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Wasp allergy with a diagnostic profile of double sensitizations to vespid venom is a frequent clinical problem in areas where different genera of wasps are present. Identification of the insect responsible for serious reactions poses a diagnostic challenge as the only effective treatment to date is immunotherapy based on the specific venom. In southern Europe, the double sensitization to Vespula and Polistes venoms is highly frequent. It has been shown that the major allergenic proteins (Phospholipase A1 and Antigen 5) share sequences across the different genera and species, which would be the cause of cross-reactivity. Additionally, the minor allergens (Dipeptidyl-peptidases, Vitellogenins) have been found to share partial sequence identity. Furthermore, venom contains other homologous proteins whose allergenic nature still remains to be clarified. The traditional diagnostic tools available are insufficient to discriminate between allergy to Vespula and Polistes in a high number of cases. IgE inhibition is the technique that best identifies the cross-reactivity. When a double sensitization has indeed been shown to exist or great uncertainty surrounds the primary sensitization, therapy with two venoms is advisable to guarantee the safety of the patient. In this case, a strategy involving alternate administration that combines effectiveness with efficiency is possible. [ABSTRACT FROM AUTHOR]