Venom immunotherapy: aqueous vs aluminium hydroxide adsorbed extracts

Venom immunotherapy (VIT) has been introduced in the late seventies of the last century and is considered as a very effective and safe treatment for patients with Hymenoptera venom allergy (1). The efficacy of VIT has been documented in three controlled studies so far, in two (2, 3) vs placebo and in two (2, 4) vs wholebody insect extract. In the three studies VIT resulted in complete protection in 75–97% of patients re-exposed to a sting by the culprit insect, wheras only 25–36% of wholebody extract treated and 25–41% of placebo-treated individuals did not develop any systemic allergic symptoms following re-exposure. The VIT was thus significantly superior to placebo and/or wholebody extract in all three studies. On the contrary there was no difference in efficacy between placebo and wholebody extract. Although in all three controlled studies aqueous venom extracts were used, many venom allergic patients in Europe today – in contrast to US – are treated with Al(OH)3 adsorbed venoms (depot preparations). The efficacy of these depot preparations however has not been documented in any placebo or wholebody extract controlled studies. This situation rises two questions: On what facts is the use of these depot preparations based? and Why are Al(OH)3 adsorbed venoms used in Europe but not in US? To question 1: The only controlled study published so far (5) was open and compared aqueous venom extracts from two sources, one dialyzed with elimination of low molecular weight components of <3.5 kD, and one not dialyzed, with an Al(OH)3 adsorbed depot preparation of Vespula venom extract in 32 Vespula venom allergic individuals. In this small study none of the 19 sting challenged patients, 12 on aqueous and seven on depot preparations, developed any systemic allergic symptoms. There was also no significant difference with regard to safety – as indicated by systemic allergic side effects – between the aqueous and depot extracts, while local reactions were observed more frequently only with the undialyzed aqueous venom preparation, most likely because of low molecular weight toxic peptides like melittin or mastoparan and biogenic amines like histamine. No difference was found between aqueous dialyzed and depot preparations regarding local reactions. There was no difference either in the IgE response between the two groups at any time, but the IgG response was significantly stronger during VIT with depot extracts. In a more recent EAACI multicenter study (6) 840 patients with venom allergy were analyzed for systemic allergic side effects during immunotherapy with either aqueous (n = 720) or depot preparations (n = 174). Of the 720 on aqueous extract 54 patients were switched to depot preparations during maintenance immunotherapy after a rush or ultra-rush regimen during the dose increase phase. While systemic side effects were observed somewhat more frequently in patients on aqueous than on depot preparations, the difference did not reach statstical significance either during the updosing or the maintenance treatment, although it is well known that side effects occur more frequently in rush or ultra-rush than in conventional protocols with aqueous extracts (7, 8) and depot extracts were of course not used in such rapid dose increase protocols. A further study compared side effects of bee venom immunotherapy in 55 patients, 40 treated with aqueous and 15 with depot preparations (9), according to a rush (only for aqueous bee venom) or a clustered protocol. An increased rate of side effects was only found for the rush protocol while there was no difference between aqueous and depot preparations applied according to the clustered protocol. In summary clinical data documenting a superiority of depot over aqueous venom preparations were lacking until today. In this issue of Allergy Rueff et al. (10) compare VIT with aqueous and Al(OH)3 adsorbed venom with regard to safety and efficacy in 65 honey bee venom allergic patients. Both side effects and treatment failures of VIT occur more frequently in bee venom than in Vespula venom allergic patients (11). Therefore a significant difference with regard to efficacy and safety will be detected more easily in this patient group. The results of this study (10) are comforting as they show comparable efficacy as indicated by a well tolerated sting challenge with a complete protection rate in 83–89% in the 46 re-exposed patients and no significant difference between groups. On the contrary both large local and systemic allergic side effects occurred significantly more often with the aqueous than with the depot preparation also during the maintenance phase when similar dosing intervals were used. This is thus the first study which documents both comparable efficacy and a significant advantage in favor of depot when compared with aqueous preparations with regard to safety. Should we then stop using aqueous venom extracts? Of course not because rapid up-dosing protocols can only be done with aqueous venoms and we need these for all highly exposed patients such as beekeepers, farmers, gardeners etc in order to provide them a rapid protection. Moreover we should not forget the inherent disadvantages of depot preparations: (a) Systemic side effects may occur with a delay, with other words, when the patient is already out of the doctors office, (b) the introduction of an additional foreign substance may induce additional side effects, such as e.g. subcutaneous granuloma formation (12), (c) Al(OH)3 adsorbed allergens have been used for many decades as an adjuvant both in rodents (13) and primates (14) to induce an IgE response. What does that mean for VIT in man? Also in this regard the study by Rueff (10) provides comforting results while showing no difference in the IgE response in the two groups. On the contrary the IgG response – inspite of the much slower updosing protocol – was somewhat stronger to the depot preparation, thus confirming the findings of an earlier study in Vespula venom allergic patients (5). To question 2: Why are aluminium hydoxide adsorbed venoms not used in US? As we hear from a commercial producer of such extracts [Mangor VM. ALK-Abello, Denmark: Personal communication 2003] in US the accepted aluminium dose is at 0.85 mg/dosage while it is 1.25 mg/dosage in Europe. In order to get European Al(OH)3 adsorbed preparations accepted in US the FDA asks for controlled studies that document the superiority of the European preparation [Slater Jay, FDA, USA: Personal communication 2003] and these were missing so far. I am personnally convinced that this approach goes in the right direction. I would even postulate that controlled studies should have to document the efficacy of any new allergen preparation, either depot or modified, and also of new ways of application, not only against placebo, but also their superiority over the corresponding aqueous unmodified allergen extract applied subcutaneously.