Skip to main content
NCBI home page
Clinical Microbiology Reviews logoLink to Clinical Microbiology Reviews
. 1994 Jul;7(3):277–289. doi: 10.1128/cmr.7.3.277

Molecular adjuvants and immunomodulators: new approaches to immunization.

A G Johnson 1
PMCID: PMC358325  PMID: 7923049

Abstract

Epitopes on microbial antigens responsible for protective immunity have begun to be identified and isolated, and their chemical structures have been determined. Ensuing knowledge of their weak immunizing capacity per se has led to an appreciation of the need for adjuvants to increase the immunogenicity of these low-molecular-weight synthetic structures. As such, a recent surge in adjuvant research has emerged. Accordingly, this review will highlight a number of those adjuvant substances whose activity in animals indicates a potential use in human vaccines. In addition, the potential of several well-defined substances, termed immunomodulators, which nonspecifically stimulate resistance of animals to multiple 50% lethal doses of microbial challenge is described. Among the most extensively characterized adjuvants of microbial origin discussed in detail are (i) the lipopolysaccharides isolated from gram-negative bacteria and their nontoxic analogs, (ii) the synthetic muramyl dipeptides and their multiple analogs, and (iii) the synthetic polyribonucleotide complexes, mimicking the interferon-inducing capacity of viruses. Discussed also are the heat-labile enterotoxin of Escherichia coli, the nonionic block copolymers, the saponins, a quinolamine derivative, and the hormone dihydroepiandrosterone.

Full text

PDF
277

Selected References

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

  1. Adams A., Mohrman M., Johnson A. G., Morin A., Deschamps de Paillette E. Polyadenylic:polyuridylic acid-induced protection of BALB/c mice against acute murine cytomegalovirus infection. J Gen Virol. 1992 Sep;73(Pt 9):2409–2413. doi: 10.1099/0022-1317-73-9-2409. [DOI] [PubMed] [Google Scholar]
  2. Allison A. C., Byars N. E. Adjuvant formulations and their mode of action. Semin Immunol. 1990 Sep;2(5):369–374. [PubMed] [Google Scholar]
  3. Araneo B. A., Dowell T., Diegel M., Daynes R. A. Dihydrotestosterone exerts a depressive influence on the production of interleukin-4 (IL-4), IL-5, and gamma-interferon, but not IL-2 by activated murine T cells. Blood. 1991 Aug 1;78(3):688–699. [PubMed] [Google Scholar]
  4. Araneo B. A., Woods M. L., 2nd, Daynes R. A. Reversal of the immunosenescent phenotype by dehydroepiandrosterone: hormone treatment provides an adjuvant effect on the immunization of aged mice with recombinant hepatitis B surface antigen. J Infect Dis. 1993 Apr;167(4):830–840. doi: 10.1093/infdis/167.4.830. [DOI] [PubMed] [Google Scholar]
  5. Aschauer H., Grob A., Hildebrandt J., Schuetze E., Stuetz P. Highly purified lipid X is devoid of immunostimulatory activity. Isolation and characterization of immunostimulating contaminants in a batch of synthetic lipid X. J Biol Chem. 1990 Jun 5;265(16):9159–9164. [PubMed] [Google Scholar]
  6. Baker P. J., Amsbaugh D. F., Stashak P. W., Caldes G., Prescott B. Direct evidence for the involvement of T suppressor cells in the expression of low-dose paralysis to type III pneumococcal polysaccharide. J Immunol. 1982 Mar;128(3):1059–1062. [PubMed] [Google Scholar]
  7. Baker P. J., Hiernaux J. R., Fauntleroy M. B., Prescott B., Cantrell J. L., Rudbach J. A. Inactivation of suppressor T-cell activity by nontoxic monophosphoryl lipid A. Infect Immun. 1988 May;56(5):1076–1083. doi: 10.1128/iai.56.5.1076-1083.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Baker P. J., Hiernaux J. R., Fauntleroy M. B., Stashak P. W., Prescott B., Cantrell J. L., Rudbach J. A. Ability of monophosphoryl lipid A to augment the antibody response of young mice. Infect Immun. 1988 Dec;56(12):3064–3066. doi: 10.1128/iai.56.12.3064-3066.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Bennett B., Check I. J., Olsen M. R., Hunter R. L. A comparison of commercially available adjuvants for use in research. J Immunol Methods. 1992 Aug 30;153(1-2):31–40. doi: 10.1016/0022-1759(92)90302-a. [DOI] [PubMed] [Google Scholar]
