Abstract
Forty-five volunteers were vaccinated twice intranasally with 10, 100, or 1,000 microg of cholera toxin B subunit (CTB). Blood and nasal and vaginal secretions were collected before and 1 week after the second vaccination from all volunteers, and the specific and total immunoglobulin A (IgA) and IgG titers were determined by enzyme-linked immunosorbent assay. Samples were also taken 6 months (n = 16) and 1 year (n = 14) after the vaccination. The 10- and 100-microg doses were well tolerated by the volunteers, but the 1,000-microg dose induced increased secretions from the nose and repetitive sneezings for several hours. The CTB-specific serum IgA and IgG increased 21- and 7-fold, respectively, 1 week after vaccination with the medium dose and increased 61- and 37-fold, respectively, after the high dose. In nasal secretions the specific IgA and IgG increased 2- and 6-fold after the medium dose and 2- and 20-fold after the high dose, respectively. In vaginal secretions the specific IgA and IgG increased 3- and 5-fold after the medium dose and 56- and 74-fold after the high dose, respectively. The lowest dose did not induce any significant antibody titer increases in serum or in secretions. The specific IgA and IgG levels in secretions were still elevated after 6 months but were decreasing 1 year after the vaccination. These results show that intranasal vaccination of humans with CTB induces strong systemic and mucosal antibody responses and suggest that CTB may be used as a carrier for antigens that induce protective immunity against systemic as well as respiratory and genital infections.
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- Bergquist C., Lagergård T., Lindblad M., Holmgren J. Local and systemic antibody responses to dextran-cholera toxin B subunit conjugates. Infect Immun. 1995 May;63(5):2021–2025. doi: 10.1128/iai.63.5.2021-2025.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bouvet J. P., Bélec L., Pirès R., Pillot J. Immunoglobulin G antibodies in human vaginal secretions after parenteral vaccination. Infect Immun. 1994 Sep;62(9):3957–3961. doi: 10.1128/iai.62.9.3957-3961.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bäckström M., Lebens M., Schödel F., Holmgren J. Insertion of a HIV-1-neutralizing epitope in a surface-exposed internal region of the cholera toxin B-subunit. Gene. 1994 Nov 18;149(2):211–217. doi: 10.1016/0378-1119(94)90152-x. [DOI] [PubMed] [Google Scholar]
- Clements M. L., Betts R. F., Tierney E. L., Murphy B. R. Resistance of adults to challenge with influenza A wild-type virus after receiving live or inactivated virus vaccine. J Clin Microbiol. 1986 Jan;23(1):73–76. doi: 10.1128/jcm.23.1.73-76.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cui Z. D., Tristram D., LaScolea L. J., Kwiatkowski T., Jr, Kopti S., Ogra P. L. Induction of antibody response to Chlamydia trachomatis in the genital tract by oral immunization. Infect Immun. 1991 Apr;59(4):1465–1469. doi: 10.1128/iai.59.4.1465-1469.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Czerkinsky C., Russell M. W., Lycke N., Lindblad M., Holmgren J. Oral administration of a streptococcal antigen coupled to cholera toxin B subunit evokes strong antibody responses in salivary glands and extramucosal tissues. Infect Immun. 1989 Apr;57(4):1072–1077. doi: 10.1128/iai.57.4.1072-1077.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Di Tommaso A., Saletti G., Pizza M., Rappuoli R., Dougan G., Abrignani S., Douce G., De Magistris M. T. Induction of antigen-specific antibodies in vaginal secretions by using a nontoxic mutant of heat-labile enterotoxin as a mucosal adjuvant. Infect Immun. 1996 Mar;64(3):974–979. doi: 10.1128/iai.64.3.974-979.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gallichan W. S., Johnson D. C., Graham F. L., Rosenthal K. L. Mucosal immunity and protection after intranasal immunization with recombinant adenovirus expressing herpes simplex virus glycoprotein B. J Infect Dis. 1993 Sep;168(3):622–629. doi: 10.1093/infdis/168.3.622. [DOI] [PubMed] [Google Scholar]
- Gallichan W. S., Rosenthal K. L. Specific secretory immune responses in the female genital tract following intranasal immunization with a recombinant adenovirus expressing glycoprotein B of herpes simplex virus. Vaccine. 1995 Nov;13(16):1589–1595. doi: 10.1016/0264-410x(95)00100-f. [DOI] [PubMed] [Google Scholar]
