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EDITORIAL
Year : 2018  |  Volume : 32  |  Issue : 1  |  Page : 1-3

Allergoid preparations for 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 Publication6-Mar-2018

Correspondence Address:
Prof. S N Gaur
Department of Respiratory Medicine, School of Medical Sciences and Research, Sharda University, Greater Noida,Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijaai.ijaai_37_17

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How to cite this article:
Gaur S N. Allergoid preparations for allergen immunotherapy: A brief overview. Indian J Allergy Asthma Immunol 2018;32:1-3

How to cite this URL:
Gaur S N. Allergoid preparations for allergen immunotherapy: A brief overview. Indian J Allergy Asthma Immunol [serial online] 2018 [cited 2018 May 26];32:1-3. Available from: http://www.ijaai.in/text.asp?2018/32/1/1/226702

Allergen immunotherapy (AIT) is now a well-established therapy for allergic diseases by modifying the natural course of disease and changing the Th2 reaction toward Th1. Thus, AIT is a disease-modifying and clinically effective therapy for the treatment of allergic diseases.[1] The first successful human trial of subcutaneous immunotherapy (SCIT) is credited to Leonard Noon, a British physician who published his results in 1911.[2] Over the last 50 years, numerous controlled studies, systematic reviews, and meta-analysis have shown the efficacy of SCIT in the treatment of allergic asthma and rhinitis.[1] The efficacy of SCIT is a dose-dependent phenomenon; SCIT is ineffective at low doses while high doses of allergen extracts increase, to some extent, the risk of systemic reactions.[3]

Attempts for modifications in AIT for the improvement in safety profile but maintaining the efficacy were being conducted in the world. The concept of allergoids was developed in the 1970s with the aim to improve the safety and efficacy of AIT.[4] This was achieved by producing allergoids that have reduced allergenicity but retained immunogenicity.[5] These properties allow allergoids to be used at high doses, with shorter up-dosing periods along with the improvements in safety and efficacy of SCIT. The allergoids have become a mainstay in AIT and have been used extensively in the European countries. Up to 50% of SCIT prescriptions in Europe are of allergoids. Allergoid preparations are available for house dust mites, grass pollen, and trees. In this editorial, we review the hypoallergenic principle described for allergoid preparations and their clinical utility.


  Allergoids Top


The term “allergoid” was used by Marsh et al. “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.”[6] The concept is that allergoids possess less reactive B-cell epitopes and thus reduced IgE binding (i.e., improved safety), while their T-cell epitopes and their immunogenic effect remain unaltered (i.e., retained efficacy).[7]


  Preparation and Composition of Allergoids Top


Allergoids are prepared by chemical modification of the allergen extracts using formaldehyde and/or glutaraldehyde. In the United States, formaldehyde was used to generate allergoids while the first European formulations were prepared with glutaraldehyde.[4] Allergoids may also be produced using carbamylation.[7] Carbamylated allergoids are primarily available for sublingual preparations. In addition, allergoids are then adsorbed to a carrier, such as aluminum hydroxide, tyrosine, or calcium phosphate to produce a depot preparation.[7] The depot preparations facilitate slow release presentation of the allergen.[8]


  Allergenicity of Allergoids Top


The most characteristic feature of allergoids is that they are less allergenic (i.e., have a lower IgE reactivity) than natural allergen preparations.[5] This property is ascribed to the reduced B-cell epitopes in allergoids.[7]In vitro experiments have documented reduced allergenicity of allergoids on the enzyme allergosorbent inhibition test which showed 100–1000-fold reduced allergenicity and also on the more functional assay, the basophil activation test.[5] In addition, allergoids have proved their reduced allergenicity on the skin prick tests.[5] Based on this characteristic, the safety profile of allergoids seems to be better compared to the natural aqueous extracts.


  Immunogenicity/antigenicity of Allergoid Top


The ability of allergoids to induce an immune response has been verified as allergoids have led to the induction of the immunomodulatory IgG4 antibodies in numerous clinical trials.[5] The immunogenic potential of allergoids is well recognized.[7] Based upon this characteristic, it is assured that the efficacy of the extracts is retained.


