Allergen-Specific Immunotherapy: The Need for Content Transparency

Abstract

Allergen-specific immunotherapy (AIT) was first introduced by Noon in 1911 as a treatment for rhinitis using timothy grass pollen extract, showing significant symptom improvement [1]. By exposing the immune system to controlled high doses of allergens, AIT fosters tolerance, reducing symptoms and potentially altering disease progression. Unlike natural allergen exposure, which is insufficient to induce tolerance, AIT delivers targeted immunomodulatory effects. AIT is widely used for allergic rhinitis, asthma, IgE-mediated food allergies, allergic conjunctivitis, atopic dermatitis and insect venom allergies. It is administered via subcutaneous immunotherapy (SCIT), which involves gradual dose escalation, or sublingual immunotherapy (SLIT), which starts at a fixed maintenance dose. Efficacy depends on both allergen quantity and immunogenicity. Some AIT products contain chemically modified allergoids to reduce IgE reactivity while preserving T-cell stimulation. However, these modifications complicate direct product comparisons. For example, Pollinex, the only licensed grass pollen SCIT in the United Kingdom, lacks full allergen characterisation, while the ALK SCIT product is well studied but remains unlicensed.

Despite international efforts, allergen quantification remains inconsistent. The CREATE and BSP90 initiatives have standardised a limited set of allergens, including Der p 1, Der f 1, Bet v 1 and Phl p 5, but exclude others, such as Der p 23, which may be clinically significant for specific patients. This lack of standardisation makes cross-product comparisons unreliable. This editorial reviews current evidence on aeroallergen content in AIT and highlights clinical implications through a case study.

Significant variability and limited transparency in allergen content across commercial immunotherapy products pose challenges to their standardisation, efficacy and safety. Allergen potency in AIT products is typically quantified by measuring the concentration of major allergens in micrograms, reflecting biological potency. Allergens are classified as major (binding IgE in > 50% of patients) or minor allergens (binding < 50% IgE), influencing their clinical relevance [2].

European manufacturers commonly use in-house reference standards based on titrated skin prick testing, resulting in arbitrary potency units that complicate cross-product comparisons. Initiatives such as the EU CREATE project have established standardised protocols using mass units (micrograms) for key allergens like Der p 1, Der f 1, Der p 2, Der f 2, Bet v 1, Phl p 1, Phl p 5 and Ole e 1 [3]. Despite these advances, inconsistencies persist due to varying manufacturing processes, allergen quantification methods and differing regulatory standards between Europe and the USA. These discrepancies hinder clinicians' ability to select appropriate AIT products, underscoring the need for greater standardisation, clearer labelling and broader inclusion of clinically significant allergens. Harmonisation of allergen quantification and regulatory oversight is essential for ensuring the safety, consistency and effectiveness of AIT.

Significant variability exists in HDM SLIT formulations. Moreno Benítez et al. (2015) analysed local products using immunoblotting and fluorescent multiplex assays, revealing Der p 1 (0.6–14.5 μg/mL), Der f 1 (0.2–12.4 μg/mL) and combined Der p 2/Der f 2 (0.2–1.5 μg/mL) [4]. This inconsistency may impact efficacy, as inadequate allergen levels can lead to suboptimal immune responses. Casset et al. (2012) assessed commercial Dermatophagoides pteronyssinus extracts, detecting Der p 1 (6.0–40.8 μg/mL) and Der p 2 (1.7–45.0 μg/mL) across all products, but at least one of Der p 5, 7, 10 or 21 was missing in eight formulations. Der p 23 is a recently identified HDM major allergen. IgE sensitisation to Der p 23 has been linked to severe asthma. While major HDM allergens (Der p 1, Der f 1, group 2 allergens and Der p 23) are included in some products, such as SQ HDM SLIT (ALK-Abelló A/S), Der p 23 remains underrepresented in many commercial HDM immunotherapy formulations [5].

Timothy grass pollen allergy is primarily driven by Phl p 1, Phl p 2 and Phl p 5 [26]. Phl p 1 is recognised by approximately 90% of grass pollen-allergic individuals, while Phl p 5 sensitises 65%–85% and Phl p 2, a defensin-like protein, is recognised by 30%–50%. Cross-reactivity is weaker with Bermuda grass (Cynodon dactylon), as Cyn d 1 and Cyn d 4 have lower homology with Timothy grass, potentially reducing immunotherapy effectiveness. In contrast, rye grass (Lolium perenne) allergens Lol p 1 and Lol p 5 both share high sequence identity with Timothy grass Phl p 5, making them highly cross-reactive. Grass pollen immunotherapy products show significant allergen variability. A 2008 ELISA study analysed Phl p 1, Phl p 2 and Phl p 5 in timothy grass extracts from four manufacturers revealing substantial changes: Phl p 1 (32–384 ng/mL), Phl p 2 (1128–6530 ng/mL) and Phl p 5 (40–793 ng/mL) [6]. A study by Rossi (2004) found no significant IgG₄ response to Phl p 12 after 8 weeks of immunotherapy, unlike other allergens such as Phl p 1, 2, 5, 6, 7, 11 and natural Phl p 4, suggesting Phl p 12 was absent from the immunotherapy product.