  10. Bernstein D. I., Harrison C. J. Effects of the immunomodulating agent R837 on acute and latent herpes simplex virus type 2 infections. Antimicrob Agents Chemother. 1989 Sep;33(9):1511–1515. doi: 10.1128/aac.33.9.1511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Bernstein D. I., Miller R. L., Harrison C. J. Adjuvant effects of imiquimod on a herpes simplex virus type 2 glycoprotein vaccine in guinea pigs. J Infect Dis. 1993 Mar;167(3):731–735. doi: 10.1093/infdis/167.3.731. [DOI] [PubMed] [Google Scholar]
  12. Brown R., Price R. J., King M. G., Husband A. J. Interleukin-1 beta and muramyl dipeptide can prevent decreased antibody response associated with sleep deprivation. Brain Behav Immun. 1989 Dec;3(4):320–330. doi: 10.1016/0889-1591(89)90031-7. [DOI] [PubMed] [Google Scholar]
  13. Carlson J. R., McGraw T. P., Keddie E., Yee J. L., Rosenthal A., Langlois A. J., Dickover R., Donovan R., Luciw P. A., Jennings M. B. Vaccine protection of rhesus macaques against simian immunodeficiency virus infection. AIDS Res Hum Retroviruses. 1990 Nov;6(11):1239–1246. doi: 10.1089/aid.1990.6.1239. [DOI] [PubMed] [Google Scholar]
  14. Cavaillon J. M., Fitting C., Caroff M., Haeffner-Cavaillon N. Dissociation of cell-associated interleukin-1 (IL-1) and IL-1 release induced by lipopolysaccharide and lipid A. Infect Immun. 1989 Mar;57(3):791–797. doi: 10.1128/iai.57.3.791-797.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Charon D., Chaby R., Malinvaud A., Mondange M., Szabó L. Chemical synthesis and immunological activities of glycolipids structurally related to lipid A. Biochemistry. 1985 May 21;24(11):2736–2742. doi: 10.1021/bi00332a021. [DOI] [PubMed] [Google Scholar]
  16. Chase J. J., Kubey W., Dulek M. H., Holmes C. J., Salit M. G., Pearson F. C., 3rd, Ribi E. Effect of monophosphoryl lipid A on host resistance to bacterial infection. Infect Immun. 1986 Sep;53(3):711–712. doi: 10.1128/iai.53.3.711-712.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Cheadle W. G., Hershman M. J., Mays B., Melton L., Polk H. C., Jr Enhancement of survival from murine polymicrobial peritonitis with increased abdominal abscess formation. J Surg Res. 1989 Aug;47(2):120–123. doi: 10.1016/0022-4804(89)90074-7. [DOI] [PubMed] [Google Scholar]
  18. Chedid L., Audibert F., Johnson A. G. Biological activities of muramyl dipeptide, a synthetic glycopeptide analogous to bacterial immunoregulating agents. Prog Allergy. 1978;25:63–105. [PubMed] [Google Scholar]
  19. Chedid L., Parant M., Parant F., Lefrancher P., Choay J., Lederer E. Enhancement of nonspecific immunity to Klebsiella pneumoniae infection by a synthetic immunoadjuvant (N-acetylmuramyl-L-alanyl-D-isoglutamine) and several analogs. Proc Natl Acad Sci U S A. 1977 May;74(5):2089–2093. doi: 10.1073/pnas.74.5.2089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Chiller J. M., Skidmore B. J., Morrison D. C., Weigle W. O. Relationship of the structure of bacterial lipopolysaccharides to its function in mitogenesis and adjuvanticity. Proc Natl Acad Sci U S A. 1973 Jul;70(7):2129–2133. doi: 10.1073/pnas.70.7.2129. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Clements J. D., Finkelstein R. A. Isolation and characterization of homogeneous heat-labile enterotoxins with high specific activity from Escherichia coli cultures. Infect Immun. 1979 Jun;24(3):760–769. doi: 10.1128/iai.24.3.760-769.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Clements J. D., Hartzog N. M., Lyon F. L. Adjuvant activity of Escherichia coli heat-labile enterotoxin and effect on the induction of oral tolerance in mice to unrelated protein antigens. Vaccine. 1988 Jun;6(3):269–277. doi: 10.1016/0264-410x(88)90223-x. [DOI] [PubMed] [Google Scholar]
  23. Clements J. D., Yancey R. J., Finkelstein R. A. Properties of homogeneous heat-labile enterotoxin from Escherichia coli. Infect Immun. 1980 Jul;29(1):91–97. doi: 10.1128/iai.29.1.91-97.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Collins W. E., Anders R. F., Ruebush T. K., 2nd, Kemp D. J., Woodrow G. C., Campbell G. H., Brown G. V., Irving D. O., Goss N., Filipski V. K. Immunization of owl monkeys with the ring-infected erythrocyte surface antigen of Plasmodium falciparum. Am J Trop Med Hyg. 1991 Jan;44(1):34–41. doi: 10.4269/ajtmh.1991.44.34. [DOI] [PubMed] [Google Scholar]
