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Vaccines for the 21st Century: A Tool for Decisionmaking
Increased local production of cytokines such as GM-CSF, which activates macrophage IL-12 and IFN, will recruit increased numbers of macrophages to the lesion. If a “depot” antigen is sitting there, these larger numbers will mean a greater immune response. In many ways, the action of an adjuvant is to overcome the immune system’s basic tone or bias, which is to nonresponse rather than response.
Common Adjuvants. Almost every vaccine experiment in animals involves the use of some form of adjuvant, although it seldom receives prominent attention. The most commonly used adjuvants in experimental animals are Freund’s adjuvant, either complete or incomplete; Bordatella pertussis; lipopolysaccharide (LPS) or the more refined lipid-A; muramyl dipeptide (MDP, the smallest component of microbacteria that has an adjuvant effect); immunostimulating complexes; glycopolymers; liposomes; and a few others. Some of these adjuvants enhance the Th1 or cellular immune pathway (e.g., Freund’s, LPS, MDP); others enhance the Th2 or humoral immune pathway (e.g., alum, pertussis).
Only one adjuvant is currently approved by FDA for use in humans: alum, a mixture of aluminum salts. When injected, shards of crystal in the alum cause inflammation, recruiting macrophages that eat the antigen associated with the crystals, thereby presenting it to the immune system. However, researchers have identified at least six groups of potentially useful agents, most of which are already in human trials:
Monophosphoric lipid-A (MPL) might be called the active ingredient of LPS, a further refinement that has lower toxicity but retains adjuvant effect. In mice, it stimulates both antibody and cell-mediated immunity. It stimulates macrophage IL-1, TNF, various colony-stimulating factors, and IFN-gamma, and it also up-regulates Class II MHC expression. Like LPS, in enhances nonspecific resistance to bacterial infection and has a global effect on the immune system. One such adjuvant is currently in Phase 3 human trials.
Muramyl dipeptides (MDPs) include hundreds of derivatives that have been synthesized and tested over the years. Two products are currently in human trials with AIDS vaccines: SAF-1, which contains a blocker polymer (see below); and NF-59, which contains a small amount of lipid. Both products stimulate antibody as well as cell-mediated immunity, costimulating T-cells and up-regulating Class II macrophages. The exact cytokine they are producing is not really clear, but they are candidates for future vaccines.
Immune-stimulating complex (ISC) was developed by a veterinarian in Europe. It contains cholesterol and safranin (a detergent derived from plants), with which the antigen is mixed, and takes the form of small particles. In animal tests (mice, cats, sheep, cattle, and monkeys), it produces very strong antibody and CMI response, and it is effective for mucosal immunization, which also produces CTL responses. A formulation called QS-21 is in Phase 1 trails in humans.