Abstract
Interest in vaccine adjuvants is intense and growing, because many of the new subunit vaccine candidates lack sufficient immunogenicity to be clinically useful. In this review, I have emphasized modern vaccine adjuvants injected parenterally, or administered orally, intranasally, or transcutaneously with licensed or experimental vaccines in humans. Every adjuvant has a complex and often multi-factorial immunological mechanism, usually poorly understood in vivo. Many determinants of adjuvanticity exist, and each adjuvanted vaccine is unique. Adjuvant safety is critical and can enhance, retard, or stop development of an adjuvanted vaccine. The choice of an adjuvant often depends upon expensive experimental trial and error, upon cost, and upon commercial availability. Extensive regulatory and administrative support is required to conduct clinical trials of adjuvanted vaccines. Finally, comparative adjuvant trials where one antigen is formulated with different adjuvants and administered by a common protocol to animals and humans can accelerate vaccine development.
Article PDF
Similar content being viewed by others
References
Ramon, G. (1925) Sur l’augmentation anormale de l’antitoxine chez les chevaux producteurs de serum antidipherique. Bull. Soc. Centr. Med. Vet. 101, 227–234.
Spriggs, D. R., and Koff, W. C. Topics in Vaccine Adjuvant Research. Boca Raton, FL.
Powell, M. F. and Newman, M. J. (1995) Vaccine Design: The Subunit and Adjuvant Approach. New York, NY: Plenum Press.
O’Hagan, D. T., ed. (2000) Vaccine Adjuvants. Preparation Methods and Research Protocols. Humana Press, Totowa, NJ.
Edelman, R. (1980) Vaccine adjuvants. Rev. Infect. Dis. 2(3), 370–383.
Gupta, R. K., Relyveld, E. H., Lindblad, E. B., Bizzini, B., Ben-Efraim, S., and Gupta, C. K. (1993) Adjuvants—a balance between toxicity and adjuvanticity. Vaccine 11(3), 293–306.
Gupta, R. K. and Siber, G. R. (1995) Adjuvants for human vaccines—current status, problems and future prospects. Vaccine 13(14), 1263–1276.
Cooper, P. D. (1994) The selective induction of different immune responses by vaccine adjuvants, in Strategies in Vaccine Design (Ada, G. L., ed.), Landes, Austin, TX, pp. 125–158.
Hunter, R. L. and Lal, A. A. (1994) Copolymer adjuvants in malaria vaccine development. Am. J. Trop. Med. Hyg. 50(4 Suppl), 52–58.
Lin, R., Tarr, P. E., and Jones, T. C. (1995) Present status of the use of cytokines as adjuvants with vaccines to protect against infectious diseases. Clin. Infect. Dis. 21(6), 1439–1449.
Cox, J.C. and Coulter, A.R. (1997) Adjuvants—a classification and review of their modes of action. Vaccine 15(3), 248–256.
O’Hagan, D. T. (1998) Recent advances in vaccine adjuvants for systemic and mucosal administration. J. Pharm. Pharmacol. 50(1), 1–10.
Aguado, T., Engers, H., Pang, T., and Pink, R. (1999) Novel adjuvants currently in clinical testing November 2–4, 1998, Fondation Merieux, Annecy, France: a meeting sponsored by the World Health Organization. Vaccine 17(19), 2321–2328.
Aucouturier, J., Dupuis, L., and Ganne, V. (2001) Adjuvants designed for veterinary and human vaccines. Vaccine 19(17–19), 2666–2672.
Douglas, R. G., Jr. (1993) The children’s vaccine initiative—will it work? J. Infect. Dis. 168, 269–274.
Wittet, S. (2000) Introducing GAVI and the Global Fund for Children’s Vaccines. Vaccine 19(4–5), 385–386.
Ramon, G. (1926) Procedes pour accroitre la production des antitoxines. Ann. Inst. Pasteur 40, 1–10.
Audibert, F. M. and Lise, L. D. (1993) Adjuvants: current status, clinical perspectives and future prospects. Immunol Today 14(6), 281–284.
Edelman, R. and Tacket, C. O. (1990) Adjuvants. Int. Rev. Immunol. 7(1), 51–66.
Granoff, D. M., Holmes, S. J., Osterholm, M. T., et al. (1993) Induction of immunologic memory in infants primed with Haemophilus influenzae type b conjugate vaccines. J. Infect. Dis. 168(3), 663–671.
Kayhty, H., Ahman, H., Ronnberg, P. R., Tillikainen, R., and Eskola, J. (1995) Pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine is immunogenic in infants and children. J. Infect. Dis. 172(5), 1273–1278.