  Efficacy of Allergoids Top


The efficacy of allergoids have been documented for house dust mites, grass pollen, and birch pollen.[5]

In a randomized clinical trial conducted in children with mild persistent asthma, the house dust mite allergoid demonstrated a steroid-sparing effect with a significant reduction in the dose of inhaled corticosteroids needed for asthma control and improved the lung function after 2 years of therapy.[9] The mean daily dose of fluticasone propionate in the immunotherapy group decreased from 330.3 μg in the baseline period to 151.5 μg, whereas in the control group, the dose decreased from 290.6 to 206.3 μg. In addition, immunotherapy with the allergoid resulted in significant improvements in the morning peak expiratory flow (P = 0.0315) as compared to the control group.[9] The house dust mite allergoid has also shown improvements in quality of life,[10] cost-savings as compared to conventional pharmacotherapy,[11] better compliance as compared to unmodified allergen extracts,[12] and improvements in patient-perceived symptoms.[13]

Grass pollen allergoid has demonstrated efficacy in nasal and bronchial allergy in the first pollen season and the maintenance of efficacy in the second and third pollen seasons.[5] The grass pollen allergoid has also shown a disease-modifying effect. In a prospective controlled study with 12-year follow-up data, there was a significant reduction (P< 0.05) in the number of patients developing new sensitizations as compared to the control group. In addition, there was a trend of lower seasonal asthma in the posttreatment years (12-year follow-up) as compared to the control group.[14] This study also demonstrated that the total hay fever symptom score (P< 0.03), use of medication (P< 0.05), and combined symptom and medication score (P< 0.03) remained lower in patients treated with grass pollen allergoid when compared with the control group.[14]


  Safety of Allergoids Top


The advantageous safety profile of allergoids allows for usage of allergoids in a clinically effective dose and without increasing the risk of adverse events. In general, the allergoid preparations show rare incidences of “severe systemic side effects:” The German Regulatory Authorities (Paul Ehrlich Institute) has published the rates of 0.0005%–0.01% per injection.[5]

In a recently published prospective, longitudinal, web-based survey of “real-life” respiratory AIT in 4316 patients, the safety profile of allergoids was significantly better as compared to natural allergen extracts (P = 0.001). Patients receiving allergoids in SCIT had a significantly lesser chance of developing a systemic reaction in comparison to the natural extracts.[15]

The main reason for allergoids preparations not to be used earlier was due to few side effects reported with the allergoids allergen extracts, mainly due to additives such as aluminum hydroxide, aldehydes, and phenol. Now, the clinically effective dose schedule for additives is regulated and is practically safe. Therefore, it is recommended that the composition of the adjuvants and residual products such as aldehydes and aluminum hydroxide should be in the permissible limits as per the European Pharmacopoeia. Thus, the use of aluminum hydroxide as adjuvant in products for specific immunotherapy is regulated in the European Pharmacopoeia. Now, no safety concerns have resulted from the use of aluminum hydroxide in AIT using allergoid preparations.[16]


  Dosing Schedule of Allergoids Top


Immunotherapy involves an up-dosing phase and a maintenance phase. The up-dosing phase of natural AIT extracts can extend up to 4–6 months (16–24 weeks). In contrast, the up-dosing of allergoids can be completed in 4–8 weeks.[9],[17] Furthermore, the maintenance dose of allergoids can be given at an interval of 4–8 weeks, thereby improving patient and physician acceptability.


