Immunotherapy Desensitisation Sublingual SLIT alternative to Subcutaneous Injections SCIT (allergy shots)

Allergen immunotherapy (AIT) has been used for over 100 years.

Different names like ‘desensitisation’, ‘hyposensitisation’, and even ‘vaccines’ have been used—sometimes incorrectly—to describe the process of giving small, increasing amounts of an allergen to reduce allergic reactions. However, there has been a lot of debate over how well AIT actually works. This disagreement has affected how much people know about AIT, whether it’s available in some countries, and whether health systems will pay for it.

 

Experts at the European Academy of Allergy and Clinical Immunology (EAACI) have put together a guide on how to properly use allergen immunotherapy.

Their full advice is available here: 

EAACI Allergen Immunotherapy Guidelines

We provide direct links to original articles on allergen specific immunotherapy:

 

Part I published in the Journal of Allergy and Clinical Immunology 7 July 2015

Part II published in the Journal of Allergy and Clinical Immunology February 2016

EAACI: A European Declaration on Immunotherapy. Designing the future of allergen specific immunotherapy

 

WHAT IS SIT? Specific allergen immunotherapy (SIT) is a disease-modifying therapy is in which increasing doses of whole allergen extract are administered in increasing dose in order to desensitise the allergic subject.

Allergen specific immunotherapy has been shown to be effective in rigorous double-blind placebo-controlled clinical trials in both children and adults. A recent WHO position paper stated that immunotherapy is an effective treatment for patients with allergic rhinitis/conjunctivitis, allergic asthma and allergic reactions from stinging insects.

Specific immunotherapy with standardised house dust mite (HDM) vaccine significantly improved symptoms and reduced medication use in mild to moderate allergic asthmatic patients. SIT also reduced skin prick test reactivity to Der p. Complying with the EAACI immunotherapy guidelines, SIT with standardised HDM vaccine was a safe treatment, SIT has long-term effects on asthmatic symptoms in young adults.

Whilst efficacious, this form of therapy is associated with the risk of adverse, IgE-mediated events including systemic anaphylaxis.

WHEN IS IT USED? Specific immunotherapy is only used when IgE sensitisation and presence of symptoms due to a specific allergen are confirmed.
Allergic rhinitis (hay fever), mild allergic asthma, occasionally it is used in eczema with proven sensitisation (there are contraindications).
SIT is currently offered for airborne allergy (weeds, grasses, trees, animals, house dust mites, moulds), severe systemic reaction to venom of stinging insects (bees, wasps).

This method is also used for sensitivity to some drugs only in an inpatients setting (for example in case of TB treatment, aspirin sensitivity), when no alternative medication is available and a long-term use of drug is required.

Oral immunotherapy (OIT) is still not widely used as a treatment for food allergy due to its risk of severe side effects. Currently, it is only available for children in strictly controlled hospital settings, which are unfortunately difficult to access in many private healthcare systems.

The standard treatment for confirmed food allergies remains strict avoidance of the allergen and carrying emergency medication (such as an adrenaline auto-injector) in case of accidental exposure.

OIT remains a topic of significant research and debate in the management of food allergies. While it has shown promise in desensitising patients to allergens such as peanuts, milk, and eggs, it is not yet widely adopted as a standard treatment due to its associated risks and side effects.

The primary approach for managing food allergies continues to be strict avoidance of the allergen and preparedness with emergency medications, such as adrenaline auto-injectors, in case of accidental exposure. This is because OIT carries a substantial risk of adverse reactions, including gastrointestinal distress, localised itching, and, in severe cases, anaphylaxis, which can be life-threatening.

Additionally, a notable proportion of patients develop eosinophilic esophagitis (EoE), a chronic allergic condition affecting the oesophagus, during or after OIT treatment. These factors have limited its routine clinical use despite its potential benefits in raising tolerance thresholds.

Recent studies have highlighted that OIT is most effective in controlled research settings, where desensitisation rates for peanut, egg, and milk allergies range between 60% and 80%. However, this desensitisation is not equivalent to a cure, as patients must continue regular exposure to maintain their tolerance, and many remain at risk of reactions if they discontinue therapy.

The concept of sustained unresponsiveness—where a patient can stop treatment temporarily without losing tolerance—has been explored, but data is still limited, with only 30-70% of patients achieving this outcome in peanut and milk OIT trials. The variability in protocols, dosing, and patient responses further complicates its broader application.