Tacket, C. O., Losonsky, G., Lubeck, M. D., et al. (1992) Initial safety and immunogenicity studies of an oral recombinant adenohepatitis B vaccine. Vaccine 10(10), 673–676.
Ockenhouse, C. F., Sun, P. F., Lanar, D. E., et al. (1998) Phase I/IIa safety, immunogenicity, and efficacy trial of NYVAC-Pf7, a pox-vectored, multiantigen, multistage vaccine candidate for Plasmodium falciparum malaria. J. Infect. Dis. 177(6), 1664–1673.
Stover, C. K., Bansal, G. P., Hanson, M. S., et al. (1993) Protective immunity elicited by recombinant bacille Calmette-Guerin (BCG) expressing outer surface protein A (OspA) lipoprotein: a candidate Lyme disease vaccine. J. Exp. Med. 178(1), 197–209.
Evans, T. G., Keefer, M. C., Weinhold, K. J., et al. (1999) A canarypox vaccine expressing multiple human immunodeficiency virus type 1 genes given alone or with rgp120 elicits broad and durable CD8+ cytotoxic T lymphocyte responses in seronegative volunteers. J. Infect. Dis. 180(2), 290–298.
Gonzalez, C., Hone, D., Noriega, F. R., et al. (1994) Salmonella typhi vaccine strain CVD 908 expressing the circumsporozoite protein of Plasmodium falciparum: strain construction and safety and immunogenicity in humans. J. Infect. Dis. 169(4), 927–931.
Edelman, R., Palmer, K., Russ, K. D., et al. (1998) Safety and immunogenicity of recombinant Bacille Calmette-Guerin (rBCG) expressing Borrelia burgdorferi outer surface protein A (OspA) lipoprotein in adult volunteers: A candidate Lyme disease Vaccine. Vaccine 17(7–8), 904–914.
Wang, R., Doolan, D. L., Le, T. P., et al. (1998) Induction of antigen-specific cytotoxic T lymphocytes in humans by a malaria DNA vaccine. Science 282(5388), 476–480.
MacGregor, R. R., Boyer, J. D., et al. (1998) First human trial of a DNA-based vaccine for treatment of human immunodeficiency virus type 1 infection: safety and host response [In Process Citation]. J. Infect. Dis. 178(1), 92–100.
Davenport, F. M. (1968) Seventeen years’ experience with mineral oil adjuvant influenza virus vaccines. Ann. Allergy 26(6), 288–292.
Podda, A. (2001) The adjuvanted influenza vaccines with novel adjuvants: experience with the MF59-adjuvanted vaccine. Vaccine 19(17–19), 2673–2680.
Saul, A., Lawrence, G., Smillie, A., et al. (1999) Human phase I vaccine trials of 3 recombinant asexual stage malaria antigens with Montanide ISA720 adjuvant. Vaccine 17(23–24), 3145–3159.
Hoffman, S. L., Edelman, R., Bryan, J. P., et al. (1994) Safety, immunogenicity, and efficacy of a malaria sporozoite vaccine administered with monophosphoryl lipid A, cell wall skeleton of mycobacteria, and squalane as adjuvant. Am. J. Trop. Med. Hyg. 51(5), 603–612.
Fries, L. F., Gordon, D. M., Richards, R. L., et al. (1992) Liposomal malaria vaccine in humans: a safe and potent adjuvant strategy. Proc. Natl. Acad. Sci. USA 89(1), 358–362.
Lidgate, D. M. and Byars, N. E. (1995) Development of an emulsion-based muramyl dipeptide adjuvant formulation for vaccines, in Vaccine Design: The Subunit and Adjuvant Approach (Powell, M. F. and Newman, M. J., ed.), New York, NY, Plenum, 313–324.
Wintsch, J., Chaignat, C. L., Braun, D. G., et al. (1991) Safety and immunogenicity of a genetically engineered human immunodeficiency virus vaccine. J. Infect. Dis. 163(2), 219–225.
Stoute, J. A., Slaoui, M., Heppner, D. G., et al. (1997) A preliminary evaluation of a recombinant circumsporozoite protein vaccine against Plasmodium falciparum malaria. RTS,S Malaria Vaccine Evaluation Group [see comments]. N. Engl. J. Med. 336(2), 86–91.
Lesourd, B. M., Vincent-Falquet, J. C., Deslandes, D., Musset, M., and Moulias, R. (1988) Influenza vaccination in the elderly: improved antibody response with Imuthiol (Na diethyldithiocarbamate) adjuvant therapy. Int. J. Immunopharmacol. 10(2), 135–143.
