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 Table of Contents  
REVIEW ARTICLE
Year : 2018  |  Volume : 32  |  Issue : 2  |  Page : 43-46

Future modalities in allergen immunotherapy: A brief overview


Department of Respiratory Medicine, School of Medical Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, India

Date of Web Publication12-Oct-2018

Correspondence Address:
Dr. S N Gaur
Department of Respiratory Medicine, School of Medical Sciences and Research, Sharda University, Knowledge Park-III, Greater Noida - 201 306, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijaai.ijaai_20_18

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  Abstract 

Allergen immunotherapy (AIT) is the only disease-modifying modality for the treatment of allergic diseases. The well-known and approved formulations are subcutaneous immunotherapy (SCIT), sublingual immunotherapy (SLIT) and allergoids. The drawbacks of the conventional AIT such as the risk of anaphylaxis led to the development of allergoids, Future approaches in AIT may permit (1) shorter treatment regimens, (2) improved safety, (3) improved compliance and (4) newer indications for AIT, which are discussed in the article.

Keywords: Allergen immunotherapy, allergoids, subcutaneous immunotherapy, sublingual immunotherapy


How to cite this article:
Gaur S N. Future modalities in allergen immunotherapy: A brief overview. Indian J Allergy Asthma Immunol 2018;32:43-6

How to cite this URL:
Gaur S N. Future modalities in allergen immunotherapy: A brief overview. Indian J Allergy Asthma Immunol [serial online] 2018 [cited 2018 Nov 13];32:43-6. Available from: http://www.ijaai.in/text.asp?2018/32/2/43/243227


  Introduction Top


Allergen immunotherapy (AIT) is the only disease-modifying modality for the treatment of allergic diseases and has been utilized for >100 years. Among the well-known and approved formulations are subcutaneous immunotherapy (SCIT), sublingual immunotherapy (SLIT) and allergoids. Improvements in AIT are warranted because the current protocols SCIT and SLIT are associated with long treatment duration and allergic side effects. As a result, a limited number of patients opt for AIT over symptomatic therapies and furthermore the treatment adherence is low.[1] The drawbacks of the conventional AIT such as the risk of anaphylaxis led to the development of allergoids, which are associated with improvements in safety, clinical efficacy, and dosing convenience. Thereby, they have been accepted as the preferred form of SCIT in Europe. Currently, in India, conventional aqueous SCIT is the accepted form of AIT. An editorial on allergoids was published in the last edition of this journal.[2]

Future approaches in AIT may permit such as: (1) shorter treatment regimens, (2) improved safety, (3) improved compliance, and (4) newer indications for AIT.

Briefly, the future approaches have been summarized in [Figure 1].
Figure 1: Future approaches in allergen immunotherapy

Click here to view


New routes of allergen immunotherapy

Oral immunotherapy

“Oral immunotherapy (OIT) involves mixing an allergenic food into a vehicle and consuming it in gradually increasing doses.”[3] The induction of desensitization to food allergens such as milk, egg, and peanut has been observed in clinical trials.

Dosing protocols of OIT include three phases as follows: (1) escalation phase– done in one or more days starting from subthreshold doses which are rapidly increases, (2) dose build-up phase – usually done at homes and the dose is up-dosed biweekly or weekly, and (3) maintenance phase – may extend from months to years.

The drawbacks of the current OIT protocols are as follows:[3]

  • Disease-modifying effect is not proven
  • Adverse reactions are common, and it has low tolerability
  • Time and labor intensive
  • Requiring close monitoring and involvement of physicians and family members.


