Adjuvants

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An adjuvant is an agent or a mixture of agents which possesses the ability to bind to a specific antigen. Upon administration to a host, it enhances cellmediated immunity (CMI) triggered by the presence of the antigen.1 Immu-noadjuvant effects have been associated with the induction of T helper cell type 2 responses, while the specific underlying mechanisms are still under investigation. T helper cell type 2 responses are intimately associated with the human immune system's production of anti-inflammatory cytokines (primarily IL-4, IL-10 and IL-13) and stimulation of ^-cells to proliferate, differentiate and produce antibodies. Literature work has focused on immunoadjuvants describing microscopic as well as macroscopic phenomena associated with their incipient chemistry at the biological level. One of the remarkable properties of adjuvants is their capacity to bind or adsorb a large number of antigenic molecules over a wide surface area, thus enhancing the interaction of immune cells with the presenting antigens and stimulating2 immune response. Among the oldest adjuvant species known to date are alum and metal oxides, aluminum-oxygen-containing compounds like aluminum hydroxide, aluminum oxide as well as others (ZrO2, silica, hematite and magnetite, etc.). The aluminum-oxygen compounds are the oldest adjuvants experimented with and constitute a very specific family of metallopharmaceuticals approved for safe use at the clinical level.

Of the aluminum-containing adjuvants used today, three appear to be the most prevalent: aluminum hydroxide, aluminum phosphate and alum (KAl(SO4)212H2O). These three agents are included in many vaccines and have been licensed for use by the US Food and Drug Administration.3 The total aluminum currently licensed to be present in a vaccine is in the range 0.85-0.125mg/dose. Following is an account of these adjuvants widely used in metallopharmaceuticals.

4.2.1 Alum

The chemical composition of alum is KAl(SO4)212H2O. It is a widely used adjuvant in a number of pharmaceutical products linked to immunization.4 The pharmaceutical itself is a mineral gel adjuvant, prepared by two different approaches. The first one is based on the alum-antigen co-precipitation method, involving treatment of alum with NaOH to a final pH 7, leading to the precipitation of Al(OH)3. The method tends to yield heterogeneous precipitates. The advantages of this method are quite important in that (a) it induces a granulomatous reaction at the injection site and (b) it promotes antigen presentation by macrophages and activation of the ensuing immunocascade. The second method employs initial adsorption of antigen onto preformed Al(OH)3 gels. It has the advantage that it facilitates freezing or spray-freeze-drying (SFD) of antigen-adjuvant complexes. SFD is a novel and effective drying process for the production of stable adjuvanted vaccine formulations.5 It has been shown to (a) minimize adjuvant coagulation and (b) preserve immuno-genicity of the vaccine antigen.

The mechanisms by which immune adjuvants function are still a matter of scientific conjecture. Key to delineating those mechanisms is the role of aluminum or its derivative Al(OH)3, derived from alum through the treatment process. It is logical to deduce that interactions arise between Al(III) and cellular targets such as proteins, as a result of which biological activity develops or is enhanced through mediated action(s) of the associated presenting antigen in the mineral gel adjuvant. One such role that aluminum might play originates in its ability as a trivalent cationic metal ion to neutralize negatively charged molecular targets (e.g. plasma protein fibrinogen), raising hydrophobic effects that potentially lead to (a) protein precipitation on hydrophilic surfaces (e.g. Al(OH)3) and (b) changes in the tertiary structure of interacting proteins adsorbed onto hydrophilic/hydrophobic surfaces. In this respect, critical is (a) the link between hydrophilicity/hydrophobicity of aluminum-oxygen species and the adjuvant cytochemistry and (b) the correlation of the magnitude of the adjuvancy with the magnitude of the inflammatory response (granuloma-tous reaction), produced by the metal-oxygen species and the surface area for antigen presentation.

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