Gravenstein, S., Duthie, E. H., Miller, B. A., et al. (1989) Augmentation of influenza antibody response in elderly men by thymosin alpha one. A double-blind placebo-controlled clinical study. J. Am. Geriatr. Soc. 37(1), 1–8.
Goodman, M. G. (1995) A new approach to vaccine adjuvants: Immunopotentiation by intracellular T-helper-like signals transmitted by loxoribine, in Vaccine Design: The Subunit and Adjuvant Approach (Powell, M. F., Newman, M. J., eds.), Plenum, New York, 581–610.
Hess, G., Kreiter, F., Kosters, W., and Deusch, K. (1996) The effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on hepatitis B vaccination in haemodialysis patients. J. Viral Hepat. 3(3), 149–153.
Drabick, J. J., Tang, D. B., Moran, E. E., Trofa, A. F., Foster, J. S., and Zollinger, W. D. (1997) A randomized, placebo-controlled study of oral cimetidine as an immunopotentiator of parenteral immunization with a group B meningococcal vaccine. Vaccine 15(10), 1144–1148.
Evans, T. G., Judd, M. E., Dowell, T., Poe, S., Daynes, R. A., and Araneo, B. A. (1996) The use of oral dehydroepiandrosterone sulfate as an adjuvant in tetanus and influenza vaccination of the elderly. Vaccine 14(16), 1531–1537.
Levine, M. M. and Dougan, G. (1998) Optimism over vaccines administered via mucosal surfaces. Lancet 351(9113), 1375–1376.
Tacket, C. O., Reid, R. H., Boedeker, E. C., et al. (1994) Enteral immunization and challenge of volunteers given enterotoxigenic E. coli CFA/II encapsulated in biodegradable microspheres. Vaccine 12(14), 1270–1274.
Lambert, J. S., Keefer, M., Mulligan, M. J., et al. (2001) A Phase I safety and immunogenicity trial of UBI(R) microparticulate monovalent HIV-1 MN oral peptide immunogen with parenteral boost in HIV- 1 seronegative human subjects. Vaccine 19(23–24), 3033–3042.
Lowell, G. H. (1997) Proteosomes for Improved Nasal, Oral, or Injectable Vaccines, in New Generation Vaccines, (Levine, M. M., Woodrow, G. C., Kaper, J. B., and Cobon, G. S., ed.), Marcel Dekker, New York, Inc., 193–206.
Fries, L. F., Montemarano, A. D., Mallett, C. P., Taylor, D. N., Hale, T. L., and Lowell, G. H. (2001) Safety and Immunogenicity of a Proteosome-Shigella flexneri 2a Lipopolysaccharide Vaccine Administered Intranasally to Healthy Adults. Infect. Immun. 69(7), 4545–4553.
Chaicumpa, W., Chongsa-nguan, M., Kalambaheti, T., et al. (1998) Immunogenicity of liposome-associated and refined antigen oral cholera vaccines in Thai volunteers. Vaccine 16(7), 678–684.
Moldoveanu, Z., Love-Homan, L., Huang, W. Q., and Krieg, A. M. (1998) CpG DNA, a novel immune enhancer for systemic and mucosal immunization with influenza virus Vaccine 16(11–12), 1216–1224.
Gould-Fogerite, S., Edghill-Smith, Y., Kheiri, M., et al. (1994) Lipid matrix-based subunit vaccines: a structure-function approach to oral and parenteral immunization. AIDS Res. Hum. Retroviruses 10(Suppl 2), S99–103:S99–103.
Cryz, S. J., Jr. and Gluck, R. (1998) Immunopotentiating reconstituted influenza virosomes as a novel antigen delivery system. Dev. Biol. Stand. 92, 219–23:219–223.
Spangler, B. D. (1992) Structure and function of cholera toxin and the related Escherichia coli heat-labile enterotoxin. Microbiol. Rev. 56(4), 622–647.
Holmgren, J., Czerkinsky, C., Lycke, N., and Svennerholm, A. M. (1994) 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. 50(5 Suppl), 42–54.
Russell, M. W., Moldoveanu, Z., White, P. L., Sibert, G. J., Mestecky, J., and Michalek, S. M. (1996) Salivary, nasal, genital, and systemic antibody responses in monkeys immunized intranasally with a bacterial protein antigen and the Cholera toxin B subunit. Infect. Immun. 64(4), 1272–1283.
Saldinger, P. F., Blum, A. L., and Corthesy-Theulaz, I. E. (1997) Perspectives of anti-H. pylori vaccination. J. Physiol. Pharmacol. 48 Suppl 4:59–65:59–65.
Rudin, A., Riise, G. C., and Holmgren, J. (1999) Antibody responses in the lower respiratory tract and male urogenital tract in humans after nasal and oral vaccination with cholera toxin B subunit. Infect. Immun. 67(6), 2884–2890.
