio_cholerae strains producing inactive cholera toxin analogs, Infection and Immunity. 62:3051–3057.PubMedGoogle Scholar
  28. Hashigucci, K., Ogawa, H., Ishidate,T, Yamashita, R., Kamiya, H.,Watanabe, K., Hattori, N., Sato, T., Suzuki, Y, and Nagamine, T, et al., 1996, Antibody responses in volunteers induced by nasal influenza vaccine combined with Escherichia coli heat-labile enterotoxin B subunit containing a trace amount of the holotoxin, Vaccine. 14(2):113–119.PubMedCrossRefGoogle Scholar
  29. Hathaway, L.J., Partidos, C.D., Vohra, P., and Steward, M.W., 1995, Induction of systemic immune responses to measles virus synthetic peptides administered intranasally, Vaccine. 13(16):1495–1500.PubMedCrossRefGoogle Scholar
  30. Katz, J.M., Lu, X., Galphin, J.C., and Clements, J.D., 1996, Heat-labile enterotoxin from E. coli as an adjuvant for oral influenza vaccination. In: Options for the Control of Influenza III. L.E. Brown, A.W. Hampson, and R.G. Webster. New York, Elsevier Science: 292–297.Google Scholar
  31. Katz, J.M., Lu, X., Young, S.A., and Galphin, J.C., 1997, Adjuvant activity of the heat-labile enterotoxin from enterotoxigenic Escherichia coli for oral administration of inactivated influenza virus vaccine, J Infect Dis. 175(2):352–363.PubMedCrossRefGoogle Scholar
  32. Komase, K., Tamura, S.-L, Matsuo, K., Watanabe, K., Hattori, N., Odaka, A., Suzuki, Y, Kurata, T., and Aizawa, C., 1998, Mutants of Escherichia coli heat-labile enterotoxin as an adjuvant for nasal influenza vaccine, Vaccine. 16(2/3):248–254.PubMedCrossRefGoogle Scholar
  33. Langermann, S., Palaszynski, S., Sadziene, A., Stover, C.K., and Koenig, S., 1994, Systemic and mucosal immunity induced by BCG vector expressing outer-surface protein A of Borrelia burgdorferi, Nature. 372(6506):552–555.PubMedCrossRefGoogle Scholar
  34. Lee, C.K., Weltzin, R., Thomas, W.D., Jr., Kleanthous, H., Ermak, T.H., Soman, G, Hill, J.E., Ackerman, S.K., and Monath, T.P., 1995, Oral immunization with recombinant Helicobacter pylori urease induces secretory IgA antibodies and protects mice from challenge with Helicobacter felis, J Infect Dis. 172(1):161–172.PubMedCrossRefGoogle Scholar
  35. Levi, R., Aboud-Pirak, E., Leclerc, C., Lowell, G.H., and Arnon, R., 1995, Intranasal immunization of mice against influenza with synthetic peptides anchored to proteosomes, Vaccine. 13(14):1353–1359.PubMedCrossRefGoogle Scholar
  36. Levine, M.M., Kaper, IB., Black, R.E., and Clements, M.L., 1983, New knowledge on pathogenesis of bacterial enteric infections as applied to vaccine development, Mircobiological Reviews. 47:510–550.Google Scholar
  37. Lillard, J.W., Jr., Boyaka, P.N., Hedrick, J.A., Zlotnik, A., and McGhee,.R., 1999, Lymphotactin acts as an innate mucosal adjuvant, J Immunol. 162(4):1959–1965.PubMedGoogle Scholar
  38. Lobet, Y, Cluff, C.W., and Cieplak, J., 1991, Effect of site-directed mutagenic alterations on ADP-ribosyltransferase activity of the A subunit of Escherichia coli heat-labile enterotoxin, Infection and Immunity. 59:2870–2879.PubMedGoogle Scholar