  25. Daynes R. A., Araneo B. A., Dowell T. A., Huang K., Dudley D. Regulation of murine lymphokine production in vivo. III. The lymphoid tissue microenvironment exerts regulatory influences over T helper cell function. J Exp Med. 1990 Apr 1;171(4):979–996. doi: 10.1084/jem.171.4.979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Daynes R. A., Dudley D. J., Araneo B. A. Regulation of murine lymphokine production in vivo. II. Dehydroepiandrosterone is a natural enhancer of interleukin 2 synthesis by helper T cells. Eur J Immunol. 1990 Apr;20(4):793–802. doi: 10.1002/eji.1830200413. [DOI] [PubMed] [Google Scholar]
  27. Denis M., Chadee K. Human neutrophils activated by interferon-gamma and tumour necrosis factor-alpha kill Entamoeba histolytica trophozoites in vitro. J Leukoc Biol. 1989 Sep;46(3):270–274. doi: 10.1002/jlb.46.3.270. [DOI] [PubMed] [Google Scholar]
  28. Dijkstra J., Mellors J. W., Ryan J. L., Szoka F. C. Modulation of the biological activity of bacterial endotoxin by incorporation into liposomes. J Immunol. 1987 Apr 15;138(8):2663–2670. [PubMed] [Google Scholar]
  29. Ellouz F., Adam A., Ciorbaru R., Lederer E. Minimal structural requirements for adjuvant activity of bacterial peptidoglycan derivatives. Biochem Biophys Res Commun. 1974 Aug 19;59(4):1317–1325. doi: 10.1016/0006-291x(74)90458-6. [DOI] [PubMed] [Google Scholar]
  30. Field A. K., Tytell A. A., Lampson G. P., Hilleman M. R. Inducers of interferon and host resistance. II. Multistranded synthetic polynucleotide complexes. Proc Natl Acad Sci U S A. 1967 Sep;58(3):1004–1010. doi: 10.1073/pnas.58.3.1004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Galanos C., Lüderitz O., Freudenberg M., Brade L., Schade U., Rietschel E. T., Kusumoto S., Shiba T. Biological activity of synthetic heptaacyl lipid A representing a component of Salmonella minnesota R595 lipid A. Eur J Biochem. 1986 Oct 1;160(1):55–59. doi: 10.1111/j.1432-1033.1986.tb09939.x. [DOI] [PubMed] [Google Scholar]
  32. Galanos C., Lüderitz O., Rietschel E. T., Westphal O., Brade H., Brade L., Freudenberg M., Schade U., Imoto M., Yoshimura H. Synthetic and natural Escherichia coli free lipid A express identical endotoxic activities. Eur J Biochem. 1985 Apr 1;148(1):1–5. doi: 10.1111/j.1432-1033.1985.tb08798.x. [DOI] [PubMed] [Google Scholar]
  33. Gustafson G. L., Rhodes M. J. Bacterial cell wall products as adjuvants: early interferon gamma as a marker for adjuvants that enhance protective immunity. Res Immunol. 1992 Jun;143(5):483–574. doi: 10.1016/0923-2494(92)80058-s. [DOI] [PubMed] [Google Scholar]
  34. Han I. H., Johnson A. G. Regulation of the immune system by synthetic polynucleotides. VI. Amplification of the immune response in young and aging mice. J Immunol. 1976 Aug;117(2):423–427. [PubMed] [Google Scholar]
  35. Harrison L. C., Campbell I. L. Cytokines: an expanding network of immuno-inflammatory hormones. Mol Endocrinol. 1988 Dec;2(12):1151–1156. doi: 10.1210/mend-2-12-1151. [DOI] [PubMed] [Google Scholar]
  36. Henricson B. E., Perera P. Y., Qureshi N., Takayama K., Vogel S. N. Rhodopseudomonas sphaeroides lipid A derivatives block in vitro induction of tumor necrosis factor and endotoxin tolerance by smooth lipopolysaccharide and monophosphoryl lipid A. Infect Immun. 1992 Oct;60(10):4285–4290. doi: 10.1128/iai.60.10.4285-4290.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Ho R. J., Burke R. L., Merigan T. C. Antigen-presenting liposomes are effective in treatment of recurrent herpes simplex virus genitalis in guinea pigs. J Virol. 1989 Jul;63(7):2951–2958. doi: 10.1128/jvi.63.7.2951-2958.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Holmgren J., Czerkinsky C., Lycke N., Svennerholm A. M. Mucosal immunity: implications for vaccine development. Immunobiology. 1992 Feb;184(2-3):157–179. doi: 10.1016/S0171-2985(11)80473-0. [DOI] [PubMed] [Google Scholar]
  39. Homma J. Y., Matsuura M., Kanegasaki S., Kawakubo Y., Kojima Y., Shibukawa N., Kumazawa Y., Yamamoto A., Tanamoto K., Yasuda T. Structural requirements of lipid A responsible for the functions: a study with chemically synthesized lipid A and its analogues. J Biochem. 1985 Aug;98(2):395–406. doi: 10.1093/oxfordjournals.jbchem.a135294. [DOI] [PubMed] [Google Scholar]
  40. Hui G. S., Tam L. Q., Chang S. P., Case S. E., Hashiro C., Siddiqui W. A., Shiba T., Kusumoto S., Kotani S. Synthetic low-toxicity muramyl dipeptide and monophosphoryl lipid A replace Freund complete adjuvant in inducing growth-inhibitory antibodies to the Plasmodium falciparum major merozoite surface protein, gp195. Infect Immun. 1991 May;59(5):1585–1591. doi: 10.1128/iai.59.5.1585-1591.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Hunter R., Olsen M., Buynitzky S. Adjuvant activity of non-ionic block copolymers. IV. Effect of molecular weight and formulation on titre and isotype of antibody. Vaccine. 1991 Apr;9(4):250–256. doi: 10.1016/0264-410x(91)90108-i. [DOI] [PubMed] [Google Scholar]