- Gorse G. J., Otto E. E., Powers D. C., Chambers G. W., Eickhoff C. S., Newman F. K. Induction of mucosal antibodies by live attenuated and inactivated influenza virus vaccines in the chronically ill elderly. J Infect Dis. 1996 Feb;173(2):285–290. doi: 10.1093/infdis/173.2.285. [DOI] [PubMed] [Google Scholar]
- Haneberg B., Kendall D., Amerongen H. M., Apter F. M., Kraehenbuhl J. P., Neutra M. R. Induction of specific immunoglobulin A in the small intestine, colon-rectum, and vagina measured by a new method for collection of secretions from local mucosal surfaces. Infect Immun. 1994 Jan;62(1):15–23. doi: 10.1128/iai.62.1.15-23.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hashigucci K., Ogawa H., Ishidate T., Yamashita R., Kamiya H., Watanabe K., Hattori N., Sato T., Suzuki Y., Nagamine T. 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. 1996 Feb;14(2):113–119. doi: 10.1016/0264-410x(95)00174-y. [DOI] [PubMed] [Google Scholar]
- Hirabayashi Y., Kurata H., Funato H., Nagamine T., Aizawa C., Tamura S., Shimada K., Kurata T. Comparison of intranasal inoculation of influenza HA vaccine combined with cholera toxin B subunit with oral or parenteral vaccination. Vaccine. 1990 Jun;8(3):243–248. doi: 10.1016/0264-410x(90)90053-o. [DOI] [PubMed] [Google Scholar]
- Holmgren J. Actions of cholera toxin and the prevention and treatment of cholera. Nature. 1981 Jul 30;292(5822):413–417. doi: 10.1038/292413a0. [DOI] [PubMed] [Google Scholar]
- Holmgren J., Czerkinsky C., Lycke N., Svennerholm A. M. Strategies for the induction of immune responses at mucosal surfaces making use of cholera toxin B subunit as immunogen, carrier, and adjuvant. Am J Trop Med Hyg. 1994;50(5 Suppl):42–54. [PubMed] [Google Scholar]
- Holmgren J., Svennerholm A. M. Bacterial enteric infections and vaccine development. Gastroenterol Clin North Am. 1992 Jun;21(2):283–302. [PubMed] [Google Scholar]
- Hopkins S., Kraehenbuhl J. P., Schödel F., Potts A., Peterson D., de Grandi P., Nardelli-Haefliger D. A recombinant Salmonella typhimurium vaccine induces local immunity by four different routes of immunization. Infect Immun. 1995 Sep;63(9):3279–3286. doi: 10.1128/iai.63.9.3279-3286.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hordnes K., Tynning T., Kvam A. I., Jonsson R., Haneberg B. Colonization in the rectum and uterine cervix with group B streptococci may induce specific antibody responses in cervical secretions of pregnant women. Infect Immun. 1996 May;64(5):1643–1652. doi: 10.1128/iai.64.5.1643-1652.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jertborn M., Svennerholm A. M., Holmgren J. Evaluation of different immunization schedules for oral cholera B subunit-whole cell vaccine in Swedish volunteers. Vaccine. 1993;11(10):1007–1012. doi: 10.1016/0264-410x(93)90125-h. [DOI] [PubMed] [Google Scholar]
- Jertborn M., Svennerholm A. M., Holmgren J. Saliva, breast milk, and serum antibody responses as indirect measures of intestinal immunity after oral cholera vaccination or natural disease. J Clin Microbiol. 1986 Aug;24(2):203–209. doi: 10.1128/jcm.24.2.203-209.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lehner T., Bergmeier L. A., Panagiotidi C., Tao L., Brookes R., Klavinskis L. S., Walker P., Walker J., Ward R. G., Hussain L. Induction of mucosal and systemic immunity to a recombinant simian immunodeficiency viral protein. Science. 1992 Nov 20;258(5086):1365–1369. doi: 10.1126/science.1360702. [DOI] [PubMed] [Google Scholar]
- Mancini G., Carbonara A. O., Heremans J. F. Immunochemical quantitation of antigens by single radial immunodiffusion. Immunochemistry. 1965 Sep;2(3):235–254. doi: 10.1016/0019-2791(65)90004-2. [DOI] [PubMed] [Google Scholar]
- Mazanec M. B., Lamm M. E., Lyn D., Portner A., Nedrud J. G. Comparison of IgA versus IgG monoclonal antibodies for passive immunization of the murine respiratory tract. Virus Res. 1992 Apr;23(1-2):1–12. doi: 10.1016/0168-1702(92)90063-f. [DOI] [PubMed] [Google Scholar]
- McDermott M. R., Bienenstock J. Evidence for a common mucosal immunologic system. I. Migration of B immunoblasts into intestinal, respiratory, and genital tissues. J Immunol. 1979 May;122(5):1892–1898. [PubMed] [Google Scholar]