Michetti, P., Kreiss, C., Kotloff, K. L., et al. (1999) Oral immunization with urease and Escherichia coli heat-labile enterotoxin is safe and immunogenic in Helicobacter pylori-infected adults. Gastroenterology 116(4), 804–812.
Hall, E. R., Wierzba, T. F., Ahren, C., et al. (2001) Induction of systemic antifimbria and antitoxin antibody responses in Egyptian children and adults by an oral, killed enterotoxigenic Escherichia coli plus cholera toxin B subunit vaccine. Infect. Immun. 69(5), 2853–2857.
Kotloff, K. L., Sztein, M. B., Wasserman, S. S., Losonsky, G. A., DiLorenzo, S. C., and Walker, R. I. (2001) Safety and immunogenicity of oral inactivated whole-cell Helicobacter pylori vaccine with adjuvant among volunteers with or without subclinical infection. Infect. Immun. 69(6), 3581–3590.
Douce, G., Turcotte, C., Cropley, I., et al. (1995) Mutants of Escherichia coli heat-labile toxin lacking ADP- ribosyltransferase activity act as nontoxic, mucosal adjuvants. Proc. Natl. Acad. Sci. USA 92(5), 1644–1648.
Douce, G., Fontana, M., Pizza, M., Rappuoli, R., and Dougan, G. (1997) Intranasal immunogenicity and adjuvanticity of site-directed mutant derivatives of cholera toxin. Infect. Immun. 65(7), 2821–2828.
Simmons, C.P., Mastroeni, P., Fowler, R., et al. (1999) MHC class I-restricted cytotoxic lymphocyte responses induced by enterotoxin-based mucosal adjuvants. J. Immunol. 163(12), 6502–6510.
Bowman, C. C. and Clements, J. D. (2001) Differential biological and adjuvant activities of cholera toxin and Escherichia coli heat-labile enterotoxin hybrids. Infect. Immun. 69(3), 1528–1535.
Bourguignon, P., Bisteau, M., Veenstra, S., et al. (2001) Reactogenicity and passage into the brains of enterotoxins and cpg-oligonucleotides administered intranasally to mice. Final Program and Abstracts of The Fourth Annual Conference on Vaccine Research, April 23–25, 2001, Hyatt Regency Crystal City Hotel, Arlington, VA.
Tacket, C. O., Kelly, S. M., Schodel, F., et al. (1997) Safety and immunogenicity in humans of an attenuated Salmonella typhi vaccine vector strain expressing plasmid-encoded hepatitis B antigens stabilized by the Asd-balanced lethal vector system [published erratum appears in Infect. Immun. Sep;65(9), 3981]. Infect. Immun. 65(8), 3381–3385.
Tacket, C. O., Galen, J., Sztein, M. B., et al. (2000) Safety and immune responses to attenuated Salmonella enterica serovar typhi orallive vector vaccines expressing tetanus toxin fragment C. Clin. Immunol. 97(2), 146–153.
Tacket, C. O., 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. Nature 4, 607–609.
Tacket, C. O., Mason, H. S., Losonsky, G., Estes, M. K., Levine, M. M., and Arntzen, C. J. (2000) Human immune responses to a novel norwalk virus vaccine delivered in transgenic potatoes. J. Infect. Dis. 182(1), 302–305.
Glenn, G. M., Rao, M., Matyas, G. R., and Alving, C. R. (1998) Skin immunization made possible by cholera toxin [letter]. Nature 391(6670), 851.
Glenn, G. M., Taylor, D. N., Li, X., Frankel, S., Montemarano, A., and Alving, C. R. (2000) Transcutaneous immunization: a human vaccine delivery strategy using a patch. Nat. Med. 6(12), 1403–1406.
Scharton-Kersten, T., Yu, J., Vassell, R., O’Hagan, D., Alving, C. R., and Glenn, G. M. (2000) Transcutaneous immunization with bacterial ADP-ribosylating exotoxins, subunits, and unrelated adjuvants. Infect. Immun. 68(9), 5306–5313.
Zierhut, M., Bieber, T., Brocker, E. B., Forrester, J. V., Foster, C.S., and Streilein, J.W. (1996) Immunology of the skin and the eye. Immunol. Today 17(10), 448–450.
Tacket, C. O., Roy, M. J., Widera, G., Swain, W. F., Broome, S., and Edelman, R. (1999) Phase 1 safety and immune response studies of a DNA vaccine encoding hepatitis B surface antigen delivered by a gene delivery device. Vaccine 17(22), 2826–2829.
