Skip to main content
NCBI home page
Infection and Immunity logoLink to Infection and Immunity
. 1996 May;64(5):1706–1713. doi: 10.1128/iai.64.5.1706-1713.1996

Intranasal and intramuscular proteosome-staphylococcal enterotoxin B (SEB) toxoid vaccines: immunogenicity and efficacy against lethal SEB intoxication in mice.

G H Lowell 1, R W Kaminski 1, S Grate 1, R E Hunt 1, C Charney 1, S Zimmer 1, C Colleton 1
PMCID: PMC173982  PMID: 8613381

Abstract

Intranasal or intramuscular (i.m.) immunization of mice and i.m. immunization of rabbits with formalinized staphylococcal enterotoxin B (SEB) toxoid in saline elicited higher anti-SEB serum immunoglobulin G (IgG) titers when the toxoid was formulated with proteosomes. In addition, intranasal immunization of mice with this proteosome-toxoid vaccine elicited high levels of anti-SEB IgA in lung and intestinal secretions, whereas the toxoid without proteosomes did not. Two i.m. immunizations with proteosome-toxoid plus alum also induced higher murine serum responses than alum-adjuvanted toxoid without proteosomes. Furthermore, proteosome-toxoid delivered intranasally in saline or i.m. with either saline or alum afforded significant protection against lethal SEB challenge in two D-galactosamine-sensitized murine models of SEB intoxication, i.e., the previously described i.m. challenge model and a new respiratory challenge model of mucosal SEB exposure. Efficacy correlated with the induction of high serum levels of anti-SEB IgG. In contrast, intranasal or i.m. immunization with toxoid in saline without proteosomes was not significantly protective in either challenge model. Proteosome-toxoid plus alum given i.m. also elicited more significant protection against respiratory challenge than the alum-adjuvanted toxoid alone. The capacity of proteosomes to enhance both i.m. and intranasal immunogenicity and efficacy of SEB toxoid indicates that testing such proteosome-SEB toxoid vaccines in the nonhuman primate aerosol challenge model of SEB intoxication prior to immunogenicity trials in humans is warranted. These data expand the applicability of the proteosome mucosal vaccine delivery system to protein toxoids and suggest that respiratory delivery of proteosome vaccines may be practical for enhancement of both mucosal and systemic immunity against toxic or infectious diseases.

