Some mechanisms of adjuvant action are discussed below, and which are summarized in Table 2. Vaccine adjuvants can (1) increase the potency of small, antigenically weak synthetic or recombinant peptides. (2) They can enhance the speed, vigor, and persistence of the immune response to stronger antigens. For example, aluminum adjuvants used with licensed pediatric vaccines (e.g., DTP) elicit early and higher antibody response after primary immunization than do unadjuvanted preparations. (3) Adjuvants can increase the immune response to vaccines in immunologically immature, immunosup-pressed, or senescent individuals. (4) Adjuvants can select for, or modulate humeral or cell-mediated immunity, and they can do this in several ways. First, antigen processing can be modulated, leading to vaccines that can elicit both helper T cells and cytotoxic lymphocytes (CTL) (reviewed in [7,43]). Second, depending upon the adjuvant, the immune response can be modulated in favor of MHC class I or MHC class II response (7,43). For example, the QS-21 adjuvant can elicit MHC class I CTL responses when mixed with protein antigens, peptides, or inactivated viruses (44,45). Many other adjuvants elicit principally MHC class II antibody responses when combined with protein antigens or inactivated organisms (7,43). Third, adjuvants can modulate the immune response by preferentially stimulating T-helper type 1 (Th1) or Th2 CD4(+) T-helper cells (reviewed in [7,43]). The Th1 response is accompanied by secretion of interleukin-2 (IL-2), interferon-gamma (IFN-y), and TNF-beta leading to a CMI response, including activation of macrophages and CTL and high levels of IgG2a antibodies in mice. The Th2 response is modulated by secretion of IL-4, IL-5, IL-6, and IL-10 which provide better help for B-cell
Beneficial Effects of Vaccine Adjuvants
• Increase the potency of antigenically weak peptides.
• Enhance the speed, vigor, and persistence of the immune response to stronger antigens.
• Modulate antibody avidity, specificity, quantity, isotype, and subclass.
• Select for or enhance the cytotoxic T-cell response.
• Increase the immune response to vaccines in immunologically immature, suppressed, or senescent individuals.
• Decrease the amount of antigen required, thus reducing the cost and the likelihood of antigen competition in combination vaccines.
responses, including those of IgG1, IgE, and IgA isotypes in mice. Aluminum salts principally stimulate the Th2 response (46), while the Th1 response is stimulated by many adjuvants, such as muramyl dipeptide, monophosphoryl lipid A, and QS-21 (7,47). (5) Vaccine adjuvants can modulate antibody avidity, specificity, quantity, isotype, and subclass against epitopes on complex immunogens (8,48,49). For example, only certain adjuvants, vehicles and adjuvant formulations can induce the development of the protective IgG2a antibody isotype against Plasmodium yoelii (8). (6) Vaccine adjuvants can decrease the amount of antigens in combination vaccines, thus reducing the liklihood of antigen competition and carrier-specific epitope suppression. In addition, by reducing the quantity of antigen needed to protect, adjuvants can decrease the cost and increase the availability of vaccines. On the other hand, the high cost of some modern adjuvants may offset the savings realized by the reduced antigen requirement, thereby paradoxically driving up vaccine cost overall.
One must remember that in vivo, most adjuvants have complex and multi-factorial immunological mechanisms, often poorly understood. The immuno-logical mechanisms utilized by many adjuvants are under investigation. The discussion of the promising adjuvants in this book will include what is known about their immunological mechanisms. Such information will include answers to some of the following questions. Does the adjuvant induce humoral or cell mediated immunity? Which IG isotypes dominate? Which cytokines are induced? Are CD4(+) T-helper cells or CD8(+) cytotoxic T-lymphocytes induced? The list of such questions is extensive, and grows in proportion to our understanding of immunological mechanisms.
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