Enioutina, E. Y., Visic, D., and Daynes, R. A. (2000) The induction of systemic and mucosal immune responses to antigen- adjuvant compositions administered into the skin: alterations in the migratory properties of dendritic cells appears to be important for stimulating mucosal immunity. Vaccine 18(24), 2753–2767.
Glenn, G. M., Scharton-Kersten, T., Vassell, R., Matyas, G. R., Alving, C. R. (1999) Transcutaneous immunization with bacterial ADP-ribosylating exotoxins as antigens and adjuvants. Infect. Immun. 67(3), 1100–1106.
Guerna, F., Taylor, D. N., Hall, E. R., et al. (2001) Safety and immunogenicity of a transcutaneously administered prototype traveler’s diarrhea vaccine consisting of heat-labile toxin (LT) and CS6 colonization factor of enterotoxigenic Escherichia coli (ETEC). Final Program and Abstracts of The Fourth Annual Conference on Vaccine Research, April 23–25, 2001, Hyatt Regency Crystal City Hotel, Arlington, VA.
Krieg, A. M. (1996) An innate immune defense mechanism based on the recognition of CpG motifs in microbial DNA. J. Lab. Clin. Med. 128(2), 128–133.
Newman, M. J. and Powell, M. F. (1995) Immunological and formulation design consideratins for subunit vaccines. In Vaccine Design: The Subunit and Adjuvant Approach (Powell M. F. and Newman, M. J., eds.), Plenum, New York, pp. 1–42.
Newman, M. J., Wu, J. Y., Gardner, B. H., et al. (1992) Saponin adjuvant induction of ovalbumin-specific CD8+ cytotoxic T lymphocyte responses. J. Immunol. 148(8), 2357–2362.
Newman, M. J., Munroe, K. J., Anderson, C. A., et al. (1994) Induction of antigen-specific killer T lymphocyte responses using subunit SIVmac251 gag and env vaccines containing QS-21 saponin adjuvant. AIDS Res. Hum. Retroviruses 10(7), 853–861.
Ulanova, M., Tarkowski, A., Hahn-Zoric, M., and Hanson, L. A. (2001) The Common vaccine adjuvant aluminum hydroxide up-regulates accessory properties of human monocytes via an interleukin-4-dependent mechanism. Infect. Immun. 69(2), 1151–1159.
Yip, H. C., Karulin, A. Y., Tary-Lehmann, M., et al. (1999) Adjuvant-guided type-1 and type-2 immunity: infectious/noninfectious dichotomy defines the class of response. J. Immunol. 162(7), 3942–3949.
Gupta, R. K. and Siber, G. R. (1994) Comparison of adjuvant activities of aluminium phosphate, calcium phosphate and stearyl tyrosine for tetanus toxoid. Biologicals 22(1), 53–63.
Kensil, C. R., Wu, J. Y., and Soltysik, S. (1995) Structural and immunological characterization of the vaccine adjuvant QS-21. Pharm. Biotechnol. 6, 525–541.
Ulrich, J. T. and Myers, K. R. (1995) Monophosphoryl lipid A as an adjuvant: Past experiences and new directions, in The Subunit and Adjuvant Approach (Powell, M. F. and Newman, M. J., ed.). Plenum, New York, pp. 495–524.
Hui, G. S., Chang, S. P., Gibson, H., et al. (1991) Influence of adjuvants on the antibody specificity to the Plasmodium falciparum major merozoite surface protein, gp195. J. Immunol. 147(11), 3935–3941.
Kenney, J. S., Hughes, B. W., Masada, M. P., and Allison, A. C. (1989) Influence of adjuvants on the quantity, affinity, isotype and epitope specificity of murine antibodies. J. Immunol. Methods 121(2), 157–166.
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(15), 5409–5413.
Nardin, E. H., Oliveira, G. A., Calvo-Calle, J. M., et al. (2000) Synthetic malaria peptide vaccine elicits high levels of antibodies in vaccinees of defined HLA genotypes. J. Infect. Dis. 182(5), 1486–1496.
Goldenthal, K. L., Cavagnaro, J. A., Alving, C. R., and Vogel, F.R. (1993) NCVDG working groups: Safety evaluation of vaccine adjuvants: National cooperative vaccine development meeting working group. AIDS Res. Hum. Retrovirus 9, S47-S51.
Bussiere, J. L., McCormick, G. C., and Green, J. D. (1995) Preclinical safety assessment considerations in vaccine development, in Vaccine Design: The Subunit and Adjuvant Approach (Powell, M.F. and Newman, M.J., ed.). Plenum, New York, NY, pp. 61–79.