  39. Lowell, GH., Colleton, C., Frost, D, Kaminski, R.W., Hughes, M., Hatch, J., Hooper, C., Estep, J., Pitt, L., and Topper, M., et al., 1996, Immunogenicity and efficacy against lethal aerosol staphylococcal enterotoxin B challenge in monkeys by intramuscular and respiratory delivery of proteosome-toxoid vaccines, Infect Immun. 64(11):4686–4693.PubMedGoogle Scholar
  40. Lowell, GH., Kaminski, R.W., VanCott, T.C., Slike, B., Kersey, K., Zawoznik, E., Loomis-Price, L., Smith, G, Redfield, R.R., and Amselem, S., et al., 1997, Proteosomes, emulsomes, and cholera toxin B improve nasal immunogenicity of human immunodeficiency virus gp160 in mice: induction of serum, intestinal, vaginal, and lung IgA and IgG, J Infect Dis. 175(2):292–301.PubMedCrossRefGoogle Scholar
  41. Lycke, N, Tsuji, T., and Holmgren, J., 1992, The adjuvant effect of Vibrio cholerae and Escherichia coli heat-labile enterotoxins is linked to their ADP-ribosyltransferase activity, European Journal of Immunology. 22:2277–2281.PubMedCrossRefGoogle Scholar
  42. Mason, H.S., Ball, J.M., Shi, J.J., Jiang, X., Estes, M.K., and Arntzen, C.J., 1996, Expression of Norwalk virus capsid protein in transgenic tobacco and potato and its oral immunogenicity in mice, Proc Natl Acad Sci USA. 93(11):5335–5340.PubMedCrossRefGoogle Scholar
  43. Merritt, E.A., Sarfaty, S., Pizza, M., Domenighini, M., Rappuoli, R., and Hol, W.G, 1995, Mutation of a buried residue causes loss of activity but no conformational change in the heat-labile enterotoxin of Escherichia coli, Nature Structural Biology. 2:269–272.PubMedCrossRefGoogle Scholar
  44. Michalek, S.M., Childers, N.K., Katz, J., Dertzbaugh, M., Zhang, S., Russell, M.W., Macrina, F.L., Jackson, S., and Mestecky, J., 1992, Liposomes and conjugate vaccines for antigen delivery and induction of mucosal immune responses, Adv Exp Med Biol. 327:191–198.PubMedCrossRefGoogle Scholar
  45. Moldoveanu, Z., Porter, D.C., Lu, A., McPherson, S., and Morrow, CD, 1995, Immune responses induced by administration of encapsidated poliovirus replicons which express HIV-1 gag and envelope proteins, Vaccine. 13(11):1013–1022.PubMedCrossRefGoogle Scholar
  46. Morrow, CD., Moldovenu, Z., Anderson, M.J., and Porter, D.G, 1996, Poliovirus replicons as a vector for mucosal vaccines. In: Mucosal vaccines. K. Hiroshi, PL. Ogra, and J.R. McGhee. New York, Academic Press: 137–146.CrossRefGoogle Scholar
  47. Morrow, CD., Novak, M.J., Ansardi, D.C., Porter, D.C., and Moldoveanu, Z., 1999, Recombinant viruses as vectors for mucosal immunity, Curr Top Microbiol Immunol. 236:255–273.PubMedCrossRefGoogle Scholar
  48. Moss, J., Stanley, S.J., Vaughan, M., and Tsuji, T, 1993, Interaction of ADP-ribosylation factor with Escherichia coli enterotoxin that contains an inactivating lysine 112 substitution, Journal of Biological Chemistry. 268:6383–6387.PubMedGoogle Scholar
  49. Mrsny, R.J., Daugherty, A.L., Fryling, CM., and FitzGerald, DJ., 1999, Mucosal administration of a chimera composed of Pseudomonas exotoxin and the gp120 V3 loop sequence of HIV-1 induces both salivary and serum antibody responses [In Process Citation], Vaccine. 17(11–12):1425–1433.PubMedCrossRefGoogle Scholar
  50. Muster, T., Ferko, B., Klima, A., Purtscher, M., Trkola, A., Schulz, P., Grassauer, A., Engelhardt, O.G., Garcia-Sastre, A., and Palese, P., et al., 1995, Mucosal model of immunization against human immunodeficiency virus type 1 with a chimeric influenza virus, J Virol. 69(11):6678–6686.PubMedGoogle Scholar