One of the most significant recent advancements is approval of Palforzia, a standardised peanut OIT product, for children aged 4-17. This marks a step towards more regulated OIT practices, but its use is still restricted to specialised hospital settings due to safety concerns.

Despite this progress, many allergists remain cautious, as real-world efficacy—particularly in preventing severe reactions from accidental exposures—has not been definitively established. Moreover, the logistical challenges of OIT, including frequent medical visits, strict home monitoring, and long-term commitment, make it impractical for many families.

For patients with mild oral symptoms related to pollen-food cross-reactivity (Oral Allergy Syndrome or Pollen-Food Allergy Syndrome), allergen immunotherapy (AIT) for their primary respiratory allergies—such as birch pollen—can sometimes alleviate their food-related symptoms.

This occurs because the immune modulation from immunotherapy may reduce cross-reactive responses to structurally similar proteins in certain fruits and vegetables. However, this improvement is not guaranteed, and many patients still need to avoid raw forms of trigger foods even after successful pollen immunotherapy.

Emerging alternatives to OIT, such as anti-IgE, have shown promise in recent trials. A 2025  study demonstrated that  a monoclonal antibody targeting IgE, was more effective and better tolerated than multi-allergen OIT in patients with highly sensitive food allergies.

The study found that anti-IgE treatment allowed a higher proportion of participants to safely consume small amounts of multiple allergens without severe reactions, highlighting its potential as a safer alternative for those with severe allergies.

While OIT represents a significant scientific advancement, its clinical use remains limited by safety concerns, logistical challenges, and the need for further research. Strict avoidance and emergency preparedness remain the cornerstone of food allergy management.

For those with pollen-related oral symptoms, treating the underlying respiratory allergy might offer some relief, though dietary modifications are often still necessary. Ongoing research into biologics like anti-IgE may provide safer and more effective options in the near future.

HOW IS IT DONE? Specific immunotherapy can be administered in several ways: 

Subcutaneous immunotherapy (SCIT), commonly known as allergy shots, was an initially established method with over a century of clinical use. It typically involves weekly injections during the initial buildup phase, lasting three to four months, followed by monthly maintenance injections for three to five years.

Multiple studies emphasise that SCIT is highly effective for allergic rhinitis, asthma, and insect venom allergies, with long-term benefits persisting after treatment cessation. However, its use requires careful monitoring due to the risk of systemic reactions, such as anaphylaxis, require administered under careful clinical supervision in a hospital setting.

Sublingual immunotherapy (SLIT) has gained broader acceptance as a safer and more convenient alternative, particularly for patients who prefer avoiding injections. Administered daily under the tonuge, SLIT is self-administered at home after an initial supervised dose.

Allergy treatment SLIT

Recent research confirms its efficacy for grass pollen, house dust mite, particularly in reducing symptoms and medication use. Unlike SCIT, SLIT rarely causes severe systemic reactions, making it suitable for children and adults.  Monthly monitoring is recommended to ensure compliance.

Experimental routes like intralymphatic and epicutaneous immunotherapy continue to be investigated but are not yet part of routine clinical practice. Intralymphatic immunotherapy, which involves injecting allergens directly into lymph nodes, has shown promise in early trials for reducing the number of required doses while maintaining efficacy.

Similarly, epicutaneous immunotherapy (applying allergens via skin patches) offers a needle-free option, particularly for peanut allergy, but remains under study. These methods aim to improve safety and convenience but require further validation before widespread adoption.

The composition of allergen vaccines varies significantly between manufacturers, with differences in allergen extracts, dosing, and additives. This means products are not interchangeable, and switching brands mid-treatment is generally avoided. Regulatory standards also differ between regions—for example, the US has stricter requirements for standardisation compared to European agencies, leading to variations in available treatments. 

The treatment (allergen vaccines) from different manufactures are not interchangeable, Although the main component of any vaccine is allergen its dose and preservative components are different for each manufacturer. Vaccines (and treatment approach) in the US are absolutely different comparing to vaccines used in European Countries and Great Britain.

Emerging strategies combine immunotherapy with biologics like anti-IgE to enhance safety and efficacy, particularly for severe or multi-allergic patients. Trials have shown that pre-treatment with anti IgE can reduce adverse reactions during immunotherapy, allowing for faster dose escalation.

Additionally, research into peptide-based vaccines and adjuvants seeks to improve immune modulation. These innovations could reshape this method in the coming years, offering more personalised options.

