The adjuvants

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For the scope of this chapter, we will focus on only a few select adjuvants that have been in human clinical trials. For a more complete list of candidate adjuvants, readers are directed to the National Institute of Health (NIH) website for a Compendium of Adjuvants ( (4). Historically, adjuvants were used to boost the immune response to infectious disease vaccine antigens and were generally evaluated by measuring antibody responses. Alum, an adjuvant effective at doing this with many whole-cell vaccines, was approved for clinical use in 1926 (5) and for the past 70 yr has remained the only adjuvant routinely used in commercial vaccines. Since then, advances in the field of vaccinology have provoked a renewed and intense interest in new and more potent adjuvants.

The complexity of most adjuvants coupled with the multifaceted nature of the induced immune response has made it exceedingly difficult to define the exact mechanism by which they exert their immune-stimulating activity. However, in a very general sense, adjuvants can be segregated into classes based on their modes of action (6). For example, some adjuvants act as depots shielding the antigen from rapid dispersal, degradation, and elimination. This depot effect allows for delayed release and prolonged exposure of the antigen to the immune system resulting in the promotion of a stronger response. The most notable adjuvants in this category include the aluminum salts and oil emulsions. A second major adjuvant class includes compounds known to trigger cytokine elaboration. The best-characterized adjuvants in this category are derived from bacterial products, or their synthetic analogs, and as such are ligands for Toll-like receptors (TLRs). MPLâ„¢ adjuvant and CpG oligonucleotides (ODNs) are prime examples of this class of adjuvants. Activation of TLRs through adjuvant binding results in stimulation of the innate immune response and secretion of a cascade of cytokines that ultimately stimulates the adaptive immune response. Other adjuvants function by enhancing presentation of antigen by antigen-presenting cells (APCs). This category includes compounds that encourage aggregate formation to target uptake by phagocytic APCs, as well as compounds that target antigens to the major histocompatibility complex (MHC) class I presentation pathway, which is critical for CTL induction. Saponins, such as QS-21 and GPI-0100, are adjuvants known for their ability to induce CTL responses with soluble protein antigens.

The classification of adjuvants by mode of action is obviously oversimplified and incomplete. Most adjuvants have multiple mechanisms of action and fall within several categories. Nonetheless, by matching the characteristic mode of action with what is required of a protective response, investigators can more logically select appropriate adjuvants. It also highlights the potential benefit of combining adjuvants with different characteristics into a single formulation to achieve a more robust response. A good example is the SBAS-2 adjuvant system from Glaxo-SmithKline, which unites the cytokine-stimulating capacity of MPL adjuvant with the CTL-inducing properties of QS-21 (7).

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