  51. O’Neal, CM., Clements, J.D., Estes, M.K., and Conner, M.E., 1998, Rotavirus 2/6 viruslike particles administered intranasally with cholera toxin, Escherichia coli heat-labile toxin (LT), and LT-R192G induce protection from rotavirus challenge, J Virol. 72(4):3390–3393.Google Scholar
  52. Oplinger, M.L., Bakar, S., Trofa, A.F., Clements, J.D., Gibbs, P., Pazzaglia, G, Bourgeouis, A.L., and Scott, D.A., 1997, Safety and immunogenicity in volunteers of a new candidate mucosal adjuvant, LT(R192G). Program and abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, D.C, American Society for Microbiology.Google Scholar
  53. Partidos, CD., Pizza, M., Rappuoli, R., and Steward, M.W., 1996, The adjuvant effect of a non-toxic mutant of heat-labile enterotoxin of Escherichia coli for the induction of measles virus-specific CTL responses after intranasal co-immunization with a synthetic peptide, Immunology. 89(4):483–487.PubMedCrossRefGoogle Scholar
  54. Pizza, M., Domenighini, M., Hol, W., Giannelli, V, Fontana, M.R., Giuliani, M.M., Magagnoli, C., Peppoloni, S., Manetti, R., and Rappuoli, R., 1994, Probing the structure-activity relationship of Escherichia coli LT-A by site-directed mutagenesis, Molecular Microbiology. 14:51–60.PubMedCrossRefGoogle Scholar
  55. Roberts, M., Bacon, A., Rappuoli, R., Pizza, M., Cropley, I., Douce, G, Dougan, G, Marinaro, M., McGhee, J., and Chatfield, S., 1995, A mutant pertussis toxin molecule that lacks ADP-ribosyltransferase activity, PT-9K/129G, is an effective mucosal adjuvant for intranasally delivered proteins, Infect Immun. 63(6):2100–2108.PubMedGoogle Scholar
  56. Rosenthal, K.L., Copeland, K.F.T., and Gallichan, W.S., 1996, Recombinant adenoviruses as vectors for mucosal immunity. In: Mucosal vaccines. K. Hiroshi, P.L. Ogra, and J.R. McGhee. New York, Academic Press.Google Scholar
  57. Schodel, F. and Curtiss, R., 3rd, 1995, Salmonellae as oral vaccine carriers, Dev Biol Stand. 84:245–253.PubMedGoogle Scholar
  58. Sixma, T.K., Kalk, K.H., Vanzanten, B.A.M., Dauter, Z., Kingma, J., Witholt, B., and Hol, W.GJ., 1993, Refined structure of Escherichia coli heat-labile enterotoxin, a close relative of cholera toxin, Journal of Molecular Biology. 230:890–918.PubMedCrossRefGoogle Scholar
  59. Sixma, T.K., Pronk, S.E., Kalk, K.H., Wartna, E.S., vanZanten, B.A.M., Witholt, B., and Hol, W.G.J., 1991, Crystal structure of a cholera toxin-related heat-labile enterotoxin from E. coli, Nature (London). 351:371–377.CrossRefGoogle Scholar
  60. Smith, R.E., Donachie, A.M., and Mowat, A.M., 1998, Immune stimulating complexes as mucosal vaccines, Immunol Cell Biol. 76(3):263–269.PubMedCrossRefGoogle Scholar
  61. Staats, H.F., Nichols, W.G, and Palker, T.J., 1996, Mucosal immunity to HIV-1: systemic and vaginal antibody responses after intranasal immunization with the HIV-1 C4/V3 peptide T1SP10 MN(A), J Immunol. 157(1):462–472.PubMedGoogle Scholar
  62. Tacket, CO., Mason, H.S., Losonsky, G, Clements, J.D., Levine, M.M., and Arntzen, C.J., 1998, Immunogenicity in humans of a recombinant bacterial antigen delivered in a transgenic potato, Nat Med. 4(5):607–609.PubMedCrossRefGoogle Scholar