While SCIT use is decreasing in favour of SLIT, the method remain the cornerstones of allergen immunotherapy, ongoing research is refining the protocols and exploring novel delivery methods. The treatment demonstrates robust long-term benefits for appropriately selected individuals. Experimental routes and adjunctive therapies hold promise but are not yet ready for routine use. 

 
DURATION As the treatment is long term and the minimum duration is three years it needs to be thought through carefully before the start as it is difficult in some countries to find highly qualified specialist to continue your treatment. Our centre participates in Global Allergy Network can help people who are already on treatment and those who just think to start.
 

ALLERGENS (VACCINESSwitching allergen vaccines between manufacturers during treatment is strongly discouraged due to differences in allergen extracts, standardisation methods, and formulations. Each manufacturer uses unique processing techniques, allergen concentrations, and additives, making their products biologically distinct. Even if the active allergen is the same, variations in potency or composition can affect treatment efficacy and safety.

For instance, European vaccines often include modified allergens (allergoids) or adjuvants like aluminium hydroxide, while US formulations typically use unmodified aqueous extracts. These differences mean that switching vaccines mid-treatment could disrupt immune tolerance or trigger adverse reactions, so, if possible, sticking to one product throughout the course is recommended.

The effectiveness of AIT can vary depending on whether a patient is mono-sensitised (allergic to one allergen) or poly-sensitised (allergic to multiple allergens). Early treatment for mono-sensitised individuals tends to lead to better outcomes, as the immune system can focus on building tolerance to a single trigger. In contrast, poly-sensitised patients may experience reduced efficacy, particularly if their allergies have progressed over time.

However, recent studies suggest that tailored approaches, such as targeting the most clinically relevant allergens or using molecular allergology to identify key triggers, can improve results even in poly-sensitised cases. For example, component-resolved diagnostics can help pinpoint which allergens drive symptoms, allowing for more precise vaccine formulations.

A notable difference between the US and European approaches lies in how allergens are combined. In the US, it’s common to mix multiple allergen extracts into a single vaccine, especially for polysensitised patients. This practice is based on the idea that simultaneous exposure can induce broader tolerance.

However, European guidelines generally advise against mixing, as combining extracts can dilute individual allergen doses and reduce efficacy. Instead, European allergists prefer administering allergens separately or using homologous groups (e.g., related pollens) to maintain optimal dosing.

Emerging technologies are refining allergen vaccines, with recombinant allergens and peptide-based formulations showing promise. These innovations aim to improve standardisation and reduce side effects by using purified or engineered allergens rather than crude extracts.

For instance, recombinant hypoallergens—modified versions of natural allergens that provoke fewer IgE-mediated reactions—are being tested in clinical trials. Additionally, adjuvants like monophosphoryl lipid A (MPL) or virus-like particles (VLPs) are being explored to boost immune modulation without increasing allergenicity. While these advances are for reserach use and are not yet mainstream, they represent a shift toward more personalised and effective treatment options.

Maintaining consistency with a single manufacturer’s vaccine throughout treatment remains critical due to product variability. Early intervention for mono-sensitised patients tends to give the best results, though poly-sensitised individuals can still benefit from carefully tailored approaches. 

Referrence:

  1. Larché, M. (2000). Immunoregulation by CD4+ T cells in allergy. British Medical Bulletin, 56(4), 1034–1048. https://doi.org/10.1258/0007142001903287

  2. Boquete, M., Carballada, F., Expósito, F., & González, A. (2000). Specific immunotherapy in monosensitized and polysensitized patients with respiratory allergy. Allergologia et Immunopathologia, 28(3), 89–93. https://doi.org/10.1016/S0301-0546(00)79007-4

  3. Wang, H. Y., Lin, X. P., Hao, C. L., Zhang, C. Q., Sun, B. Q., Zheng, J. P., Chen, P., Sheng, J. Y., Wu, A., & Zhong, N. S. (2006). A multicenter epidemiological study on childhood asthma in China. Zhonghua Jie He He Hu Xi Za Zhi, 29(10), 679–687. (Chinese Journal of Tuberculosis and Respiratory Diseases)

  4. Cools, M., Van Bever, H. P., Weyler, J. J., & Stevens, W. J. (2000). Risk factors and prevalence of allergic sensitization in Flemish schoolchildren. Allergy, 55(1), 69–73. https://doi.org/10.1034/j.1398-9995.2000.00291.x

  5. Wood, R. A., Chinthrajah, R. S., et al. (2025). Treatment of multi-food allergy with omalizumab compared to omalizumab-facilitated multi-allergen OIT. Journal of Allergy and Clinical Immunology, 155(2), AB444. https://doi.org/10.1016/j.jaci.2024.12.1022

  6. Dantzer, J. A., et al. (2025). Long-term outcomes of omalizumab in multi-food allergy treatment: Post-discontinuation food reintroduction. Journal of Allergy and Clinical Immunology, 155(2), AB445.