  42. Hunter R., Strickland F., Kézdy F. The adjuvant activity of nonionic block polymer surfactants. I. The role of hydrophile-lipophile balance. J Immunol. 1981 Sep;127(3):1244–1250. [PubMed] [Google Scholar]
  43. Iigo M., Nakajima Y., Nishikata K., Hoshi A. Enhanced antitumor effect of combination therapy with interleukin-2 and polyribonucleotides against adenocarcinoma 755. J Biol Response Mod. 1989 Apr;8(2):147–154. [PubMed] [Google Scholar]
  44. JOHNSON A. G., GAINES S., LANDY M. Studies on the O antigen of Salmonella typhosa. V. Enhancement of antibody response to protein antigens by the purified lipopolysaccharide. J Exp Med. 1956 Feb 1;103(2):225–246. doi: 10.1084/jem.103.2.225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Jirik F. R., Podor T. J., Hirano T., Kishimoto T., Loskutoff D. J., Carson D. A., Lotz M. Bacterial lipopolysaccharide and inflammatory mediators augment IL-6 secretion by human endothelial cells. J Immunol. 1989 Jan 1;142(1):144–147. [PubMed] [Google Scholar]
  46. Jupin C., Parant M., Chedid L. Involvement of reactive oxygen metabolites in the candidacidal activity of human neutrophils stimulated by muramyl dipeptide or tumor necrosis factor. Immunobiology. 1989 Nov;180(1):68–79. doi: 10.1016/S0171-2985(89)80031-2. [DOI] [PubMed] [Google Scholar]
  47. Kalish M. L., Check I. J., Hunter R. L. Murine IgG isotype responses to the Plasmodium cynomolgi circumsporozoite peptide (NAGG)5. I. Effects of carrier, copolymer adjuvants, and lipopolysaccharide on isotype selection. J Immunol. 1991 May 15;146(10):3583–3590. [PubMed] [Google Scholar]
  48. Kanegasaki S., Kojima Y., Matsuura M., Homma J. Y., Yamamoto A., Kumazawa Y., Tanamoto K., Yasuda T., Tsumita T., Imoto M. Biological activities of analogues of lipid A based chemically on the revised structural model. Comparison of mediator-inducing, immunomodulating and endotoxic activities. Eur J Biochem. 1984 Sep 3;143(2):237–242. doi: 10.1111/j.1432-1033.1984.tb08364.x. [DOI] [PubMed] [Google Scholar]
  49. Kawakami M., Pekala P. H., Lane M. D., Cerami A. Lipoprotein lipase suppression in 3T3-L1 cells by an endotoxin-induced mediator from exudate cells. Proc Natl Acad Sci U S A. 1982 Feb;79(3):912–916. doi: 10.1073/pnas.79.3.912. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Kensil C. R., Barrett C., Kushner N., Beltz G., Storey J., Patel U., Recchia J., Aubert A., Marciani D. Development of a genetically engineered vaccine against feline leukemia virus infection. J Am Vet Med Assoc. 1991 Nov 15;199(10):1423–1427. [PubMed] [Google Scholar]
  51. Kensil C. R., Patel U., Lennick M., Marciani D. Separation and characterization of saponins with adjuvant activity from Quillaja saponaria Molina cortex. J Immunol. 1991 Jan 15;146(2):431–437. [PubMed] [Google Scholar]
  52. Khanna R., Ahmad S., Khan H. M., Kumar H., Mahdi A. A. Vaccination of rhesus monkeys against Plasmodium knowlesi with aqueous suspension of MDP as an adjuvant. Indian J Malariol. 1991 Jun;28(2):99–104. [PubMed] [Google Scholar]
  53. Khullar N., Gupta C. M., Sehgal S. Immune response studies in relation to protection induced by using MDP as an adjuvant in malaria. Immunol Invest. 1988 Mar;17(1):1–17. doi: 10.3109/08820138809055714. [DOI] [PubMed] [Google Scholar]
  54. Khullar N., Sehgal S. Histopathological studies in relation to protection induced by using MDP as an adjuvant in malaria. Indian J Malariol. 1991 Dec;28(4):243–248. [PubMed] [Google Scholar]
  55. Kotani S., Takada H., Takahashi I., Ogawa T., Tsujimoto M., Shimauchi H., Ikeda T., Okamura H., Tamura T., Harada K. Immunobiological activities of synthetic lipid A analogs with low endotoxicity. Infect Immun. 1986 Dec;54(3):673–682. doi: 10.1128/iai.54.3.673-682.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Kotani S., Takada H., Takahashi I., Tsujimoto M., Ogawa T., Ikeda T., Harada K., Okamura H., Tamura T., Tanaka S. Low endotoxic activities of synthetic Salmonella-type lipid A with an additional acyloxyacyl group on the 2-amino group of beta (1-6) glucosamine disaccharide 1,4'-bisphosphate. Infect Immun. 1986 Jun;52(3):872–884. doi: 10.1128/iai.52.3.872-884.