Kaji, M., Kaji, Y., Kaji, M., et al. (1992) Phase 1 clinical tests of influenza MDP-virosome vaccine (KD-5382). Vaccine 10(10), 663–667.
Jacobson, R. M., Swan, A., Adegbenro, A., Ludington, S. L., Wollan, P. C., and Poland, G. A. (2001) Making vaccines more acceptable—methods to prevent and minimize pain and other common adverse events associated with vaccines. Vaccine 19(17–19), 2418–2427.
Schultz, N., Oratz, R., Chen, D., Zeleniuch-Jacquotte, A. Abeles, G., and Bystryn, J. C. (1995) Effect of DETOX as an adjuvant for melanoma vaccine. Vaccine 13(5), 503–508.
Keitel, W., Couch, R., Bond, N., Adair, S., Van Nest, G., and Dekker, C. (1993) Pilot evaluation of influenza virus vaccine (IVV) combined with adjuvant. Vaccine 11(9), 909–913.
Duarte Cano, C. A. (1999) The multi-epitope polypeptide approach in HIV-1 vaccine development. Genetic Analysis: Biomolecular Engineering 15, 149–153.
Brewer, M. A., Edwards, K. M., Palmer, P. S., and Hinson, H. P. (1994) Bacille Calmette-Guerin immunization in normal healthy adults. J. Infect. Dis. 170(2), 476–479.
Kemp, E. B., Belshe, R. B., and Hoft, D. F. (1996) Immune responses stimulated by percutaneous and intradermal bacille Calmette-Guerin. (J. Infect. Dis.) 174(1), 113–119.
Rinn, K., Schiffman, K., Otero, H. O., and Disis, M. L. (1999) Antigen-specific recall urticaria to a peptide-based vaccine. J. Allergy Clin. Immunol. 104(1), 240–242.
Gordon, D. M., Duffy, P. E., Heppner, D. G., et al. Phase I safety and immunogenicity testing of clinical lots of the synthetic Plasmodium falciparum vaccine SPf66 produced under good manufacturing procedure conditions in the United States. Am. J. Trop. Med. Hyg. (1996) 55(1), 63–68.
Amador, R., Moreno, A., Murillo, L. A., et al. (1992) Safety and immunogenicity of the synthetic malaria vaccine SPf66 in a large field trial. J. Infect. Dis. 166(1), 139–144.
Evans, T. G., McElrath, M. J., Matthews, T., et al. (2001) QS-21 promotes an adjuvant effect allowing for reduced antigen dose during HIV-1 envelope subunit immunization in humans. Vaccine 19(15–16), 2080–2091.
Waters, R. V., Terrell, T. G., Jones, G. H. (1986) Uveitis induction in the rabbit by muramyl dipeptides. Infect. Immun. 51(3), 816–825.
Allison, A. C. and Byars, N. E. (1991) Immunological adjuvants: desirable properties and side-effects. Mol. Immunol. 28(3), 279–284.
McElrath, M. J. (1994) Adjuvant effects on human immune responses in recipients of candidate HIV vaccines. IBC Conference, “Novel Vacccine Stategies for Mucosal Immunization, Genetic Approaches and Adjuvants,” Rockville, MD, pp. 24–26.
Pearson, C. M. (1963) Experimental joint disease: Observations on adjuvant-induced arthritis. J. Chronic. Dis. 16, 863–874.
Kleinau, S., Erlandsson, H., Holmdahl, R., and Klareskog, L. (1991) Adjuvant oils induce arthritis in the DA rat. I. Characterization of the disease and evidence for an immunological involvement. J. Autoimmun. 4(6), 871–880.
Murray, R., Cohen, P., and Hardegree, M. C. (1972) Mineral oil adjuvants: biological and chemical studies. Ann. Allergy 30(3), 146–151.
Salk, J. and Salk, D. (1977) Control of influenza and poliomyelitis with killed virus vaccines. Science 195(4281), 834–847.
Stuart-Harris, C. H. (1969) Adjuvant influenza vaccines. Bull. WHO 41, 617–621.
Beebe, G. W., Simon, A. H., and Vivona, S. (1972) Long-term mortality follow-up of Army recruits who received adjuvant influenza virus vaccine in 1951–1953. Am. J. Epidemiol. 95(4), 337–346.
Page, W. F., Norman, J. E., and Benenson, A. S. (1993) Long-Term Follow-up of Army Recruits Immunized with Freund’s Incomplete Adjuvanted Vaccine. Vaccine Res. 2(3), 141–149.
Jacobson, R. M., Adegbenro, A., Pankratz, V. S., and Poland, G. A. (2001) Adverse events and vaccination- the lack of power and predictability of infrequent events in pre-licensure study. Vaccine 19(17–19), 2428–2433.