Tree pollen sensitization varies, influenced by the local distribution of tree species. In the United Kingdom, common allergenic trees include birch, hazel, alder, ash, and oak, each associated with specific primary allergens: Bet v 1 (birch), Cor a 1 (hazel), Aln g 1 (alder), Fra e 1 (ash) and Que a 1 (oak). These trees belong to the birch homologous group, characterised by structural homology among their major allergens, resulting in significant IgE cross-reactivity. The plane tree (Platanus acerifolia) is another major tree pollen allergy in the United Kingdom. Unlike birch-related species, Pla a 1 and Pla a 2 are structurally distinct, thus birch pollen AIT does not provide cross-protection. Duffort et al. (2006) highlighted substantial variability in allergen concentrations in olive pollen extracts used for immunotherapy, with the Ole e 1 to Ole e 9 ratio ranging from 0.6 to 390.4 [7]. Limited research exists on allergen content in commercially available immunotherapy extracts for other tree pollens.

Can f 1 to Can f 7 are dog allergens, with Can f 1, Can f 2 and Can f 5 most frequently linked to sensitisation. A 2011 study of five European manufacturers found up to a 20-fold difference in total protein content, with one extract lacking detectable Can f 1 and Can f 2 [8]. Similarly, a study by van der Veen et al. (1996) reported Can f 1 levels ranging from 3.8 to 170 μg/mL in commercial extracts, some of which were contaminated with HDM allergens (Der p 1 and Der p 2). The age of this study may mean cross-reactivity and measurements are less accurate, but there is no newer data. Fel d 1, Fel d 2, Fel d 4 and Fel d 7 are cat allergens, with Fel d 1 being the primary sensitizer. Data on commercially available cat immunotherapy extracts is limited, but one study showed Fel d 1 concentration significantly influences immune response [9]. Extracts with 15 μg of Fel d 1 resulted in better immunologic outcomes compared to 0.6 μg or 3 μg [9].

A major challenge in AIT is the significant variability in allergen content across commercial products. Studies consistently demonstrate discrepancies in the concentrations of major allergens, even among products targeting the same allergen source. Compounding this issue is the lack of transparency from manufacturers regarding allergen composition. Additionally, no centralised platform exists to compare allergen content across brands, further complicating product selection. In clinical practice, performing a skin prick test with the SLIT product may help confirm its immunogenicity in an individual patient.

International efforts, including the CREATE initiative, have established standardised benchmarks for select allergens, such as Der p 1, Der f 1, Der p 2, Der f 2, Bet v 1, Phl p 1 and Phl p 5. While these guidelines have improved standardisation, they exclude other clinically relevant allergens, such as Der p 23. Expanding these standards is critical to ensuring comprehensive allergen coverage in AIT. Recognising these challenges, the EAACI guidelines on immunotherapy implicitly address product inconsistency by recommending the use of AIT products with clinical trial data supporting their efficacy. However, many AIT products available in Europe lack rigorous phase III RCTs, making it difficult to assess their true clinical benefit. Given these inconsistencies, component-resolved diagnostics may play a role in guiding AIT selection by identifying patient-specific sensitisations. Aligning treatment with individual allergen profiles potentially enhances efficacy and immune tolerance. standardisation, greater transparency and expanded allergen coverage are essential for ensuring AIT's safety and clinical effectiveness.

In conclusion, the success of AIT relies on accurate and transparent allergen quantification in commercial products. Standardised labelling with detailed allergen profiles, including other clinically significant components, is crucial for informed treatment decisions. Component-resolved diagnostics aid personalised therapy but depend on reliable allergen content data. Variability in allergen concentrations exposes gaps in standardisation. Stricter regulatory guidelines are needed to harmonise quantification methods and ensure batch-to-batch consistency. Further research should assess the clinical impact of individual allergens. Addressing these challenges will enhance AIT's effectiveness, bridging diagnostic advances with clinical practice for improved patient outcomes.

Melvin Lee Qiyu: Writing – original draft, Writing – review & editing, Visualization, Methodology, Investigation, Data curation. Tom Dawson: Writing – review & editing, Validation, Supervision, Resources, Conceptualization.

The authors declare no conflicts of interest.