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Kotani S., Takada H., Tsujimoto M., Ogawa T., Harada K., Mori Y., Kawasaki A., Tanaka A., Nagao S., Tanaka S. Immunobiologically active lipid A analogs synthesized according to a revised structural model of natural lipid A. Infect Immun. 1984 Jul;45(1):293–296. doi: 10.1128/iai.45.1.293-296.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Kumazawa Y., Matsuura M., Homma J. Y., Nakatsuru Y., Kiso M., Hasegawa A. B cell activation and adjuvant activities of chemically synthesized analogues of the nonreducing sugar moiety of lipid A. Eur J Immunol. 1985 Feb;15(2):199–201. doi: 10.1002/eji.1830150218. [DOI] [PubMed] [Google Scholar]
  59. Kumazawa Y., Nakatsuka M., Takimoto H., Furuya T., Nagumo T., Yamamoto A., Homma Y., Inada K., Yoshida M., Kiso M. Importance of fatty acid substituents of chemically synthesized lipid A-subunit analogs in the expression of immunopharmacological activity. Infect Immun. 1988 Jan;56(1):149–155. doi: 10.1128/iai.56.1.149-155.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Kunimoto D. Y., Nordan R. P., Strober W. IL-6 is a potent cofactor of IL-1 in IgM synthesis and of IL-5 in IgA synthesis. J Immunol. 1989 Oct 1;143(7):2230–2235. [PubMed] [Google Scholar]
  61. LANDY M., JOHNSON A. G. Studies on the O antigen of Salmonella typhosa. IV. Endotoxic properties of the purified antigen. Proc Soc Exp Biol Med. 1955 Oct;90(1):57–62. doi: 10.3181/00379727-90-21937. [DOI] [PubMed] [Google Scholar]
  62. LANDY M., JOHNSON A. G., WEBSTER M. E., SAGIN J. F. Studies on the O antigen of Salmonella typhosa. II. Immunological properties of the purified antigen. J Immunol. 1955 Jun;74(6):466–478. [PubMed] [Google Scholar]
  63. Lacour F., Spira A., Lacour J., Prade M. Polyadenylic-polyuridylic acid, an adjunct to surgery in the treatment of spontaneous mammary tumors in C3H-He mice and transplantable melanoma in the hamster. Cancer Res. 1972 Mar;32(3):648–649. [PubMed] [Google Scholar]
  64. Lacour J., Lacour F., Spira A., Michelson M., Petit J. Y., Delage G., Sarrazin D., Contesso G., Viguier J. Adjuvant treatment with polyadenylic-polyuridylic acid (Polya.Polyu) in operable breast cancer. Lancet. 1980 Jul 26;2(8187):161–164. doi: 10.1016/s0140-6736(80)90057-4. [DOI] [PubMed] [Google Scholar]
  65. Lacour J., Lacour F., Spira A., Michelson M., Petit J. Y., Delage G., Sarrazin D., Contesso G., Viguier J. Adjuvant treatment with polyadenylic-polyuridylic acid in operable breast cancer: updated results of a randomised trial. Br Med J (Clin Res Ed) 1984 Feb 25;288(6417):589–592. doi: 10.1136/bmj.288.6417.589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Lam C., Hildebrandt J., Schütze E., Rosenwirth B., Proctor R. A., Liehl E., Stütz P. Immunostimulatory, but not antiendotoxin, activity of lipid X is due to small amounts of contaminating N,O-acylated disaccharide-1-phosphate: in vitro and in vivo reevaluation of the biological activity of synthetic lipid X. Infect Immun. 1991 Jul;59(7):2351–2358. doi: 10.1128/iai.59.7.2351-2358.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Lam C., Schütze E., Hildebrandt J., Aschauer H., Liehl E., Macher I., Stütz P. SDZ MRL 953, a novel immunostimulatory monosaccharidic lipid A analog with an improved therapeutic window in experimental sepsis. Antimicrob Agents Chemother. 1991 Mar;35(3):500–505. doi: 10.1128/aac.35.3.500. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Lebbar S., Cavaillon J. M., Caroff M., Ledur A., Brade H., Sarfati R., Haeffner-Cavaillon N. Molecular requirement for interleukin 1 induction by lipopolysaccharide-stimulated human monocytes: involvement of the heptosyl-2-keto-3-deoxyoctulosonate region. Eur J Immunol. 1986 Jan;16(1):87–91. doi: 10.1002/eji.1830160117. [DOI] [PubMed] [Google Scholar]
  69. Leclerc C., Vogel F. R. Synthetic immunomodulators and synthetic vaccines. Crit Rev Ther Drug Carrier Syst. 1986;2(4):353–406. [PubMed] [Google Scholar]
  70. Lee B. K., Mohrman M., Odean M. J., Johnson A. G., Morin A., Deschamps de Paillette E. Polyadenylic: polyuridylic acid-induced determinants of host resistance to cytomegalovirus and their potentiation by hyperthermia. J Immunother (1991) 1992 Aug;12(2):105–114. doi: 10.1097/00002371-199208000-00005. [DOI] [PubMed] [Google Scholar]