  Preference for Allergoids Top


In a large real-world survey, approximately 50% of the prescriptions in AIT (SCIT) were for allergoid SCIT.[15]


  Summary Top


Allergoids are now the preferred form of SCIT in Europe, by demonstrating by improving the safety and efficacy of AIT. The features, effects, and clinical implications of allergoids are produced in [Table 1].
Table 1: Features, effects and clinical implications of allergoids

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  References Top

1.
Pajno GB, Bernardini R, Peroni D, Arasi S, Martelli A, Landi M, et al. Clinical practice recommendations for allergen-specific immunotherapy in children: The Italian consensus report. Ital J Pediatr 2017;43:13.  Back to cited text no. 1
    
2.
Lukan N. Present and future of subcutaneous aero-allergen immunotherapy. In: Metodiev K, editor. Immunotherapy – Myths, Reality, Ideas, Future. Croatia: InTech; 2017. Available from: https://www.intechopen.com/books/immunotherapy-myths-reality-ideas-future/present-and-future-of-subcutaneous-aero-allergen-immunotherapy. [Last accessed on 2018 Jan 10].  Back to cited text no. 2
    
3.
Bousquet J, Lockey R, Malling HJ. Allergen immunotherapy: Therapeutic vaccines for allergic diseases. A WHO position paper. J Allergy Clin Immunol 1998;102:558-62.  Back to cited text no. 3
    
4.
Ring J, Gutermuth J. 100 years of hyposensitization: history of allergen-specific immunotherapy (ASIT). Allergy 2011;66:713-24.  Back to cited text no. 4
    
5.
Brehler R, Kahlert H, Thum-Oltmer S. Hypoallergenic Preparations in SCIT. Allergo J 2010;19:477-84.  Back to cited text no. 5
    
6.
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. 6
    
7.
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. 7
    
8.
Cox L, Jacobsen L. Comparison of allergen immunotherapy practice patterns in the United States and Europe. Ann Allergy Asthma Immunol 2009;103:451-59.  Back to cited text no. 8
    
9.
Zielen S, Kardos P, Madonini E. Steroid-sparing effects with allergen-specific immunotherapy in children with asthma: A randomized controlled trial. J Allergy Clin Immunol 2010;126:942-9.  Back to cited text no. 9
    
10.
Cruz Niesvaara D, Cumplido Bonny JA, Hernández Suárez HR, Almeida Quintana L, Carrillo Díaz T. Short-term improvement in health-related quality of life in adult rhinitis/asthma patients treated with acaroid®. Allergol Immunopathol (Madr) 2014;42:169-71.  Back to cited text no. 10
    
11.
García Robaina JC, Polanco Sánchez C, Estella Pérez E. Savings associated with high-dose hypoallergenic house dust mite immunotherapy in rhinitis and/or asthma patients in Spain. Clinicoecon Outcomes Res 2016;8:235-41.  Back to cited text no. 11
    
12.
Egert-Schmidt AM, Kolbe JM, Mussler S, Thum-Oltmer S. Patients' compliance with different administration routes for allergen immunotherapy in Germany. Patient Prefer Adherence 2014;8:1475-81.  Back to cited text no. 12
    
13.
Roger Reig A, Ibero Iborra M, Carrillo Díaz T, López Abad R, Sánchez Moreno V, Álvarez Nieto J, et al. Perceived efficacy and satisfaction of patients with subcutaneous hypoallergenic high-dose house dust mite extract. Eur Ann Allergy Clin Immunol 2017;49:100-5.  Back to cited text no. 13
    
14.
Eng PA, Borer-Reinhold M, Heijnen IA, Gnehm HP. Twelve-year follow-up after discontinuation of preseasonal grass pollen immunotherapy in childhood. Allergy 2006;61:198-201.  Back to cited text no. 14
    
15.
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. 15
    
16.
European Medicines Agency. CHMP Safety Working Party's Response to the PDCO Regarding Aluminium Hydroxide Contained in Allergen Products; June, 2010. p. 44.  Back to cited text no. 16
    
17.
Chaker AM, Al-Kadah B, Luther U, Neumann U, Wagenmann M. An accelerated dose escalation with a grass pollen allergoid is safe and well-tolerated: A randomized open label phase II trial. Clin Transl Allergy 2015;6:4.  Back to cited text no. 17
    



 
 
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