Agents listed in Table 1 are examples of the many varieties of immuno-potentiators used during the past 30 years. The majority of adjuvants are being developed and tested by industry. The list of adjuvants is incomplete, because I have not conducted an exhaustive literature search, because the results have appeared in abstracts in nonindexed publications, and because many studies are proprietary.
The adjuvants marked by an asterisk in Table 1 have completed trial in man, or they are now undergoing clinical trial. Promising adjuvants not yet tested in humans are also listed. In some instances, adjuvants have been combined in an adjuvant formulation hoping to gain a synergistic or additive effect.
2.1.1. Vaccine Adjuvants vs Nonspecific Enhancers of Immunity
Agents listed in Table 1 enhance specific antigens and are administered concurrently with the antigen. Adjuvants not administered in a single dose, at or near the time of antigen injection, and into the same injection site as the antigen, are not listed. Thus, adjuvants administered repeatedly as nonspecific enhancers of immune response are largely excluded. Immunopotentiating agents administered to humans separately in time or location from the vaccine may be impractical for vaccinating large numbers of persons, and potentially unsafe because of their physiological effects on the entire body. They may have a role, however, in immunizing a small number of high-risk, immunocompetent individuals, such as renal dialysis patients at risk for hepatitis B or the very elderly at risk of influenza. Examples of such "whole body" adjuvants used in humans to augment vaccines include Na diethyldithiocarbamate (13), thymosin alpha one (14), loxoribine (15), granulocyte-macrophage stimulating factor (16,17), cimetidine (18), and dehydroepiandrosterone sulfate (19). The results of such trials to date have been disappointing.
2.1.2. Carriers, Vehicles, and Adjuvant Formulations
Several terms used in Table 1 need to be defined. A "carrier" has several meanings: it is an immunogenic protein bound to a hapten or a weakly immunogenic antigen (20). Carriers increase the immune response by providing T-cell help to the hapten or antigen. A carrier may also be a living organism (or vector) bearing genes for expression of the foreign hapten or antigen (21,22). A DNA vaccine is a carrier in the sense that, like some living vectors, it carries a plasmid-based DNA vector encoding the production of the protein antigen upon inoculation into the host (23).
A "vehicle" provides a substrate for the adjuvant, the antigen, or the antigen-carrier complex. Vehicles are not immunogenic (unlike carriers), but most vehicles can enhance antigens. Their immunostimulatory effects are often augmented by the addition of conventional adjuvants to constitute "adjuvant formulations."
Examples of adjuvant formulations tested in humans with a variety of antigens include monophosphoryl lipid A and cell wall skeleton of Mycobacterium phlei adjuvants in a squalane-in-water emulsion vehicle (24), monophosphoryl lipid A adjuvant in a liposome vehicle (25), threonyl-muramyl dipeptide adjuvant and Pluronic L-121 block polymer adjuvant in a vehicle emulsion of squalane and Tween-80 (26), muramyl tripeptide-dipalmitoyl phosphatidyle-thanolamine adjuvant in a squalene-in-water emulsion vehicle (27), and monophosphoryl lipid A and QS-21 adjuvants in a proprietary oil-in-water emulsion (28).