Keefer, M. C., Wolff, M., Gorse, G. J., et al. (1997) Safety profile of phase I and II preventive HIV type 1 envelope vaccination: experience of the NIAID AIDS Vaccine Evaluation Group. AIDS Res. Hum. Retroviruses 13(14), 1163–1177.
Butler, N. R., Feng, S., Benson, P. F., et al. (1962) Response of infants to pertussis vaccine at one week and to poliomyelitis, diptheria, and tetanus vaccine at six months. Lancet 2, 112–114.
Cvjetanovic, B. and Uemura, K. (1965) The present status of field and laboratory studies of typhoid and paratyphoid vaccines with special reference to studies sponsored by the World Health Organization. Bull WHO 32, 29–36.
Woolridge, R. L., Grayston, J. T., Chang, I. A., et al. (1967) Long-term follow-up of the initial (1959–1960) trachoma vaccine field on Taiwan. Am. J. Opthalmol. 63, 1650–1653.
Kasel, J. A., Couch, R. B., Douglas, R. G., Jr. (1971) Antigenicity of alum and aqueous adenovirus hexon antigen vaccines in man. J. Immunol. 107(3), 916–919.
Davenport F. M., Hennessy, A. V., and Askin, F. B. (1968) Lack of adjuvant effect of AIPO4 on purified influenza virus haemagglutinins in man. J. Immunol. 100, 1139–1140.
Claesson, B. A., Trollfors, B., Lagergard, T., (1988) Clinical and immunologic responses to the capsular polysaccharide of Haemophilus influenzae type b alone or conjugated to tetanus toxoid in 8- to 23-month-old children. J. Pediatr. 112(5), 695–702.
O’Hagan, D. T., Jeffery, H., Davis, S. S. (1993) Long-term antibody responses in mice following subcutaneous immunization with ovalbumin entrapped in biodegradable microparticles. Vaccine 11(9), 965–969.
Gupta, R. K., Rost, B. E., Relyveld, E., and Siber, G. R. (1995) Adjuvant properties of aluminum and calcium compounds, in Vaccine Design: The Subunit and Adjuvant Approach (Powell, M. F. and Newman, M. J., ed.), Plenum, New York, pp. 229–248.
World Health Organization. (1977) Manual for the Production and Control of Vaccines — Tetanus Toxoid World Health Organization.
Bumford, R. (1989) Aluminum salts: prospectives in their use as adjuvants, in Immunological Adjuvants and Vaccines (Gregoriadis, G., Allison, A.C., Poste, G., ed.) Plenum, New York, pp. 35–41.
Stewart-Tull, D. E. S. (1989) Recommendations for the assessment of adjuvants (immunopotentiators), in Immunological Adjuvants and Vaccines (Gregoriadis, G., Allison, A.C., and Poste, G., ed.). Plenum, New York, pp. 213–226.
Hardegree, M. C., Pittman, M., and Maloney, C. J. (1972) Influence of mouse strain on the assayed potency (unitage) of tetanus toxoid. Appl. Microbiol. 24(1), 120–126.
Murphey-Corb, M., Ohkawa, S., Martin, L., et al. (1993) Comparative efficacy of a whole killed SIV vaccine in combination with various adjuvants. Sixth Annual Meeting of the National Cooperative Vaccine Development Group for AIDS.
Tacket, C. O., Rennels, M. B., and Mattheis, M. J. (1997) Initial clinical evaluation of new vaccine candidates: Phase 1 and 2 clinical trials of safety, immunogenicity, and preliminary efficacy, in new generation vaccines (Levine, M. M., Woodrow, G. C., Kaper, J. B., and Cobon, G., eds.), Marcel Dekker, New York, 35–45.
U.S.Food and Drug Administration. (1991) General biological products standards. Anonymous code of federal regulations. Department of Health and Human Services, Bethesda, MD, pp. 43–53.
Davenport, L. W. (1995) Regulatory considerations in vaccine design, in Vaccine Design, in The Subunit and Adjuvant Approach (Powell, M. F. and Newman, M. J., eds.), Plenum, New York, pp. 81–96.
Edelman, R. (1997) Adjuvants for the Future, in New Generation Vaccines (Levine, M. M., Woodrow, G. C., Kaper, J.B., and Cobon, G.S., ed.). Marcel Dekker, New York, pp. 173–192.
Kim, S. K., Ragupathi, G., Musselli, C., Choi, S. J., Park, Y.S., and Livingston, P.O. (1999) Comparison of the effect of different immunological adjuvants on the antibody and T-cell response to immunization with MUC1-KLH and GD3-KLH conjugate cancer vaccines. Vaccine 18(7–8), 597–603.