Full Text

The Full Text of this article is available as a PDF (562.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abraham E. Intranasal immunization with bacterial polysaccharide containing liposomes enhances antigen-specific pulmonary secretory antibody response. Vaccine. 1992;10(7):461–468. doi: 10.1016/0264-410x(92)90395-z. [DOI] [PubMed] [Google Scholar]
  2. Alving C. R. Liposomes as carriers of antigens and adjuvants. J Immunol Methods. 1991 Jun 24;140(1):1–13. doi: 10.1016/0022-1759(91)90120-5. [DOI] [PubMed] [Google Scholar]
  3. Bean A. G., Freiberg R. A., Andrade S., Menon S., Zlotnik A. Interleukin 10 protects mice against staphylococcal enterotoxin B-induced lethal shock. Infect Immun. 1993 Nov;61(11):4937–4939. doi: 10.1128/iai.61.11.4937-4939.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Beisel W. R. Pathophysiology of staphylococcal enterotoxin, type B, (SEB) toxemia after intravenous administration to monkeys. Toxicon. 1972 Aug;10(5):433–440. doi: 10.1016/0041-0101(72)90167-5. [DOI] [PubMed] [Google Scholar]
  5. Chelen C. J., Fang Y., Freeman G. J., Secrist H., Marshall J. D., Hwang P. T., Frankel L. R., DeKruyff R. H., Umetsu D. T. Human alveolar macrophages present antigen ineffectively due to defective expression of B7 costimulatory cell surface molecules. J Clin Invest. 1995 Mar;95(3):1415–1421. doi: 10.1172/JCI117796. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Choi Y., Lafferty J. A., Clements J. R., Todd J. K., Gelfand E. W., Kappler J., Marrack P., Kotzin B. L. Selective expansion of T cells expressing V beta 2 in toxic shock syndrome. J Exp Med. 1990 Sep 1;172(3):981–984. doi: 10.1084/jem.172.3.981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cuatrecasas P. Gangliosides and membrane receptors for cholera toxin. Biochemistry. 1973 Aug 28;12(18):3558–3566. doi: 10.1021/bi00742a032. [DOI] [PubMed] [Google Scholar]
  8. 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]
  9. Dickinson B. L., Clements J. D. Dissociation of Escherichia coli heat-labile enterotoxin adjuvanticity from ADP-ribosyltransferase activity. Infect Immun. 1995 May;63(5):1617–1623. doi: 10.1128/iai.63.5.1617-1623.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Edelman R. An update on vaccine adjuvants in clinical trial. AIDS Res Hum Retroviruses. 1992 Aug;8(8):1409–1411. doi: 10.1089/aid.1992.8.1409. [DOI] [PubMed] [Google Scholar]
  11. Edelman R., Russell R. G., Losonsky G., Tall B. D., Tacket C. O., Levine M. M., Lewis D. H. Immunization of rabbits with enterotoxigenic E. coli colonization factor antigen (CFA/I) encapsulated in biodegradable microspheres of poly (lactide-co-glycolide). Vaccine. 1993;11(2):155–158. doi: 10.1016/0264-410x(93)90012-m. [DOI] [PubMed] [Google Scholar]
  12. Edelman R., Tacket C. O. Adjuvants. Int Rev Immunol. 1990;7(1):51–66. doi: 10.3109/08830189009061764. [DOI] [PubMed] [Google Scholar]
  13. Eldridge J. H., Gilley R. M., Staas J. K., Moldoveanu Z., Meulbroek J. A., Tice T. R. Biodegradable microspheres: vaccine delivery system for oral immunization. Curr Top Microbiol Immunol. 1989;146:59–66. doi: 10.1007/978-3-642-74529-4_6. [DOI] [PubMed] [Google Scholar]
  14. Eldridge J. H., Staas J. K., Meulbroek J. A., Tice T. R., Gilley R. M. Biodegradable and biocompatible poly(DL-lactide-co-glycolide) microspheres as an adjuvant for staphylococcal enterotoxin B toxoid which enhances the level of toxin-neutralizing antibodies. Infect Immun. 1991 Sep;59(9):2978–2986. doi: 10.1128/iai.59.9.2978-2986.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hajishengallis G., Hollingshead S. K., Koga T., Russell M. W. Mucosal immunization with a bacterial protein antigen genetically coupled to cholera toxin A2/B subunits. J Immunol. 1995 May 1;154(9):4322–4332. [PubMed] [Google Scholar]
  16. Holmgren J., Lycke N., Czerkinsky C. Cholera toxin and cholera B subunit as oral-mucosal adjuvant and antigen vector systems. Vaccine. 1993 Sep;11(12):1179–1184. doi: 10.1016/0264-410x(93)90039-z. [DOI] [PubMed] [Google Scholar]
  17. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  18. Levi R., Aboud-Pirak E., Leclerc C., Lowell G. H., Arnon R. Intranasal immunization of mice against influenza with synthetic peptides anchored to proteosomes. Vaccine. 1995 Oct;13(14):1353–1359. doi: 10.1016/0264-410x(94)00083-y. [DOI] [PubMed] [Google Scholar]
  19. Liu C. T., Hilmas D. E. Effect of X irradiation on survival of rabbits with staphylococcal B enterotoxemia. Radiat Res. 1978 Nov;76(2):402–409. [PubMed] [Google Scholar]
  20. Livingston P. O., Calves M. J., Helling F., Zollinger W. D., Blake M. S., Lowell G. H. GD3/proteosome vaccines induce consistent IgM antibodies against the ganglioside GD3. Vaccine. 1993 Sep;11(12):1199–1204. doi: 10.1016/0264-410x(93)90043-w. [DOI] [PubMed] [Google Scholar]
  21. Lowell G. H., Ballou W. R., Smith L. F., Wirtz R. A., Zollinger W. D., Hockmeyer W. T. Proteosome-lipopeptide vaccines: enhancement of immunogenicity for malaria CS peptides. Science. 1988 May 6;240(4853):800–802. doi: 10.1126/science.2452484. [DOI] [PubMed] [Google Scholar]