  7. Yang, J., & Lei, S. (2023). Efficacy and safety of sublingual versus subcutaneous immunotherapy in children with allergic rhinitis: A systematic review and meta-analysis. Frontiers in Immunology, 14, 1274241. https://doi.org/10.3389/fimmu.2023.1274241

  8. Muraro, A., Roberts, G., et al. (2018). EAACI guidelines on allergen immunotherapy: Executive statement. Allergy, 73(4), 739–743. https://doi.org/10.1111/all.13420

  9. Pfaar, O., Devillier, P., et al. (2023). Adherence and persistence in allergen immunotherapy (APAIT): A reporting checklist for retrospective studies. Allergy, 78(8), 2277–2289. https://doi.org/10.1111/all.15723

  10. Cherrez-Ojeda, I., Zuberbier, T., Rodas-Valero, G., Sánchez, J. M., Rudenko, M., Dramburg, S., Demoly, P., Caimmi, D., Gómez, R. M., Ramón, G. D., Fouda, G. E., Quimby, K. R., Chong-Neto, H., Calderón Llosa, O., Larco, J. I., Monge Ortega, O. P., Faytong-Haro, M., Pfaar, O., Bousquet, J., & Robles-Velasco, K. (2024). Evaluation of the quality and reliability of ChatGPT-4’s responses on allergen immunotherapy using validated tools. https://doi.org/10.22541/au.173538245.59171682/v1

 

Allergen Immunotherapy Module

The Allergen Immunotherapy Module, developed by leading experts in the field, offers both foundational and advanced insights into how AIT works to build immune tolerance and improve outcomes for allergic patients. The module emphasises a personalised approach, combining modern diagnostic tools like molecular IgE testing with digital health solutions such as mobile apps and e-diaries to tailor treatments more effectively.

Recent advances highlighted in the module include the growing use of predictive biomarkers to identify which patients are most likely to respond well to AIT. Research from the past three years has strengthened the understanding of immune mechanisms behind both sublingual (SLIT) and subcutaneous (SCIT) immunotherapy, including how they modify T-cell responses and promote long-term tolerance. The module also explores emerging trends, such as the integration of biologics like omalizumab with AIT to enhance efficacy, particularly in complex or severe allergy cases.

The course features three comprehensive lectures delivered by distinguished specialists. Professor Paolo Matricardi, an immunologist renowned for his work on asthma and allergy biomarkers, contributes his expertise on precision medicine in AIT. Professor Marek Jutel, a key figure in allergology, discusses clinical applications and the latest evidence on SLIT and SCIT protocols. Professor Mohamed Shamji, a leading researcher in AIT mechanisms, focuses on the immunological changes driving successful treatment outcomes.

This educational resource is designed for healthcare professionals seeking to optimise AIT in clinical practice, incorporating the latest research on personalised dosing, patient stratification, and real-world monitoring through digital tools. By blending cutting-edge science with practical guidance, the module aims to improve patient care through more targeted and effective immunotherapy strategies.

Challenges in allergy diagnosis and treatment in 2022 – Paolo M. Matricardi

How AIT offers a personalized patients management approach – Marek Jutel

Molecular diagnosis in respiratory allergies and its clinical relevance – Mohamed Shamji

Mechanistic Insights into Allergen Immunotherapy (AIT)

IL-10–Producing Innate Lymphoid Cells (ILC2s)

Recent research has identified a specific type of immune cell, the IL-10–producing type 2 innate lymphoid cell (ILC2-IL-10+), as a crucial regulator of allergic inflammation. These cells are now understood to contribute significantly to the clinical improvements seen with both sublingual (SLIT) and subcutaneous (SCIT) immunotherapy.

  • A key study demonstrated that both grass-pollen SCIT and SLIT restore the ability of ILC2s to produce IL-10. This occurs after the cells are stimulated with a combination of IL-2, IL-7, IL-33, and retinoic acid (RA).