  71. Lei M. G., Morrison D. C. Specific endotoxic lipopolysaccharide-binding proteins on murine splenocytes. I. Detection of lipopolysaccharide-binding sites on splenocytes and splenocyte subpopulations. J Immunol. 1988 Aug 1;141(3):996–1005. [PubMed] [Google Scholar]
  72. Lew A. M., Anders R. F., Edwards S. J., Langford C. J. Comparison of antibody avidity and titre elicited by peptide as a protein conjugate or as expressed in vaccinia. Immunology. 1988 Oct;65(2):311–314. [PMC free article] [PubMed] [Google Scholar]
  73. Loppnow H., Brade H., Dürrbaum I., Dinarello C. A., Kusumoto S., Rietschel E. T., Flad H. D. IL-1 induction-capacity of defined lipopolysaccharide partial structures. J Immunol. 1989 May 1;142(9):3229–3238. [PubMed] [Google Scholar]
  74. Loppnow H., Brade L., Brade H., Rietschel E. T., Kusumoto S., Shiba T., Flad H. D. Induction of human interleukin 1 by bacterial and synthetic lipid A. Eur J Immunol. 1986 Oct;16(10):1263–1267. doi: 10.1002/eji.1830161013. [DOI] [PubMed] [Google Scholar]
  75. Lycke N., Holmgren J. Strong adjuvant properties of cholera toxin on gut mucosal immune responses to orally presented antigens. Immunology. 1986 Oct;59(2):301–308. [PMC free article] [PubMed] [Google Scholar]
  76. Lycke N., Tsuji T., Holmgren J. The adjuvant effect of Vibrio cholerae and Escherichia coli heat-labile enterotoxins is linked to their ADP-ribosyltransferase activity. Eur J Immunol. 1992 Sep;22(9):2277–2281. doi: 10.1002/eji.1830220915. [DOI] [PubMed] [Google Scholar]
  77. MERRITT K., JOHNSON A. G. STUDIES ON THE ADJUVANT ACTION OF BACTERIAL ENDOTOXINS ON ANTIBODY FORMATION. VI. ENHANCEMENT OF ANTIBODY FORMATION BY NUCLEIC ACIDS. J Immunol. 1965 Mar;94:416–422. [PubMed] [Google Scholar]
  78. Matsumoto K., Ogawa H., Kusama T., Nagase O., Sawaki N., Inage M., Kusumoto S., Shiba T., Azuma I. Stimulation of nonspecific resistance to infection induced by 6-O-acyl muramyl dipeptide analogs in mice. Infect Immun. 1981 May;32(2):748–758. doi: 10.1128/iai.32.2.748-758.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  79. Minami A., Fujimoto K., Ozaki Y., Nakamura S. Augmentation of host resistance to microbial infections by recombinant human interleukin-1 alpha. Infect Immun. 1988 Dec;56(12):3116–3120. doi: 10.1128/iai.56.12.3116-3120.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Mitchell M. S., Kan-Mitchell J., Kempf R. A., Harel W., Shau H. Y., Lind S. Active specific immunotherapy for melanoma: phase I trial of allogeneic lysates and a novel adjuvant. Cancer Res. 1988 Oct 15;48(20):5883–5893. [PubMed] [Google Scholar]
  81. Morris C. K., Johnson A. G. Regulation of the immune system by synthetic polynucleotides. VII. Suppression induced by pretreatment with poly A:U. Cell Immunol. 1978 Sep;39(2):345–354. doi: 10.1016/0008-8749(78)90110-7. [DOI] [PubMed] [Google Scholar]
  82. Morrison D. C., Ryan J. L. Bacterial endotoxins and host immune responses. Adv Immunol. 1979;28:293–450. doi: 10.1016/s0065-2776(08)60802-0. [DOI] [PubMed] [Google Scholar]
  83. Morrison D. C., Ulevitch R. J. The effects of bacterial endotoxins on host mediation systems. A review. Am J Pathol. 1978 Nov;93(2):526–618. [PMC free article] [PubMed] [Google Scholar]
  84. Murphey-Corb M., Martin L. N., Davison-Fairburn B., Montelaro R. C., Miller M., West M., Ohkawa S., Baskin G. B., Zhang J. Y., Putney S. D. A formalin-inactivated whole SIV vaccine confers protection in macaques. Science. 1989 Dec 8;246(4935):1293–1297. doi: 10.1126/science.2555923. [DOI] [PubMed] [Google Scholar]
  85. Nedrud J. G., Sigmund N. Cholera toxin as a mucosal adjuvant: III. Antibody responses to nontarget dietary antigens are not increased. Reg Immunol. 1990;3(5):217–222. [PubMed] [Google Scholar]
  86. Newman M. J., Wu J. Y., Gardner B. H., Munroe K. J., Leombruno D., Recchia J., Kensil C. R., Coughlin R. T. Saponin adjuvant induction of ovalbumin-specific CD8+ cytotoxic T lymphocyte responses. J Immunol. 1992 Apr 15;148(8):2357–2362. [PubMed] [Google Scholar]
  87. Nolibe D., Thang M. N. Stimulation of natural killer cytotoxicity by long-term treatment with double-stranded polynucleotides without induction of hyporesponsiveness. Cancer Immunol Immunother. 1988;27(2):114–120. doi: 10.1007/BF00200014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Odean M. J., Frane C. M., Van derVieren M., Tomai M. A., Johnson A. G. Involvement of gamma interferon in antibody enhancement by adjuvants. Infect Immun. 1990 Feb;58(2):427–432. doi: 10.1128/iai.58.2.427-432.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. Onozuka K., Shinomiya H., Cho N., Saito-Taki T., Nakano M. The adjuvant effect of a muramyl dipeptide (MDP) analog on temperature-sensitive Salmonella mutant vaccine. Int J Immunopharmacol. 1989;11(7):781–787. doi: 10.1016/0192-0561(89)90132-x. [DOI] [PubMed] [Google Scholar]