Epicutaneous immunotherapy

In epicutaneous immunotherapy (EPIT), allergen is administered to the nonvascularized epidermis thereby reducing the risk of the allergen reaching the vasculature and therefore improving the safety.[1] The rationale for selecting EPIT as a route is that a high numbers of antigen presenting cells are present in the skin.[4] In EPIT, the keratinocytes can be activated which increases the immunogenicity.[1]

Clinical trials with EPIT have documented the clinical efficacy for aeroallergens (grass pollen) and a trend toward improvement for cow's milk food allergy. The trial for cow's milk food allergy showed that EPIT was well tolerated with no systemic anaphylactic reactions, but a significant increase of local eczematous skin reactions was observed.[1]

Current limitations of EPIT are as follows:[1]

  • Allergen dose used in skin patches cannot readily be increased beyond a certain concentration
  • Cost
  • Application to any accidentally impaired skin barrier would represent a considerate risk for systemic allergic effects.


Intralymphatic immunotherapy

In intralymphatic immunotherapy (ILIT), allergens are injected directly into the inguinal lymph nodes under ultrasound guidance.[4] The concept of ILIT is attractive as the allergen dose delivered into the lymph nodes is 100 times more as compared to the other routes.[1] Furthermore, the concentration of allergen in the lymph node is of importance as interaction of antigen-presenting dendritic cells, T cell and B cells (which are responsible for the immune response) is more likely here because of a high concentration of these cells in the lymph nodes.[1]

Evaluations of ILIT have been undertaken for aeroallergens (birch, grass, dust mites, cat, and dog allergy), bee venom, and food allergen (ovalbumin).[1],[5],[6] The efficacy of ILIT has been demonstrated in clinical and nonclinical studies.[1] The positive clinical studies used a 4-week interval between the injections, while one study with a 2-week interval revealed no clinical improvement.[1] Advantages of ILIT include – lesser number of injected doses, long-lasting efficacy with minimal injections, enhanced patient compliance and has shown to be well tolerated.[1],[6] However, higher rates of systemic reactions have been reported in one human study of 11 patients receiving ILIT, 2 cases of anaphylaxis, 1 case of a moderate-to-severe systemic hypersensitivity reaction, and one of a large local reaction at the injection site were reported.[5]

Current limitations of ILIT are as follows:[5],[7]

  • Adverse reactions can be precipitated due to leakage of allergens from the lymph node
  • Evidence has been generated for a limited number of allergens
  • Limited knowledge on efficacy, safety, and mechanism of action.


New formulations of allergen immunotherapy

Allergoids

The term “allergoid” has been used “to denote an allergen derivative for which the residual allergenic reactogenicity relative to the native allergen has been significantly reduced, while the original antigenic properties (both immunogenic and reactogenic) have been retained to a high degree.”[8] The principle of allergoids are that:[9]

  1. They possess less reactive B-cell epitopes and thus reduced IgE binding (i.e., improved safety)
  2. They retain T-cell epitopes, and their immunogenic effect remains unaltered (i.e., retained efficacy).


The advantages of allergoids include improved safety profile and being depot preparations; they are associated with a convenient dosing schedule. In a large real-world survey, it has been documented that allergoids contribute to approximately 50% of the total SCIT preparations.[10] Allergoid preparations have been studied for house dust mite and pollen allergens.

Peptides

In peptide immunotherapy, short soluble synthetic peptides containing the immunodominant T-cell epitopes of major allergen proteins are used.[11] The selection of peptides for AIT is based on the following two principles:

  1. Lacking the ability to cross-link IgE molecules
  2. Retaining the ability to be recognized by and modulate allergen-specific T cells.


Peptide immunotherapy is being developed for the treatment of allergic and autoimmune diseases where pathogenesis is T-cell dependent.[12] The advantages of peptide immunotherapy include a short treatment durations and improved safety.[12] Peptide immunotherapy has been most studied for cat allergy. While the earlier studies showed a beneficial effect,[11],[12] a recently held phase III study did not meet the primary endpoint.[13] This phase III study had a large placebo effect, similar to that of the active treatment group.