Christodoulides, M., Rattue, E., and Heckels, J. E. (1999) Effect of adjuvant composition on immune response to a multiple antigen peptide (MAP) containing a protective epitope from Neisseria meningitidis class 1 porin. Vaccine 18(1–2), 131–139.
Hunsmann, G. (1995) Protection of macaques against simian immunodeficiency virus infection with inactivated vaccines: comparison of adjuvants, doses and challenge viruses. Vaccine 13, 295–300.
Keefer, M. C., Graham, B. S., and McElrath, M. J. (1996) Safety and immunogenicity of Env 2–3, a human immunodeficiency virus type 1 candidate vaccine, in combination with a novel adjuvant, MTP- PE/MF59. NIAID AIDS Vaccine Evaluation Group. AIDS Res. Hum. Retroviruses 12(8), 683–693.
Graham, B. S., Keefer, M. C., McElrath, M. J., et al. (1996) (2000) Safety and immunogenicity of a candidate HIV-1 vaccine in healthy adults: recombinant glycoprotein (rgp) 120. A randomized, double-blind trial. NIAID AIDS Vaccine Evaluation Group. Ann. Intern. Med. 125(4), 270–279.
McCormack, S., Tilzey, A., Carmichael, A., et al. A phase I trial in HIV negative healthy volunteers evaluating the effect of potent adjuvants on immunogenicity of a recombinant gp120W61D derived from dual tropic R5X4 HIV-1ACH320. Vaccine 18(13), 1166–1177.
Ballou, W. R., Hoffman, S. L., Sherwood, J. A., et al. (1987) Safety and efficacy of a recombinant DNA Plasmodium falciparum sporozoite vaccine. Lancet 1(8545), 1277–1281.
Herrington, D. A., Clyde, D. F., Losonsky, G., et al. (1987) Safety and immunogenicity in man of a synthetic peptide malaria vaccine against Plasmodium falciparum sporozoites. Nature 328(6127), 257–259.
Patarroyo, M. E., Amador, R., Clavijo, P., et al. (1988) A synthetic vaccine protects humans against challenge with asexual blood stages of Plasmodium falciparum malaria. Nature 332(6160), 158–161.
Alonso, P. L., Smith, T., Schellenberg, J. R., et al. (1994) Randomised trial of efficacy of SPf66 vaccine against Plasmodium falciparum malaria in children in southern Tanzania [see comments]. Lancet 344(8931), 1175–1181.
Fries, L. F., Gordon, D. M., Schneider, I., et al. (1992) Safety, immunogenicity, and efficacy of a Plasmodium falciparum vaccine comprising a circumsporozoite protein repeat region peptide conjugated to Pseudomonas aeruginosa toxin A. Infect. Immun. 60(5), 1834–1839.
Brown, A. E., Singharaj, P., Webster, H. K., et al. (1994) Safety, immunogenicity and limited efficacy study of a recombinant Plasmodium falciparum circumsporozoite vaccine in Thai soldiers. Vaccine 12(2), 102–108.
Stoute, J. A., Kester, K. E., Krzych, U., et al. (1998) Long-term efficacy and immune responses following immunization with the RTS,S malaria vaccine. J. Infect. Dis. 178(4), 1139–1144.
Gordon, D. M., McGovern, T. W., Krzych, U., et al. (1995) Safety, immunogenicity, and efficacy of a recombinantly produced Plasmodium falciparum circumsporozoite protein-hepatitis B surface antigen subunit vaccine. J. Infect. Dis. 171(6), 1576–1585.
Heppner, D. G., Gordon, D. M., Gross, M., et al. (1996) Safety, immunogenicity, and efficacy of Plasmodium falciparum repeatless circumsporozoite protein vaccine encapsulated in liposomes. J. Infect. Dis. 174(2), 361–366.
Lawrence, G., Cheng, Q. Q., Reed, C., et al. (2000) Effect of vaccination with 3 recombinant asexual-stage malaria antigens on initial growth rates of Plasmodium falciparum in non-immune volunteers. Vaccine 18(18), 1925–1931.
Kester, K. E., McKinney, D. A., Tornieporth, N., et al. (2001) Efficacy of Recombinant Circumsporozoite Protein Vaccine Regimens against Experimental Plasmodium falciparum Malaria. J. Infect. Dis. 183(4), 640–647.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Edelman, R. The development and use of vaccine adjuvants. Mol Biotechnol 21, 129–148 (2002). https://doi.org/10.1385/MB:21:2:129
Issue Date:
DOI: https://doi.org/10.1385/MB:21:2:129