  63. Tribble, D.R., Bakar, S., Oplinger, M.L., Bourgeouis, A.L., Clements, J.D., Trofa, A.F., Pazzaglia, G, Pace, J., Walker, R.I., and Gibbs, P., et al. 1997, Safety and enhanced immunogenicity in volunteers of an oral, inactivated, whole cell Campy lob acter vaccine co-administered with a modified E. coli heat-labile enterotoxin adjuvant, LT (R192G). Program and abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, D.C, American Society for Microbiology.Google Scholar
  64. Tsuji, T, Inoue, T, Miyama, A., Okamoto, K., Honda, T, and Miwatani, T, 1990, A single amino acid substitution in the A subunit of Escherichia coli enterotoxin results in loss of its toxic activitiy, Journal of Biological Chemistry. 265:22520–22525.PubMedGoogle Scholar
  65. Weltzin, R., Kleanthous, H., Guirakhoo, F., Monath, T.P, and Lee, C.K., 1997, Novel intranasal immunization techniques for antibody induction and protection of mice against gastric Helicobacter felis infection, Vaccine. 15(4):370–376.PubMedCrossRefGoogle Scholar
  66. Wu, H.Y., Nahm, M.H., Guo, Y., Russell, M.W, and Briles, D.E., 1997, Intranasal immunization of mice with PspA (pneumococcal surface protein A) can prevent intranasal carriage, pulmonary infection, and sepsis with Streptococcus pneumoniae, J Infect Dis. 175(4):839–846.PubMedCrossRefGoogle Scholar
  67. Xu-Amano, J., Jackson, R.J., Fujihashi, K., Kiyono, H., Staats, H.F., and McGhee, J.R., 1994, Helper Th1 and Th2 cell responses following mucosal or systemic immunization with cholera toxin, Vaccine. 12(10):903–911.PubMedCrossRefGoogle Scholar
  68. Xu-Amano, J., Kiyono, H., Jackson, R.J., Staats, H.F., Fujihashi, K., Burrows, P.D., Elson, CO., Pillai, S., and McGhee, J.R., 1993, Helper T cell subsets for immunoglobulin A responses: oral immunization with tetanus toxoid and cholera toxin as adjuvant selectively induces Th2 cells in mucosal associated tissues, Journal of Experimental Medicine. 178:1309–1320.PubMedCrossRefGoogle Scholar
  69. Yamamoto, M., Vancott, J.L., Okahashi, N., Marinaro, M., Kiyono, H., Fujihashi, K., Jackson, R.J., Chatfield, S.N., Bluethmann, H., and McGhee, J.R., 1996, The role of Th1 and Th2 cells for mucosal IgA responses, Ann N Y Acad Sci. 778:64–71.PubMedCrossRefGoogle Scholar
  70. Yamamoto, S., Kiyono, H., Yamamoto, M., Imaoka, K., Fujihashi, K., Van Ginkel, EW., Noda, M., Takeda, Y, and McGhee, J.R., 1997a, A nontoxic mutant of cholera toxin elicits Th2-type responses for enhanced mucosal immunity, Proc Natl Acad Sci USA. 94(10):5267–5272.PubMedCrossRefGoogle Scholar
  71. Yamamoto, S., Takeda, Y, Yamamoto, M., Kurazono, H., Imaoka, K., Yamamoto, M., Fujihashi, K., Noda, M., Kiyono, H., and McGhee, J.R., 1997b, Mutants in the ADP-ribosyltransferase cleft of cholera toxin lack diarrheagenicity but retain adjuvanticity, Journal of Experimental Medicine. 185:1203–1210.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1999

Authors and Affiliations

  • Lucía Cárdenas-Freytag
    • 1
  • Elly Cheng
    • 1
  • Aysha Mirza
    • 2
  1. 1.Department of Microbiology and ImmunologyTulane University School of MedicineUSA
  2. 2.Department of PediatricsNew OrleansUSA

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