  90. Parant M. A., Audibert F. M., Chedid L. A., Level M. R., Lefrancier P. L., Choay J. P., Lederer E. Immunostimulant activities of a lipophilic muramyl dipeptide derivative and of desmuramyl peptidolipid analogs. Infect Immun. 1980 Mar;27(3):826–831. doi: 10.1128/iai.27.3.826-831.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  91. Parant M. A., Parant F. J., Chedid L. A. Enhancement of resistance to infections by endotoxin-induced serum factor from Mycobacterium bovis BCG-infected mice. Infect Immun. 1980 Jun;28(3):654–659. doi: 10.1128/iai.28.3.654-659.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  92. Parant M., Parant F., Vinit M. A., Chedid L. Action protectrice du "tumor necrosis factor" (TNF) obtenu par recombinaison génétique contre l'infection expérimentale bactérienne ou fongique. C R Acad Sci III. 1987;304(1):1–4. [PubMed] [Google Scholar]
  93. Proctor R. A., Will J. A., Burhop K. E., Raetz C. R. Protection of mice against lethal endotoxemia by a lipid A precursor. Infect Immun. 1986 Jun;52(3):905–907. doi: 10.1128/iai.52.3.905-907.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  94. Ribi E., Cantrell J. L., Takayama K., Qureshi N., Peterson J., Ribi H. O. Lipid A and immunotherapy. Rev Infect Dis. 1984 Jul-Aug;6(4):567–572. doi: 10.1093/clinids/6.4.567. [DOI] [PubMed] [Google Scholar]
  95. Rietschel E. T., Brade L., Schade U., Seydel U., Zähringer U., Brandenburg K., Helander I., Holst O., Kondo S., Kuhn H. M. Bacterial lipopolysaccharides: relationship of structure and conformation to endotoxic activity, serological specificity and biological function. Adv Exp Med Biol. 1990;256:81–99. doi: 10.1007/978-1-4757-5140-6_5. [DOI] [PubMed] [Google Scholar]
  96. Sacco A. G., Yurewicz E. C., Subramanian M. G. Effect of varying dosages and adjuvants on antibody response in squirrel monkeys (Saimiri sciureus) immunized with the porcine zona pellucida Mr = 55,000 glycoprotein (ZP3). Am J Reprod Immunol. 1989 Sep;21(1):1–8. doi: 10.1111/j.1600-0897.1989.tb00990.x. [DOI] [PubMed] [Google Scholar]
  97. Sanchez-Pescador L., Burke R. L., Ott G., Van Nest G. The effect of adjuvants on the efficacy of a recombinant herpes simplex virus glycoprotein vaccine. J Immunol. 1988 Sep 1;141(5):1720–1727. [PubMed] [Google Scholar]
  98. Shaha C., Suri A., Talwar G. P. Induction of infertility in female rats after active immunization with 24 kD antigens from rat testes. Int J Androl. 1990 Feb;13(1):17–25. doi: 10.1111/j.1365-2605.1990.tb00956.x. [DOI] [PubMed] [Google Scholar]
  99. Sidorczyk Z., Zähringer U., Rietschel E. T. Chemical structure of the lipid A component of the lipopolysaccharide from a Proteus mirabilis Re-mutant. Eur J Biochem. 1983 Dec 1;137(1-2):15–22. doi: 10.1111/j.1432-1033.1983.tb07789.x. [DOI] [PubMed] [Google Scholar]
  100. Takada H., Kotani S., Tsujimoto M., Ogawa T., Takahashi I., Harada K., Katsukawa C., Tanaka S., Shiba T., Kusumoto S. Immunopharmacological activities of a synthetic counterpart of a biosynthetic lipid A precursor molecule and of its analogs. Infect Immun. 1985 Apr;48(1):219–227. doi: 10.1128/iai.48.1.219-227.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  101. Takahashi I., Kotani S., Takada H., Tsujimoto M., Ogawa T., Shiba T., Kusumoto S., Yamamoto M., Hasegawa A., Kiso M. Requirement of a properly acylated beta(1-6)-D-glucosamine disaccharide bisphosphate structure for efficient manifestation of full endotoxic and associated bioactivities of lipid A. Infect Immun. 1987 Jan;55(1):57–68. doi: 10.1128/iai.55.1.57-68.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  102. Takayama K., Olsen M., Datta P., Hunter R. L. Adjuvant activity of non-ionic block copolymers. V. Modulation of antibody isotype by lipopolysaccharides, lipid A and precursors. Vaccine. 1991 Apr;9(4):257–265. doi: 10.1016/0264-410x(91)90109-j. [DOI] [PubMed] [Google Scholar]