Contiguous overlapping peptides

An investigational molecule for the treatment of birch pollen-induced rhinitis/rhinoconjunctivitis has been investigated in studies. This molecule contains three overlapping 49–71 amino acid peptides and has no ability to form the original Bet v 1 (major allergen of birch pollen) three-dimensional structure.[11] The advantage of these long peptides have markedly reduced IgE binding and did not induce anaphylaxis in sensitized mice. However, in human trials, they were associated with WAO grade 3 systemic reactions. These reactions are likely to be T-cell mediated rather than IgE-dependent anaphylaxis as they occurred between 4 and 6 h after injection.[11]

Recombinant allergens

As the molecular allergy has progressed, most major allergen components of common inhalants with important implications have been characterized. The examples of dominant major allergens include:

  1. Phl p 1 and Phl p 5 in Grass Pollen
  2. Bet v 1 in Birch Pollen.


The objective of using recombinant allergens for AIT is that allow tailor-made immunotherapy for individuals, which will not induce novel sensitizations to irrelevant allergens found in extracts.[11] Recombinant allergens in AIT have been studied mainly for grass and birch pollen.

Recombinant allergens either singly such as Bet v 1 or as the relevant recombinant grass allergen mixture (Phl p 1, Phl p 2, Phl p 5a, Phl p 5b, Phl p 6) have been shown to be highly effective in randomized controlled trials.[11]

An advantage of the recombinant allergen Bet v 1 used in clinical trial is that could be administered in higher doses than the native protein with no increase in adverse effects.[14]

Furthermore, in addition to unmodified recombinant allergens, hypoallergenic variants with lower IgE reactivity can also be produced; proof of concept has been demonstrated for both these concepts in clinical trials.[15]

New combination with allergen immunotherapy

Omalizumab plus allergen immunotherapy

Omalizumab is approved for the treatment of asthma and chronic idiopathic urticaria, however, it has also been used as an off-label treatment as an adjunct to AIT. A recent article has reviewed the published literature on the use of omalizumab along with AIT for the treatment of allergic rhinitis, asthma, venom hypersensitivity, and food allergy.

In respiratory allergies, the addition of omalizumab as an adjunct or as pretreatment to AIT can have a greater reduction in AR symptom scores than AIT monotherapy and decreases but does not eliminate, adverse events, including during rush or cluster protocols. The authors further noted that “While it is unlikely that omalizumab will be approved as a routine adjunctive treatment for inhalant AIT, this information may be applied to clinical practice for patients who have been prescribed omalizumab for asthma or urticaria. For example, while a patient with severe or unstable asthma may not be a suitable candidate for AIT, this could become a viable and important treatment option once treated with omalizumab.”[16]

For venom immunotherapy, most of the available case reports have shown that the addition of omalizumab (as pretreatment and/or maintenance) led to a decrease in the risk of systemic reactions during venom immunotherapy. Some reports did not document a benefit of the addition of omalizumab to venom immunotherapy.[16]

In food allergies, the use of omalizumab with food OIT led to a decrease in:[16]

  • Time required to reach maintenance dosing and
  • Adverse events.


It should, however, be noted that currently, the addition of omalizumab as an adjunct to AIT is not an approved indication.


  Conclusion Top


Innovation in the field of allergy and AIT has led to the development of future approaches in AIT that include:

  1. New routes of AIT
  2. New formulations of AIT and
  3. New combination with AIT.


These approaches are in various stages of clinical development. The development of certain approaches looks optimistic; however, some have been kept on hold based on the currently available literature.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Senti G, Kündig TM. Novel delivery routes for allergy immunotherapy: Intralymphatic, epicutaneous, and intradermal. Immunol Allergy Clin North Am 2016;36:25-37.  Back to cited text no. 1
    
2.
Gaur SN. Allergoid preparations for allergen immunotherapy: A brief overview. Indian J Allergy Asthma Immunol 2018;32:1-3.  Back to cited text no. 2
  [Full text]  
3.
Burbank AJ, Sood P, Vickery BP, Wood RA. Oral immunotherapy for food allergy. Immunol Allergy Clin North Am 2016;36:55-69.  Back to cited text no. 3
    
