Algorithms in Allergy: General Allergen Molecule‐Based Algorithm for Allergen‐Specific Immunotherapy

Allergen-specific immunotherapy (AIT) is among the most effective treatments for IgE-mediated allergic diseases [1]. It involves the controlled administration of disease-causing allergens, or their derivatives, to induce long-lasting clinical tolerance in patients. This tolerance is associated with—and ultimately driven by—the induction of allergen-specific IgG4 and IgA antibodies, as well as by the modulation of T-cell, B-cell, and related innate immune responses. Accurate identification of the culprit allergens responsible for a patient's symptoms is essential for the selection of an appropriate AIT vaccine. In many cases, the relevant allergen source can be determined on the basis of clinical history combined with conventional allergen extract–based IgE serology and/or provocation tests, such as skin prick testing (SPT) (Figure 1, top). However, allergen extracts frequently contain not only genuine, source-specific allergens (Gs) but also cross-reactive allergens (Cs) that share structural and immunological similarities with allergens from unrelated sources. Sensitization to such cross-reactive components may result in positive IgE test results and clinical reactivity to multiple allergen extracts. This cross-reactivity can obscure the identification of the true disease-causing allergen source and complicate the selection of the most appropriate AIT. With the availability of allergen molecules representing Gs and Cs with different extents of IgE cross-reactivity, it has become possible to refine the identification of the culprit allergen source by molecular diagnostics [2]. This concept was first proposed in 2002 [3] and is based on testing the patient with Gs and Cs from different allergen sources. The algorithm-based approach to molecular allergy diagnosis has been evaluated and was found to be helpful by clinicians in refining and optimising AIT prescription [4]. As indicated in Figure 1, (top) allergologists can identify the clinically relevant allergen sources by medical case history, traditional extract based testing and subsequent additional molecular testing. Alternatively, clinicians may proceed directly from the medical history to targeted molecular IgE testing or to broader molecular profiling using multiple allergen components (i.e., multiplex testing) in a so-called “discovery approach.” It goes without saying that only patients with clinically relevant IgE sensitizations will, in addition to symptomatic drugs, receive allergen-specific interventions, such as AIT, dietary measures, and/or allergen avoidance in the case of mono- or oligo-sensitized individuals, or biologics in polysensitized patients. For the latter, AIT may be considered carefully in a case-by-case basis (Figure 1, bottom). Although the implementation of molecular IgE diagnostics may entail additional upfront costs, there is evidence that the more precise prescription of AIT ultimately reduces overall healthcare expenditures by improving vaccine selection, particularly given that AIT vaccines are substantially more expensive than the diagnostic procedures themselves [5]. The concept of using molecular allergy diagnosis for the prescription of AIT not only seems to be helpful for clinical decision-making but meanwhile there is also evidence that the selection of patients by molecular diagnosis may improve the success of treatment. For example, it has been shown that patients who are sensitized against allergen molecules represented in the AIT vaccine may benefit over patients who have IgE sensitisations against allergens which are absent and/or do not induce blocking IgG [6]. Future prospective studies evaluating the impact of molecular versus traditional diagnosis on the clinical outcome of AIT will be useful. Whether a given AIT product is capable of inducing protective antibodies against specific allergens can also be assessed by evaluating its ability to elicit blocking, allergen-specific IgG antibodies in animal immunization models [7]. It may therefore be possible to optimize AIT vaccine selection by matching the molecular IgG antibody profiles induced by individual AIT vaccines with the IgE sensitisation profiles of patients. A full disclosure by manufacturers regarding allergen content in commercial vaccines would be needed. So far, the molecular IgE sensitisation algorithms used for AIT prescription have been mainly based on the assumption that all allergen sources contain Gs but it turns out that this is not true for all allergen sources. For example, most major allergens from mugwort and ragweed pollen [8], as well as the majority of allergens from house dust mites (HDM) and Blomia tropicalis [9], are highly cross-reactive, making it difficult to identify a genuine, source-specific allergen (G) within these allergen sources. To identify the genuine allergen source, it is therefore necessary to also consider the levels of allergen-specific IgE directed against cross-reactive components (Cs) from the different allergen sources. Figure 2 illustrates a general allergen molecule–based algorithm for the selection of allergen-specific immunotherapy, which should be applicable across all allergen sources. The following scenarios are possible: Genuine sensitisation to allergen source A is detected by IgE sensitisation to major G-As and/or higher IgE levels to C-As (Figure 2, Only A). Likewise, genuine sensitisation to allergen source B is identified by IgE sensitisation to major G-Bs and/or higher IgE levels to C-Bs than to C-As (Figure 2, Only B). Patients can also be co-sensitized which indicates that they may need AIT vaccines comprising allergen source A and B. Molecular profiles indicative of co-sensitisations are: IgE reactivity to G-As and G-Bs regardless of IgE levels with or without IgE sensitisations of different magnitudes to C-As and/or C-Bs. If there are no Gs but only Cs in two allergen sources, higher IgE levels to at least one C-A1 than the corresponding C-B1 and to at least another C-B2 than to the corresponding C-A2 may indicate co-sensitization. Finally, there is the possibility that if all G-As and all G-Bs are negative and IgE levels to each of the C-As and C-Bs are comparable, then there is “complete” cross-sensitisation. Whether AIT can then be recommended will depend on the presence and immunogenicity of the latter allergens in the AIT vaccines to be considered for treatment. The authors hope that the suggested general allergen molecule-based algorithm for allergen-specific immunotherapy will be helpful for all clinicians using molecular allergy diagnosis in their daily practice for decision making. R.V., H.-J.H., P.G., D.T. have prepared the first draft and Figures, implemented co-authors suggestions, read, revised the final manuscript. P.M.M., M.J. and S.D. have reviewed the manuscript and, when applicable, provided comments. S.D. reports research funding from Thermo Fisher Scientific and speaker´s fees from Allergopharma, ALK, Stallergenes, Chiesi, dbv Technologies, and Siemens Healthineers. Open Access funding provided by Medizinische Universität Wien/KEMÖ. Supported by the Danube Allergy Research Cluster funded by the Country of Lower Austria and by grant no. 23-75-30016 from the Russian Science Foundation for its part related to molecular allergy diagnosis. R.V. gives lectures for HVD Biotech, Vienna, Austria. P.M.M. declares speaker's fees, research support, and consultant's fees from ThermoFisher Scientific, Euroimmun, Hycor, MADX, and speaker's fees from Siemens. The authors with a Russian affiliation declare that they have prepared the article in their “personal capacity” and/or that they are employed at an academic/research institution where research or education is the primary function of the entity. No artificial intelligence tools have been used to prepare this manuscript. The data that support the findings of this study are available from the corresponding author upon reasonable request.