  103. Takayama K., Qureshi N., Beutler B., Kirkland T. N. Diphosphoryl lipid A from Rhodopseudomonas sphaeroides ATCC 17023 blocks induction of cachectin in macrophages by lipopolysaccharide. Infect Immun. 1989 Apr;57(4):1336–1338. doi: 10.1128/iai.57.4.1336-1338.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  104. Takayama K., Qureshi N., Mascagni P. Complete structure of lipid A obtained from the lipopolysaccharides of the heptoseless mutant of Salmonella typhimurium. J Biol Chem. 1983 Nov 10;258(21):12801–12803. [PubMed] [Google Scholar]
  105. Takayama K., Qureshi N., Raetz C. R., Ribi E., Peterson J., Cantrell J. L., Pearson F. C., Wiggins J., Johnson A. G. Influence of fine structure of lipid A on Limulus amebocyte lysate clotting and toxic activities. Infect Immun. 1984 Aug;45(2):350–355. doi: 10.1128/iai.45.2.350-355.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  106. Telzak E., Wolff S. M., Dinarello C. A., Conlon T., el Kholy A., Bahr G. M., Choay J. P., Morin A., Chedid L. Clinical evaluation of the immunoadjuvant murabutide, a derivative of MDP, administered with a tetanus toxoid vaccine. J Infect Dis. 1986 Mar;153(3):628–633. doi: 10.1093/infdis/153.3.628. [DOI] [PubMed] [Google Scholar]
  107. Tomai M. A., Johnson A. G. T cell and interferon-gamma involvement in the adjuvant action of a detoxified endotoxin. J Biol Response Mod. 1989 Dec;8(6):625–643. [PubMed] [Google Scholar]
  108. Tomai M. A., Solem L. E., Johnson A. G., Ribi E. The adjuvant properties of a nontoxic monophosphoryl lipid A in hyporesponsive and aging mice. J Biol Response Mod. 1987 Apr;6(2):99–107. [PubMed] [Google Scholar]
  109. Tsujimoto M., Kotani S., Kinoshita F., Kanoh S., Shiba T., Kusumoto S. Adjuvant activity of 6-O-acyl-muramyldipeptides to enhance primary cellular and humoral immune responses in guinea pigs: adaptability to various vehicles and pyrogenicity. Infect Immun. 1986 Sep;53(3):511–516. doi: 10.1128/iai.53.3.511-516.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  110. Uchiyama T., Jacobs D. M. Modulation of immune response by bacterial lipopolysaccharide (LPS): cellular basis of stimulatory and inhibitory effects of LPS on the in vitro IgM antibody response to a T-dependent antigen. J Immunol. 1978 Dec;121(6):2347–2351. [PubMed] [Google Scholar]
  111. Ullrich S. E., Fidler I. J. Liposomes containing muramyl tripeptide phosphatidylethanolamine (MTP-PE) are excellent adjuvants for induction of an immune response to protein and tumor antigens. J Leukoc Biol. 1992 Nov;52(5):489–494. doi: 10.1002/jlb.52.5.489. [DOI] [PubMed] [Google Scholar]
  112. Vosika G. J., Barr C., Gilbertson D. Phase-I study of intravenous modified lipid A. Cancer Immunol Immunother. 1984;18(2):107–112. doi: 10.1007/BF00205743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  113. Vuopio-Varkila J., Nurminen M., Pyhälä L., Mäkelä P. H. Lipopolysaccharide-induced non-specific resistance to systemic Escherichia coli infection in mice. J Med Microbiol. 1988 Mar;25(3):197–203. doi: 10.1099/00222615-25-3-197. [DOI] [PubMed] [Google Scholar]
  114. WEBSTER M. E., SAGIN J. F., LANDY M., JOHNSON A. G. Studies on the O antigen of Salmonella typhosa. I. Purification of the antigen. J Immunol. 1955 Jun;74(6):455–465. [PubMed] [Google Scholar]
  115. Warren H. S., Chedid L. A. Future prospects for vaccine adjuvants. Crit Rev Immunol. 1988;8(2):83–101. [PubMed] [Google Scholar]
  116. White A. C., Cloutier P., Coughlin R. T. A purified saponin acts as an adjuvant for a T-independent antigen. Adv Exp Med Biol. 1991;303:207–210. doi: 10.1007/978-1-4684-6000-1_22. [DOI] [PubMed] [Google Scholar]
  117. Wintsch J., Chaignat C. L., Braun D. G., Jeannet M., Stalder H., Abrignani S., Montagna D., Clavijo F., Moret P., Dayer J. M. Safety and immunogenicity of a genetically engineered human immunodeficiency virus vaccine. J Infect Dis. 1991 Feb;163(2):219–225. doi: 10.1093/infdis/163.2.219. [DOI] [PubMed] [Google Scholar]
  118. Wu J. Y., Gardner B. H., Murphy C. I., Seals J. R., Kensil C. R., Recchia J., Beltz G. A., Newman G. W., Newman M. J. Saponin adjuvant enhancement of antigen-specific immune responses to an experimental HIV-1 vaccine. J Immunol. 1992 Mar 1;148(5):1519–1525. [PubMed] [Google Scholar]
  119. Yin J. Z., Bell M. K., Thorbecke G. J. Effect of various adjuvants on the antibody response of mice to pneumococcal polysaccharides. J Biol Response Mod. 1989 Apr;8(2):190–205. [PubMed] [Google Scholar]

Articles from Clinical Microbiology Reviews are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES