Component-resolved evaluation of the content of major allergens in therapeutic extracts for specific immunotherapy of honeybee venom allergy

Abstract

Allergen-specific immunotherapy is the only curative treatment of honeybee venom (HBV) allergy, which is able to protect against further anaphylactic sting reactions. Recent analyses on a molecular level have demonstrated that HBV represents a complex allergen source that contains more relevant major allergens than formerly anticipated. Moreover, allergic patients show very diverse sensitization profiles with the different allergens. HBV-specific immunotherapy is conducted with HBV extracts which are derived from pure venom. The allergen content of these therapeutic extracts might differ due to natural variations of the source material or different down-stream processing strategies of the manufacturers. Since variations of the allergen content of therapeutic HBV extracts might be associated with therapeutic failure, we adressed the component-resolved allergen composition of different therapeutic grade HBV extracts which are approved for immunotherapy in numerous countries. The extracts were analyzed for their content of the major allergens Api m 1, Api m 2, Api m 3, Api m 5 and Api m 10. Using allergen-specific antibodies we were able to demonstrate the underrepresentation of relevant major allergens such as Api m 3, Api m 5 and Api m 10 in particular therapeutic extracts. Taken together, standardization of therapeutic extracts by determination of the total allergenic potency might imply the intrinsic pitfall of losing information about particular major allergens. Moreover, the variable allergen composition of different therapeutic HBV extracts might have an impact on therapy outcome and the clinical management of HBV-allergic patients with specific IgE to particular allergens.

Lessons from times of shortage: Interchangeability of venom preparations and dosing protocols

“…4 Purification of bee venom, however, might entail an underrepresentation of certain allergens and thus increase the risk of treatment failure. 5 While our study is likewise suggestive of a superior clinical tolerability of "purified" ALK-lyophilisiert SQ ™ in the context of inpatient rush buildup, we were not able and did not aim to statistically compare safety profiles of different venom preparations (patients were not randomized into the two treatment groups, but sorted according to a process of triage). Our data, however, allow for some descriptive observations and may thus serve as an orientation in future shortage situations.…”

“…3,4 All licensed products are derived from pure venom, but little information is available regarding specific downstream processing strategies applied by different manufacturers. 5 A superior safety profile has been attributed to both aluminum hydroxide-adsorbed depot preparations 6 and "purified" venoms 3,6,7 which are claimed to be virtually free of low molecular weight components. 4 Purification of bee venom, however, might entail an underrepresentation of certain allergens and thus increase the risk of treatment failure.…”

“…4 While this is an excellent clinical study, it does not necessarily represent the real-life situation in chronic disease where sleep disturbances may exacerbate impairment of psychomotor performance, including driving. [5][6][7] We now present the results of a real-life survey of 513 regular car drivers with seasonal allergic rhinitis on the effect of their disease on their ability to drive and the measurements they took to reduce the possibility of accidents.…”

Current challenges in molecular diagnostics of insect venom allergy

“…Among the recognized allergens in HBV only phospholipase A2 (Api m 1) and melittin peptide (Api m 4) are highly abundant components, accounting for 12% and 50% of the venom dry weight, respectively, while the hyaluronidase Api m 2 (1-3%), and a number of other allergens such as Api m 3, Api m 5, Api m 6 and Api m 10 are only present in low abundance (1% or below). Variability in allergen content and/or stability [15] may thus influence the outcome of diagnostic testing, particularly in patients with sensitizations to low abundance allergens.…”

Component‐resolved diagnostics to direct in venom immunotherapy: Important steps towards precision medicine

“…A prominent example is a study that demonstrated that only 83 Moreover, an intrinsic instability and rapid degradation of the important major allergen Api m 10 was reported recently [70]. Such a predominance of particular allergens in the venom extract is very likely to create a diagnostic information bias by favoring the detection of high abundant allergens.…”