4.
Casale TB, Stokes JR. Immunotherapy: What lies beyond. J Allergy Clin Immunol 2014;133:612-9.  Back to cited text no. 4
    
5.
Kim ST, Park SH, Lee SM, Lee SP. Allergen-specific intralymphatic immunotherapy in human and animal studies. Asia Pac Allergy 2017;7:131-7.  Back to cited text no. 5
    
6.
Creticos PS. Allergen immunotherapy: Vaccine modification. Immunol Allergy Clin North Am 2016;36:103-24.  Back to cited text no. 6
    
7.
Senti G, Kündig TM. Intralymphatic immunotherapy. World Allergy Organ J 2015;8:9.  Back to cited text no. 7
    
8.
Marsh DG, Lichtenstein LM, Campbell DH. Studies on “allergoids” prepared from naturally occurring allergens. I. Assay of allergenicity and antigenicity of formalinized rye group I component. Immunology 1970;18:705-22.  Back to cited text no. 8
    
9.
Pfaar O, Bachert C, Bufe A, Buhl R, Ebner C, Eng P, et al. Guideline on allergen-specific immunotherapy in IgE-mediated allergic diseases: S2k Guideline of the German Society for Allergology and Clinical Immunology (DGAKI), the Society for Pediatric Allergy and Environmental Medicine (GPA), the Medical Association of German Allergologists (AeDA), the Austrian Society for Allergy and Immunology (ÖGAI), the Swiss Society for Allergy and Immunology (SGAI), the German Society of Dermatology (DDG), the German Society of Oto-Rhino-Laryngology, Head and Neck Surgery (DGHNO-KHC), the German Society of Pediatrics and Adolescent Medicine (DGKJ), the Society for Pediatric Pneumology (GPP), the German Respiratory Society (DGP), the German Association of ENT Surgeons (BV-HNO), the Professional Federation of Paediatricians and Youth Doctors (BVKJ), the Federal Association of Pulmonologists (BDP) and the German Dermatologists Association (BVDD). Allergo J Int 2014;23:282-319.  Back to cited text no. 9
    
10.
Calderón MA, Vidal C, Rodríguez Del Río P, Just J, Pfaar O, Tabar AI, et al. European survey on adverse systemic reactions in allergen immunotherapy (EASSI): A real-life clinical assessment. Allergy 2017;72:462-72.  Back to cited text no. 10
    
11.
Hoffmann HJ, Valovirta E, Pfaar O, Moingeon P, Schmid JM, Skaarup SH, et al. Novel approaches and perspectives in allergen immunotherapy. Allergy 2017;72:1022-34.  Back to cited text no. 11
    
12.
Simms E, Syed I, Rudulier C, Larche M. Peptide Immunotherapy; short but long lasting? Curr Treat Options Allergy 2015;2:64-71.  Back to cited text no. 12
    
13.
Circassia. Circassia Announces Top-Line Results from Cat Allergy Phase III Study. Available from: https://www.circassia.com/media/press-releases/circassia-announces-top-line-results-from-cat-allergy-phase-iii-study/. [Last accessed on 2018 Jul 16].  Back to cited text no. 13
    
14.
Klimek L, Bachert C, Lukat KF, Pfaar O, Meyer H, Narkus A. Allergy immunotherapy with a hypoallergenic recombinant birch pollen allergen rBet v 1-FV in a randomized controlled trial. Clin Transl Allergy 2015;5:28.  Back to cited text no. 14
    
15.
Nandy A, Creticos PS, Häfner D. Recombinant allergens in specific immunotherapy. In: Kleine-Tebbe J, Jakob T, editors. Molecular Allergy Diagnostics. Cham: Springer; 2017.  Back to cited text no. 15
    
16.
Dantzer JA, Wood RA. The use of omalizumab in allergen immunotherapy. Clin Exp Allergy 2018;48:232-40.  Back to cited text no. 16
    


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