  22. Lowell G. H., Smith L. F., Seid R. C., Zollinger W. D. Peptides bound to proteosomes via hydrophobic feet become highly immunogenic without adjuvants. J Exp Med. 1988 Feb 1;167(2):658–663. doi: 10.1084/jem.167.2.658. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Mallett C. P., Hale T. L., Kaminski R. W., Larsen T., Orr N., Cohen D., Lowell G. H. Intransal or intragastric immunization with proteosome-Shigella lipopolysaccharide vaccines protects against lethal pneumonia in a murine model of Shigella infection. Infect Immun. 1995 Jun;63(6):2382–2386. doi: 10.1128/iai.63.6.2382-2386.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Marrack P., Kappler J. The staphylococcal enterotoxins and their relatives. Science. 1990 May 11;248(4956):705–711. doi: 10.1126/science.2185544. [DOI] [PubMed] [Google Scholar]
  25. Marx P. A., Compans R. W., Gettie A., Staas J. K., Gilley R. M., Mulligan M. J., Yamshchikov G. V., Chen D., Eldridge J. H. Protection against vaginal SIV transmission with microencapsulated vaccine. Science. 1993 May 28;260(5112):1323–1327. doi: 10.1126/science.8493576. [DOI] [PubMed] [Google Scholar]
  26. Mattix M. E., Hunt R. E., Wilhelmsen C. L., Johnson A. J., Baze W. B. Aerosolized staphylococcal enterotoxin B-induced pulmonary lesions in rhesus monkeys (Macaca mulatta). Toxicol Pathol. 1995 May-Jun;23(3):262–268. doi: 10.1177/019262339502300304. [DOI] [PubMed] [Google Scholar]
  27. McGhee J. R., Kiyono H. New perspectives in vaccine development: mucosal immunity to infections. Infect Agents Dis. 1993 Apr;2(2):55–73. [PubMed] [Google Scholar]
  28. McQueen C. E., Boedeker E. C., Reid R., Jarboe D., Wolf M., Le M., Brown W. R. Pili in microspheres protect rabbits from diarrhoea induced by E. coli strain RDEC-1. Vaccine. 1993;11(2):201–206. doi: 10.1016/0264-410x(93)90018-s. [DOI] [PubMed] [Google Scholar]
  29. 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]
  30. Miethke T., Wahl C., Heeg K., Echtenacher B., Krammer P. H., Wagner H. T cell-mediated lethal shock triggered in mice by the superantigen staphylococcal enterotoxin B: critical role of tumor necrosis factor. J Exp Med. 1992 Jan 1;175(1):91–98. doi: 10.1084/jem.175.1.91. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Neutra M. R., Kraehenbuhl J. P. Transepithelial transport and mucosal defence I: the role of M cells. Trends Cell Biol. 1992 May;2(5):134–138. doi: 10.1016/0962-8924(92)90099-9. [DOI] [PubMed] [Google Scholar]
  32. Orr N., Arnon R., Rubin G., Cohen D., Bercovier H., Lowell G. H. Enhancement of anti-Shigella lipopolysaccharide (LPS) response by addition of the cholera toxin B subunit to oral and intranasal proteosome-Shigella flexneri 2a LPS vaccines. Infect Immun. 1994 Nov;62(11):5198–5200. doi: 10.1128/iai.62.11.5198-5200.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Orr N., Robin G., Cohen D., Arnon R., Lowell G. H. Immunogenicity and efficacy of oral or intranasal Shigella flexneri 2a and Shigella sonnei proteosome-lipopolysaccharide vaccines in animal models. Infect Immun. 1993 Jun;61(6):2390–2395. doi: 10.1128/iai.61.6.2390-2395.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. 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]
  35. Russell M. W., Wu H. Y. Distribution, persistence, and recall of serum and salivary antibody responses to peroral immunization with protein antigen I/II of Streptococcus mutans coupled to the cholera toxin B subunit. Infect Immun. 1991 Nov;59(11):4061–4070. doi: 10.1128/iai.59.11.4061-4070.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Schantz E. J., Roessler W. G., Wagman J., Spero L., Dunnery D. A., Bergdoll M. S. Purification of staphylococcal enterotoxin B. Biochemistry. 1965 Jun;4(6):1011–1016. doi: 10.1021/bi00882a005. [DOI] [PubMed] [Google Scholar]
  37. Schlievert P. M. Role of superantigens in human disease. J Infect Dis. 1993 May;167(5):997–1002. doi: 10.1093/infdis/167.5.997. [DOI] [PubMed] [Google Scholar]
  38. Shahin R., Leef M., Eldridge J., Hudson M., Gilley R. Adjuvanticity and protective immunity elicited by Bordetella pertussis antigens encapsulated in poly(DL-lactide-co-glycolide) microspheres. Infect Immun. 1995 Apr;63(4):1195–1200. doi: 10.1128/iai.63.4.1195-1200.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Spero L., Leatherman D. L., Adler W. H. Mitogenicity of formalinized toxoids of staphylococcal enterotoxin B. Infect Immun. 1975 Nov;12(5):1018–1020. doi: 10.1128/iai.12.5.1018-1020.1975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Tseng J., Komisar J. L., Trout R. N., Hunt R. E., Chen J. Y., Johnson A. J., Pitt L., Ruble D. L. Humoral immunity to aerosolized staphylococcal enterotoxin B (SEB), a superantigen, in monkeys vaccinated with SEB toxoid-containing microspheres. Infect Immun. 1995 Aug;63(8):2880–2885. doi: 10.1128/iai.63.8.2880-2885.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Walker R. I. New strategies for using mucosal vaccination to achieve more effective immunization. Vaccine. 1994 Apr;12(5):387–400. doi: 10.1016/0264-410x(94)90112-0. [DOI] [PubMed] [Google Scholar]
  42. Warren J. R., Spero L., Metzger J. F. Antigenicity of formaldehyde-inactivated staphylococcal enterotoxin B. J Immunol. 1973 Sep;111(3):885–892. [PubMed] [Google Scholar]
  43. 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]
  44. el Guink N., Kris R. M., Goodman-Snitkoff G., Small P. A., Jr, Mannino R. J. Intranasal immunization with proteoliposomes protects against influenza. Vaccine. 1989 Apr;7(2):147–151. doi: 10.1016/0264-410x(89)90055-8. [DOI] [PubMed] [Google Scholar]

Articles from Infection and Immunity are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES