Immunological adjuvants in allergy vaccines: Past, present and future

ABSTRACT Hundreds of compounds have been tested over the years in a search for adjuvants to incorporate with antigens or allergens to enhance the immune response. Despite this, aluminum salts have been the only adjuvants that have been both registered for clinical application and used on a large scale until recently. Salts of aluminum, such as aluminum hydroxide, have been used as general immunologic adjuvants for several decades. Some allergen vaccines used for the treatment of allergy are still formulated with aluminum-based adjuvants. These formulations have generally proved efficacious and have a good safety profile compared with simple aqueous extracts. However, there is reported sensitivity and toxicity associated with use of aluminum. In addition, aluminum salts are known to be potent stimulators of T helper (h) 2 cell activity. Because Th2 activity directs towards an allergic response, aluminum salts are potentially counterproductive when used as adjuvants in the immunologic treatment of type 1 hypersensitivity. Many soluble and insoluble molecules have been reported to have adjuvant activity in experimental systems. Some of these have been used clinically, but side effects, such as local granuloma formation, have led to their withdrawal from clinical use. Newer depot-type adjuvants, such as insoluble calcium salts, tyrosine (now registered) and coupled alginates, may eliminate some of the potential problems of aluminum salts and are currently used in some allergy vaccines but have not as yet formed a complete replacement. Liposomes, iscoms and biodegradable microspheres are now being considered for clinical use as adjuvants for both oral and parenteral routes. Soluble adjuvants that are capable of directing the immune response in a more selective way are currently in development for use in allergy vaccines. One of these, the Th1-directing adjuvant monophosphoryl lipid A (MPL®; Corixa, Seattle, WA, USA), is now in clinical use in allergy vaccines formulated with the depot adjuvant L-tyrosine. Other ways of stimulating a Th 1 response using immunostimulatory DNA sequences (immunostimulatory DNA sequences (ISS) or CpG motifs) as 'built-in' adjuvants are being studied. Further interesting adjuvants reported in the literature, such as Montanide ISA 720, SAF-m, RC-529 and QS21, may also be applicable to allergy vaccination.