No abstract

Although there is a long history of exposure to allergy vaccines containing L-tyrosine, there has been no central publication reviewing its adjuvant properties in animal and human studies together with an assessment of its safe use. This paper summarizes a range of investigational data (unpublished) available to the authors as well as published literature reports. An array of in vitro and in vivo studies showed that L-tyrosine has ideal adjuvant properties, comprising a high adsorptive power for proteins, enhancement of IgG antibody induction with no stimulatory effect on IgE antibody level and action as a short-term depot adjuvant, delaying the bioavailability of allergenic materials rather than directly influencing immunocompetent cells. A series of preclinical safety investigations comprised single-dose parenteral studies in the mouse and rat, repeat-dose parenteral toxicity studies over 28 days in the rat and dog (up to 25 mg kg(-1) day(-1)) plus genotoxicity and local tolerance studies. No signs of toxicity or genotoxicity were seen; repeat-dose toxicity studies showed expected white cell and spleen weight immunostimulatory effects; local-dose site reactions were also seen and were confirmed in local tolerance studies. Findings from a range of clinical studies using allergy vaccines containing L-tyrosine reflected the lack of toxicity seen in animal work and showed evidence of enhanced immunostimulatory activity. Local injection site reactions (a common response to any form of clinical vaccination) in these studies were likely to be due to the presence of L-tyrosine per se. The lack of findings of toxicological concern found during this review supports the hypothesis that L-tyrosine is a safe adjuvant for human use.

A novel allergy vaccine (Pollinex Quattro Ragweed) has been developed for the prevention or relief of allergic symptoms caused by pollen from Ambrosia spp. (ragweed). An extract from the pollen (chemically modified by glutaraldehyde) is adsorbed onto l-tyrosine with addition of the immunostimulatory adjuvant, monophosphoryl lipid A (MPL). A specific preclinical safety testing strategy was developed to support clinical use and comprised reference to preclinical data available for the marketed non-MPL adjuvanted form of the ragweed vaccine (Pollinex R) and a new repeat dose toxicity study in the rat. Studies with Pollinex R comprised single dose subcutaneous toxicity studies in mice and rats, repeat dose (10 injections over 20 days) parenteral toxicity studies in rats and dogs, an in vitro gene mutation assay along with single and multiple injection local tolerance studies in rats and dogs. The repeat dose subcutaneous toxicity study with Pollinex Quattro Ragweed involved seven injections over 3 weeks (which was more aggressive than the four weekly doses used in the clinic) with dose levels of up to 0.5 ml per animal used. Overall, the product showed no toxicological findings of significance at levels greatly in excess of those proposed for clinical use. As is a feature with vaccination, some dose site irritation was seen.

No abstract

A novel allergy vaccine (Pollinex Quattro) has been developed for the prevention or relief of allergic symptoms caused by a variety of pollens. Within this range, the grass pollen allergy vaccine contains extracts of 12 grass pollens and rye cereal (all chemically modified by glutaraldehyde) that are adsorbed onto L-tyrosine with addition of the immunostimulatory adjuvant monophosphoryl lipid A (MPL). A specific preclinical safety testing strategy was developed to support clinical use, comprising single-dose toxicity, repeat-dose toxicity and local tolerance studies. Dose levels of up to 0.5 ml per animal (mouse) and up to 1.0 ml per animal (rat and rabbit) were used with vaccines containing 2000 or 12 000 standardized units (SU) ml(-1) of grass pollen allergoids, 50 micro g ml(-1) of MPL adjuvant and 20 mg ml(-1) of tyrosine. Overall, the product showed no toxicological findings of significance at levels greatly in excess of those proposed for clinical use. A not unexpected, but relatively minor, immunostimulatory effect was seen following repeated dosing (once weekly for 3 weeks) at 1.0 ml per rat.