  • In a clinical trial for grass-pollen SLIT, patients showed a marked increase in IL-10-producing ILC2s after 12 and 24 months of treatment. Importantly, the frequency of these cells was inversely correlated with the severity of nasal symptoms—the more of these cells present, the milder the symptoms.

  • Advanced genetic analysis (scCITE-seq) revealed that in SLIT-treated individuals, ILCs exhibit increased activity in retinol metabolism pathways (involving genes like RDH10 and ALDH1A2), JAK-STAT signalling components, and IL-10 receptors.

Regulatory T and B Cells, and TFH/TFR Dynamics

  • AIT is known to boost the populations of T regulatory (Treg), inducible Treg, and IL-10–producing T cells, both locally at the site of allergy and throughout the body. These increases are consistently correlated with better clinical outcomes.

  • B regulatory cells (Bregs) are also upregulated by AIT. These cells produce IL-10 and other regulatory mediators like IL-35 and TGF-β, and they help to promote protective IgG4 ‘blocking’ antibody responses.

  • Concerning follicular helper T cells (Tfh), both SLIT and SCIT induce special regulatory subsets: follicular regulatory T cells (Tfr) and IL-10–producing Tfh cells. This occurs alongside a suppression of the conventional, pro-inflammatory Tfh subsets.

Antibody Responses, Epithelial Restoration, and Epigenetic Regulation

  • It is well established that SCIT shifts antibody profiles towards the protective IgG4 isotype. In contrast, SLIT (and other routes) may preferentially induce IgA and IgG responses. The specific dynamics between IgA1 and IgG4 align with current scientific understanding.

  • While direct evidence on epithelial barrier restoration and changes in chromatin accessibility within TFH/TFR cells is still emerging, the overall mechanistic narrative supports the consensus: AIT works by reshaping both mucosal barrier function and the regulation of the adaptive immune response.

Overall Conclusion and Future Directions

These findings confirm that integrating multi-modal data—from clinical scores and immune profiling to serology and advanced multi-omics—is essential for refining predictive biomarkers and improving patient stratification.

Key supported highlights include:

  • The restoration of IL-10–producing ILC2s serves as both a marker for and an active mediator of successful specific immunotherapy (SIT).

  • The dynamics of regulatory lymphocytes (Tregs, Bregs, Tfr) are fundamental to establishing long-term immune tolerance.

  • A recognised gap remains in the direct epigenomic profiling of TFH/TFR subsets following SIT.


Summary of Recent Clinical Research

  1. IL-10-Producing ILC2s & AIT (Grass-Pollen Trial)

    • Title: *Induction of IL-10-producing type 2 innate lymphoid cells by allergen immunotherapy is associated with clinical response*

    • Findings: This study, published in Immunity, demonstrates that grass-pollen sublingual immunotherapy restores a population of KLRG1⁺ ILC2s that produce IL-10. This restoration is linked to clinical improvement and involves retinol metabolism, cytokine-receptor interactions, and JAK-STAT signalling pathways.

  2. Single-Cell RNA-Seq in SLIT (Japanese Cedar Pollinosis)

    • Title: Single-cell immunoprofiling after immunotherapy for allergic rhinitis…

    • Findings: Using single-cell RNA sequencing, this study analysed the immune response in Japanese cedar pollinosis before and after SLIT. It revealed detailed clonal dynamics among TH2 and regulatory T cells and identified musculin (MSC) as a potential biomarker for patients who respond well to treatment.

  3. Tolerogenic Pathways in Grass-Pollen AIT

    • Title: Single-cell RNA sequencing identifies precise tolerogenic cellular and molecular pathways induced by depigmented-polymerised grass pollen allergen extract

    • Findings: This research employed scRNA-Seq to map the precise mechanisms of a grass-pollen allergoid AIT. It provided detailed profiles of T<sub>H</sub>2A, Tfh, and IL-10⁺ regulatory B cells induced by the treatment.

  4. & 5. Comprehensive Reviews

    • Titles: Mechanisms of Allergen Immunotherapy in Allergic Rhinitis and Mechanisms and biomarkers of successful allergen-specific immunotherapy

    • Findings: These reviews synthesise current knowledge, discussing the role of IL-10-producing ILCs, the epithelial barrier, and regulatory B and T cells. They emphasise the growing need for personalised biomarkers to predict treatment success across various IgE-mediated allergies.

 
 
 
 
 
 

 

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