Mechanisms of stimulation of the immune response by aluminum adjuvants
Introduction
Aluminum salts have been used for over 70 years as adjuvants in vaccines. The adjuvant effect of aluminum salts was first reported in 1926 based on the observation that alum-precipitated diphtheria toxoid induced a better immune response than soluble diphtheria toxoid in guinea pigs [1]. Aluminum adjuvants in commercial vaccines have been characterized as aluminum oxyhydroxide (AlOOH, commonly referred to as aluminum hydroxide) and aluminum hydroxyphosphate (Al(OH)x(PO4)y, commonly referred to as aluminum phosphate). Aluminum-containing vaccines are prepared by adsorption of antigens onto aluminum hydroxide or aluminum phosphate gels or by precipitation of antigens in a solution of alum (KAl(SO4)2·12H2O). Following precipitation, the alum-containing adjuvants are similar to aluminum phosphate adjuvants in composition and physicochemical characteristics [2], [3].
Aluminum adjuvants are the only adjuvants allowed for use in human vaccines and are present in many veterinary vaccines. They have been administered to hundreds of millions of people with only rare reports of serious local reactions [4]. Indeed, adsorption and slow release of reactogenic vaccine components may reduce the incidence and severity of local and systemic reactions [5], [6]. From an immunological standpoint, the main drawbacks of aluminum adjuvants are their weak or absent adjuvant effect with certain candidate vaccine antigens, the inability to induce cell-mediated and cytotoxic T cell responses and the tendency to induce IgE-mediated immune responses [4], [7]. The adjuvant effect of aluminum compounds is generally more significant in primary than in secondary immune responses [8], [9]. As will be discussed in more detail later, aluminum adjuvants augment the type 2 immune response without enhancing the type 1 immune response [10], [11], [12]. This makes aluminum adjuvants less suitable for vaccines against certain viruses and intracellular bacteria and parasites, for which antibodies alone provide insufficient protection. The induction of antigen-specific IgE responses may predispose susceptible individuals to allergic reactions against vaccine components.
Although aluminum adjuvants have been used for a long time, surprisingly little is known about the mechanisms by which they enhance the immune response. The two most commonly cited mechanisms are formation of an antigen depot and immunostimulation. A discussion of these mechanisms is the subject of this review.
Section snippets
Depot effect
Glenny et al. suggested that precipitation of antigen with alum reduced the rate of antigen elimination from the injection site [13]. Injection sites were collected from guinea pigs 3 days after administration of alum-precipitated or soluble diphtheria toxoid. The injection sites were macerated and injected in naı̈ve guinea pigs. The recipients of the material from the alum-precipitated diphtheria toxoid injected animals, but not the soluble diphtheria toxoid injected animals, developed an
Effect of aluminum adjuvants on antigen presentation
The initiation of the immune response occurs in the lymph nodes that drain the vaccination site. Dendritic cells play a critical role in the transport of antigen to the lymph node and in presenting and activating naı̈ve antigen-specific T cells. They are present in immature form throughout the skin and mucosal tissues and at a lower density in skeletal muscle and other non-lymphoid tissues. The immature dendritic cells are highly efficient in capture and uptake of antigens by receptor-mediated
Conclusions
Surprisingly little is known about the mechanisms by which aluminum adjuvants, which have been administered in millions of doses of vaccines, enhance the immune response to vaccine antigens. The depot mechanism, if defined as the slow sustained release of antigen over days or weeks, is unlikely in the light of recent work that has demonstrated a rapid desorption of antigen. However, adsorption of antigens to aluminum compounds may help to retain antigen at the injection site at a high
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