Mineral adjuvants

Adsorption. The adsorption of the components of a vaccine on to a mineral adjuvant. The mineral adjuvants, or carriers, most often used are aluminium lydroxide, aluminium phosphate and calcium phosphate and their effect is to increase the immunogenieity and decrease the toxicity, local and systemic, of a vaccine. Diphtheria vaccine, tetanus vaccine, diphtheria/tetanus vaccine and diphtheriaAetanus/pertussis vaccine are generally prepared as adsorbed vaccines. 

Bollinger JN. 1970. Metabolic fate of mineral oil adjuvants using 14C-labeled tracers. I. Mineral Oil. J Pharm Sci 59 1084-1088. 

A number of mineral-based substances display an adjuvant effect. Although calcium phosphate, calcium chloride and salts of various metals (e.g. zinc sulfate and cerium nitrate) display some effect, aluminium-based substances are by far the most potent. Most commonly employed are aluminium hydroxide and aluminium phosphate (Table 13.13). Their adjuvanticity, coupled to their proven safety, render them particularly valuable in the preparation of vaccines for young children. They have been incorporated into millions of doses of such vaccine products so far. 

The adjuvanticity of oil emulsions was first recognized in the early 1900s. However, the first such product to gain widespread attention was Freund s complete adjuvant (FCA), developed in 1937. This product essentially contained a mixture of paraffin (i.e. mineral) oil with dead mycobacteria, formulated to form a water-in-oil emulsion. Arlacel A (mannide mono-oleate) is usually added as an emulsifier. 

Very often, vaccines are formulated with certain substances to enhance the immune response. These substances are called adjuvants (from the Latin adju-vare, which means to help ). The most common adjuvants for human use are aluminum hydroxide, aluminum phosphate, and calcium phosphate. Other adjuvants being used include bacteria and cholesterol. Mineral oil emulsions are normally the adjuvants used in animal studies. The adjuvant known as Freund s complete adjuvant consists of killed tubercle bacilli in water-inmineral oil emulsion, and Freund s incomplete adjuvant is a water-in-oil emulsion. Both these adjuvants are effective in stimulating an immune response, but they cause unacceptable side effects in humans (see Table 4.2). 

Various additional oil-based adjuvants have subsequently been developed. Adjuvant 65, for example, consists of 86% peanut oil, 10% Arlacel A and 4% aluminium monostearate (as a stabilizer). Unlike mineral oil, peanut oil is composed largely of triglycerides, which are readily metabolized by the body. Although adjuvant 65 was initially proved safe and effective in humans, it displayed less adjuventicity than FIA. Its use was largely discontinued, mainly due to the presence in its formulation of Arlacel A. 

Okishiro M et al (2009) Genetic polymorphisms of CYP2D6 10 and CYP2C19 2, 3 are not associated with prognosis, endometrial thickness, or bone mineral density in Japanese breast cancer patients treated with adjuvant tamoxifen. Cancer 115 952-961... 

Mineral Salts Immunostimulatory adjuvants Lipid particles Particulate adjuvants Mucosal adjuvants Aluminium hydroxide, aluminium phosphate, calcium phosphate Saponins (e.g., QS21), MDP derivatives, bacterial DNA (CpG oligos), LPS, MPL and synthetic derivatives, lipopeptides, cytokines (e.g., GM-CSF, IL-2, IL-12) Liposomes, virosomes, iscoms, cochleates, emulsions (e.g., Freunds adjuvant, SAF, MF59 ) Poloxamer particles, virus-like particles, PLG microparticles Cholera toxin (CT), mutant toxin (e.g., LTK63, LTR72), heat labile enterotoxin (LT), microparticles, polymerized liposomes, chitosan... 

For this reason vaccine formulation tends to follow the traditional routes innovative formulations are rare. Aluminium hydroxide, aluminium phosphate and calcium phosphate are still the only registered vaccine adjuvants for humans. Veterinary vaccines have to rely on the same components, however, a few vaccines containing a mineral oil adjuvant (Marcol) or saponin (Quil A or derivatives) have passed the registration hurdles. It remains to be seen whether and under which restrictions these adjuvants can be used in the EEC after 1996 (see also below in "Additional requirements for veterinary products"). 

The most popular and successful adjuvants have been the water in oil emulsions developed by Freund. The basic ingredients of light mineral oil (Bayol) and emulsifying agents mixtures such as Arlacel (A or C) are available commercially. The reagents are emulsified with either solutions or suspensions of the immunogen (incomplete Freund s adjuvant). The addition of mycobacteria (Mycobacterium butyricum, M. tuberculosis) in small amounts to the suspension (complete Freund s adjuvant) leads to a further enhancement of the immune response. This has been attributed to the increased local inflammatory response caused by the mycobacteria. ... 

Solubihty soluble in alkali hydroxides and mineral acids. Heat may be required to dissolve the aluminum hydroxide adjuvant. 

Indeed, lecithin-cholesterol liposomes successfully substituted for mineral-oil emulsion in the induction of delayed hypersensitivity In guinea pigs, administration of liposome-suspensions containing MDP and ovalbumin induced delayed skin reactivity similar to that observed following immunization in MDP-supplemented incomplete Freund s adjuvant (IFA) or in CFA.30,45 However, 6-0-acyl-MDP derivatives of appropriate fatty acid chain length (Cx2-C22> i 2, 3A), but not C2-C8 (9, 1, JJJ, showed in-... 

Adjuvants, such as aluminum salts or mineral oils, alter the physical state of water-soluble immunogens by forming depots and lower the rates of elimination. This results in a prolonged persistence of the immunogen in tissues and a continuous stimulation of the immune system, which can be mimicked by daily injections of very small amounts of immunogen (Herbert, 1966). 

Perez, E.A., Josse, R.G., Pritchard, K.I., Ingle, J.N., Martino, S., Findlay, B.P., Shenkier, T.N., Tozer, R.G., Palmer, M.J., Shepherd, L.E., Liu, S., Tu, D. and Goss, P.E. (2006) Effect of letrozole versus placebo on bone mineral density in women with primary breast cancer completing 5 or more years of adjuvant tamoxifen a companion study to NCIC CTG MA. 17. Journal of Clinical Oncology, 24, 3629-3635. 

---