Allergen Immunotherapy - Lyophilization Articles & Reports

Allergen Immunotherapy
August 15, 2004
JENNIFER L. HUGGINS, M.D., and R. JOHN LOONEY, M.D.
American Academy of Family Physicians
Allergen immunotherapy (also called allergy vaccine therapy) involves the administration of gradually increasing quantities of specific allergens to patients with IgE-mediated conditions until a dose is reached that is effective in reducing disease severity from natural exposure. The major objectives of allergen immunotherapy are to reduce responses to allergic triggers that precipitate symptoms in the short term and to decrease inflammatory response and prevent development of persistent disease in the long term. Allergen immunotherapy is safe and has been shown to be effective in the treatment of stinging-insect hypersensitivity, allergic rhinitis or conjunctivitis, and allergic asthma. Allergen immunotherapy is not effective in the treatment of atopic dermatitis, urticaria, or headaches and is potentially dangerous if used for food or antibiotic allergies. Safe administration of allergen immunotherapy requires the immediate availability of a health care professional capable of recognizing and treating anaphylaxis. An observation period of 20 to 30 minutes after injection is mandatory. Patients should not be taking beta-adrenergic blocking agents when receiving immunotherapy because these drugs may mask early signs and symptoms of anaphylaxis and make the treatment of anaphylaxis more difficult. Unlike antiallergic medication, allergen immunotherapy has the potential of altering the allergic disease course after three to five years of therapy. (Am Fam Physician 2004;70:689-96,703-4. Copyright? 2004 American Academy of Family Physicians.)
Allergen immunotherapy involves subcutaneous injections of gradually increasing quantities of specific allergens to an allergic patient until a dose is reached that will raise the patient's tolerance to the allergen over time, thereby minimizing symptomatic expression of the disease. Because the proteins and glycoproteins used in allergen immunotherapy are extracted from materials such as pollens, molds, pelt, and insect venoms, they were originally called allergen extracts. In 1998, the World Health Organization (WHO) proposed the term "allergen vaccine" to replace "allergen extract," because allergen immunotherapy is an immune modifier just as vaccines are.1
The efficacy of allergen immunotherapy has been known since 1911, when Noon injected an extract of grass pollen into a person in England whose allergic symptoms coincided with the pollination of grass.2 Since then, controlled studies have shown that allergen immunotherapy is effective in patients with allergic rhinitis, allergic conjunctivitis, allergic asthma, and allergic reactions to Hymenoptera venom.3-6 Patients with one or more of these diagnoses are considered for immunotherapy if they have well-defined, clinically relevant allergic triggers that markedly affect their quality of life or daily function, and if they do not attain adequate symptom relief with avoidance measures and pharmacotherapy. Despite proven efficacy, the exact mechanism of allergen immunotherapy remains unknown.
Standardization, Storage, and Mixing of Allergen Vaccines
Ideally, vaccines should be standardized with a defined potency and labeled with a common unit.15 Such standardization would eliminate the variability in vaccines and allow for safer and more effective dosing. The Bioequivalent Allergy Unit (BAU), which is assigned by the U.S. Food and Drug Administration based on quantitative skin testing performed on a reference population of allergic patients known to be highly skin-test-reactive to that allergen, reflects clinical potency and is currently used for standardization of vaccines.
Standardized allergens available in the United States include cat dander, grass pollens, dust mites, and short ragweed pollen. Unstandardized vaccines may vary widely in biologic activity based on manufacturer and by lot, depending on the allergen content of the raw material and the conditions of extraction. Furthermore, the labeling conventions of Protein Nitrogen Units (PNUs) or weight by volume (wt/V) reflect protein content but not allergenic potency. Research is underway on new technologies for DNA and protein analysis that would allow an allergen vaccine to be characterized by the content of the major allergen and the consistency of each lot to be monitored accurately.
Vaccine strength is maintained by a number of procedures, including lyophilization and reconstitution with a stabilizer that contains an antimicrobial agent. A volume effect can occur as a result of adherence of the allergen to the vial surface; the larger the surface area of the vial, the more allergen is lost. Glycerol and human serum albumin (0.03 percent) are used to mitigate the volume effect. Glycerol has the added advantage of being an antimicrobial agent. At a concentration of 50 percent, glycerol inhibits enzymatic degradation of the allergens, but it may be irritating at this concentration. The combination of human serum albumin as a stabilizer and phenol as an antimicrobial additive often is used. However, human serum albumin typically is refused by patients who are Jehovah's Witnesses.
Vaccines must be stored properly to preserve biologic activity. Vaccines should be refrigerated at 4?C (39.2?F) because storage at ambient room temperature results in loss of potency within weeks, with degradation occurring within days at higher temperatures. Critical to vaccine potency is the dilution effect: highly concentrated vaccines are more stable than dilute vaccines.18 The vaccine label should always be checked for the expiration date.
For immunotherapy to be effective, an optimal dose of each allergen must be determined. When a patient has multiple sensitivities caused by related and unrelated allergens, vaccines containing mixtures of these allergens may be prescribed. As multiple vaccines are mixed, not only will the concentration of each allergen be decreased, but certain allergens will interact. For example, fungi, dust mites, insect venoms, and cockroach have high proteolytic enzyme activity and may be combined with each other but should not be mixed with other allergens. Insect venoms usually are given alone.
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