- Menge A. C., Michalek S. M., Russell M. W., Mestecky J. Immune response of the female rat genital tract after oral and local immunization with keyhole limpet hemocyanin conjugated to the cholera toxin B subunit. Infect Immun. 1993 May;61(5):2162–2171. doi: 10.1128/iai.61.5.2162-2171.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mestecky J. The common mucosal immune system and current strategies for induction of immune responses in external secretions. J Clin Immunol. 1987 Jul;7(4):265–276. doi: 10.1007/BF00915547. [DOI] [PubMed] [Google Scholar]
- Moldoveanu Z., Clements M. L., Prince S. J., Murphy B. R., Mestecky J. Human immune responses to influenza virus vaccines administered by systemic or mucosal routes. Vaccine. 1995 Aug;13(11):1006–1012. doi: 10.1016/0264-410x(95)00016-t. [DOI] [PubMed] [Google Scholar]
- Quiding-Järbrink M., Granström G., Nordström I., Holmgren J., Czerkinsky C. Induction of compartmentalized B-cell responses in human tonsils. Infect Immun. 1995 Mar;63(3):853–857. doi: 10.1128/iai.63.3.853-857.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Quiding M., Nordström I., Kilander A., Andersson G., Hanson L. A., Holmgren J., Czerkinsky C. Intestinal immune responses in humans. Oral cholera vaccination induces strong intestinal antibody responses and interferon-gamma production and evokes local immunological memory. J Clin Invest. 1991 Jul;88(1):143–148. doi: 10.1172/JCI115270. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Roberts M., Bacon A., Rappuoli R., Pizza M., Cropley I., Douce G., Dougan G., Marinaro M., McGhee J., Chatfield S. A mutant pertussis toxin molecule that lacks ADP-ribosyltransferase activity, PT-9K/129G, is an effective mucosal adjuvant for intranasally delivered proteins. Infect Immun. 1995 Jun;63(6):2100–2108. doi: 10.1128/iai.63.6.2100-2108.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Russell M. W., Moldoveanu Z., White P. L., Sibert G. J., Mestecky J., Michalek S M. Salivary, nasal, genital, and systemic antibody responses in monkeys immunized intranasally with a bacterial protein antigen and the Cholera toxin B subunit. Infect Immun. 1996 Apr;64(4):1272–1283. doi: 10.1128/iai.64.4.1272-1283.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sanchez J., Holmgren J. Recombinant system for overexpression of cholera toxin B subunit in Vibrio cholerae as a basis for vaccine development. Proc Natl Acad Sci U S A. 1989 Jan;86(2):481–485. doi: 10.1073/pnas.86.2.481. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Snider D. P., Marshall J. S., Perdue M. H., Liang H. Production of IgE antibody and allergic sensitization of intestinal and peripheral tissues after oral immunization with protein Ag and cholera toxin. J Immunol. 1994 Jul 15;153(2):647–657. [PubMed] [Google Scholar]
- Tamura S., Shoji Y., Hasiguchi K., Aizawa C., Kurata T. Effects of cholera toxin adjuvant on IgE antibody response to orally or nasally administered ovalbumin. Vaccine. 1994 Oct;12(13):1238–1240. doi: 10.1016/0264-410x(94)90250-x. [DOI] [PubMed] [Google Scholar]
- Wassén L., Schön K., Holmgren J., Jertborn M., Lycke N. Local intravaginal vaccination of the female genital tract. Scand J Immunol. 1996 Oct;44(4):408–414. doi: 10.1046/j.1365-3083.1996.d01-320.x. [DOI] [PubMed] [Google Scholar]
- Wu H. Y., Russell M. W. Induction of mucosal immunity by intranasal application of a streptococcal surface protein antigen with the cholera toxin B subunit. Infect Immun. 1993 Jan;61(1):314–322. doi: 10.1128/iai.61.1.314-322.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- de Aizpurua H. J., Russell-Jones G. J. Oral vaccination. Identification of classes of proteins that provoke an immune response upon oral feeding. J Exp Med. 1988 Feb 1;167(2):440–451. doi: 10.1084/jem.167.2.440. [DOI] [PMC free article] [PubMed] [Google Scholar]
- de Fijter J. W., Eijgenraam J. W., Braam C. A., Holmgren J., Daha M. R., van Es L. A., van den Wall Bake A. W. Deficient IgA1 immune response to nasal cholera toxin subunit B in primary IgA nephropathy. Kidney Int. 1996 Sep;50(3):952–961. doi: 10.1038/ki.1996.396. [DOI] [PubMed] [Google Scholar]