Review of L‐tyrosine confirming its safe human use as an adjuvant

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 This paper summarizes a range of investigational data (unpublished) available to the authors as well as published literature reports.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.

Pollinex® Quattro Ragweed: safety evaluation of a new allergy vaccine adjuvanted with monophosphoryl lipid A (MPL®) for the treatment of ragweed pollen allergy

“…Recent animal studies examining macrophagic myofasciitis associated with clinical use of vaccines containing aluminium salts have shown dose site infiltration of macrophages with intracytoplasmic crystalline inclusions in rats and monkeys (Gherardi et al, 2001;Verdier et al, 2005). The findings reported in the present investigation are likely to be related to the presence of L-tyrosine in the dose formulation and it has been pointed out elsewhere that L-tyrosine injections in animals results in local swelling and an inflammatory response associated with deposited material (probably related to the low solubility of L-tyrosine) (Baldrick et al, 2002b). However such responses, as found with ragweed allergoid-containing vaccines, resolved rapidly, even after multiple injections and showed no evidence of a progressive nature.…”

“…No signs of systemic toxicity were found and although not accompanied by any change in white cell count, the changes in albumin and globulin levels along with increased spleen weight may have been due to immunostimulatory activity considering that the modified pollen extract has activity per se and MPL ® is an immunologically active adjuvant. Recent reviews of animal studies evaluating the potential toxicity of L-tyrosine and MPL ® have highlighted consistent findings associated with stimulation of the immune system (notably increased white blood cell values and increased spleen weight) in the rat and dog (Baldrick et al, 2002a;2002b). Other recent studies with allergoid/ MPL ® /L-tyrosine vaccines (house dust mite allergoids from Dermatophagoides pteronyssinus and D. farinae, 50:50 mix) and Pollinex Quattro Grass vaccine (mixture of 12 common grass plus rye cereal pollen allergoids), respectively, administered as repeated subcutaneous doses to the rat, raised neutrophil (and total white cell) count and spleen weight and/or altered albumin and globulin levels (Baldrick et al, 2002c;.…”

“…Adsorption of these allergoids to Ltyrosine to enhance both safety and efficacy has resulted in a range of allergen extract formulations with useful potential (Baldrick et al, 2002b;Newland et al, 1999;Wheeler et al, 1982;. Clinical use of these vaccines (e.g.…”

Nanoparticle Based-immunotherapy Against Allergy

“…l-tyrosine is also found in some IT but, its role is limited to act as a depot, slowing down allergen bioavailabilty, reducing the rate of dissemination from the injection site and reduce systemic reactions [37].…”

Development of Vaccine Adjuvants: A Historical Perspective

“…Although residence time is shorter than for aluminum salt systems, the benefi ts have not yet given rise to clinical trials. Use of tyrosine as an adjuvant in allergy vaccines has a long clinical history and a good record of safety [204].…”