Recent advances in vaccinology have created an array of vaccines that can be delivered to mucosal surfaces of the respiratory, gastrointestinal, and genitourinary tracts using intranasal, oral, and vaginal routes (29). Well-tolerated
Classes of Modern Vaccine Adjuvants
1. Mineral Salts
Aluminum ("Alum") Aluminum hydroxide* Aluminum phosphate* Calcium phosphate*
2. Surface-Active Agents and Microparticles Nonionic block polymer surfactants* Virosomes*
Meningococcal outer membrane proteins (Proteosomes)* Immune stimulating complexes (ISCOMs)* Cochleates
Dimethyl dioctadecyl ammonium bromide (DDA) Avridine (CP20,961) Vitamin A Vitamin E
Cell wall skeleton of Mycobacterium phlei (Detox®)* Muramyl dipeptides and tripeptides Threonyl MDP (SAF-1)* Butyl-ester MDP (Murabutide®)* Dipalmitoyl phosphatidylethanolamine MTP* Monophosphoryl lipid A* Klebsiella pneumonia glycoprotein* Bordetella pertussis* Bacillus Calmette-Guerin* V. cholerae and E. coli heat labile enterotoxin* Trehalose dimycolate CpG oligodeoxynucleotides
4. Cytokines and Hormones Interleukin-2* Interferon-a* Interferon-y*
Granulocyte-macrophage colony stimulating factor*
1,25-dihydroxy vitamin D3
5. Unique Antigen Constructs
Multiple peptide antigens attached to lysine core (MAP)*
CTL epitope linked to universal helper T-cell epitope and palmitoylated at the N terminus (Theradigm-HBV)*
6. Polyanions Dextran
Overview of Adjuvant Use Table 1 (continued)
7. Polyacrylics Polymethylmethacrylate
Acrylic acid crosslinked with allyl sucrose (Carbopol 934P)
8. Miscellaneous N-acetyl-glucosamine-3yl-acetyl-L-alanyl-D-isoglutamine (CGP-11637)* Gamma insulin + aluminum hydroxide (Algammulin)*
Transgenic plants* Human dendritic cells* Lysophosphatidyl glycerol Stearyl tyrosine Tripalmitoyl pentapeptide
9. Carriers Tetanus toxoid* Diphtheria toxoid*
Meningococcal B outer membrane protein (proteosomes)* Pseudomonas exotoxin A* Cholera toxin B subunit*
Mutant heat labile enterotoxin of enterotoxigenic E. coli*
Hepatitis B virus core*
Cholera toxin A fusion proteins
10. Living Vectors Vaccinia virus* Canarypox virus* Adenovirus*
Attenuated Salmonella typhi* Bacillus Calmette-Guerin* Steptococcus gordonni* Herpes simplex virus Polio vaccine virus Rhinovirus
Venezuelan equine encephalitis virus Yersinia enterocolitica Listeria monocytogenes Shigella
Bordetella pertussis Saccharomyces cerevisiae
11. Vehicles Water-in-oil emulsions
Mineral oil (Freund's incomplete)* Vegetable oil (peanut oil)* Squalene and squalane* Oil-in-water emulsions
Squalene + Tween-80 + Span 85 (MF59)* Liposomes*
Biodegradable polymer microspheres Lactide and glycolide* Polyphosphazenes* Beta-glucan Proteinoids
*Identifies adjuvants administered to humans.
adjuvants that enhance such vaccines will play a important role in mucosal immunization. Some of the more promising adjuvants completed, in or near clinical trial include microspheres (30) ; proteosomes (31), liposomes (32), CpG DNA (33), cochleates (34), and virus-like particles (35). Cholera toxin and the closely related heat-labile enterotoxin (LT) of enterotoxigenic Escherichia coli are powerful adjuvants that augment the local and systemic serum antibody response to coadministered antigens (36). Mutant toxin molecules have been engineered that show greatly reduced toxicity but sufficient retained adjuvanticity to enhance local IgA, systemic IgG, and cellular immune responses to coadministered vaccine antigens. Clinical trials using mutant LT toxins as adjuvants of nonliving vaccine antigens are in progress (29). Surprisingly, cholera toxin applied to the skin of volunteers allowed transdermal immunization with tetanus toxoid (37). Attenuated recombinant bacteria (38,39) and viruses (40), administered orally as live vectors of cloned genes encoding protective antigens of other pathogens, have undergone phase I trials to stimulate immune effector responses. Most of these early attempts to stimulate mucosal immune responses in volunteers using mucosal adjuvants have been only marginally successful. The first attempt to immunize volunteers against LT encoded in a transgenic plant and administered as an edible vaccine was more successful (41). It remains to be seen if other protein antigens (e.g., HBsAg) when given via transgenic plants will be immunogenic or will instead induce tolerance to the antigen.
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