Subcutaneous Allergen Immunotherapy for Allergic Disease

Examining Efficacy, Safety and Cost-Effectiveness of Current and Novel Formulations

Linda Cox; Moisés Calderón; Oliver Pfaar

Disclosures

Immunotherapy. 2012;4(6):601-616. 

In This Article

Novel Approaches for SCIT

Efforts to develop safer and more effective allergen immunotherapy have resulted in several modifications to allergen extracts. These modifications include alteration of the allergen (e.g., peptides and allergoids) and the addition of substances that can enhance the immunogenicity of the allergen extract (e.g., adjuvants).

Allergoids are chemically modified extracts that reduce IgE-binding capacity. The modification is intended to improve safety by reducing the extract's allergenicity while retaining its immunogenicity. T cell-directed peptide immunotherapy utilizing major T-cell epitopes demonstrated efficacy in terms of reduction of late-phase skin response and safety comparable to placebo with a single vaccination in cat-allergic subjects.[89] In addition to cat allergy, peptides have been used to treat bee venom allergy in small open-label studies that have demonstrated favorable effects in terms of immunological changes, late-phase skin response and live bee sting challenge response.[90]

Adjuvants enhance the effectiveness of allergen immunotherapy primarily by shifting the immune response toward Th1 production via their action on Toll-like receptors. The receptor for CpG DNA, TLR9, can lead to production of IL-10, IgG isotope switching and inhibition of other immune responses mediated by activated Th2 cells.[91] TOLAMBA™ (Dynavax Technologies, CA, USA) is a CpG adjuvant covalently linked to the major ragweed allergen, Amb a 1. A randomized, double-blind, placebo-controlled Phase II trial of 25 adults with ragweed-induced AR randomized to receive six increasing doses of TOLAMBA or placebo before the ragweed season demonstrated a significant reduction in total nasal symptom scores during the peak season in the TOLAMBA group compared with the placebo-treated patients in both the first and second ragweed season with a comparable safety profile to placebo.[92] However, there was no difference in the primary outcome, which was nasal allergen provocation response. The development of a CpG ragweed vaccine was discontinued by the company, Dynavax, after interim analysis of a subsequent large trial indicated that neither the placebo nor the CpG groups developed symptoms during the ragweed season, making it impossible to assess the therapeutic efficacy of the CpG vaccine.[205]

Another adjuvant used in allergen immunotherapy is monophosphoryl lipid A (MPL), a TLR4 agonist derived from the lipopolysaccharide of Salmonella minnesota that induces Th1 cytokines in human and animal studies. In addition to allergen immunotherapy, it has been used for many years in licensed vaccines: Melacine® (Corixa/Schering Canada, WA, USA) and the human papillomavirus, Ceravarix® (GlaxoSmithKline, Brentford, UK).[93] MPL is used in an allergen vaccine product composed of a tyrosine-absorbed (delays absorption), glutaraldehyde-modified allergoid (Pollinex® Quattro or MATA MPL, Allergy Therapeutics Ltd, Worthing, UK), which is administered as four injections given at 1–2 week intervals ending 2–4 weeks before the start of season. In a double-blind placebo-controlled trial of 1028 subjects with grass pollen-induced AR, who were randomized to receive Grass MATA MPL (n = 514; 300–2000 standardized units/injection) or placebo (n = 514) before the grass pollen season, Grass MATA MPL treatment afforded a 13.4% benefit over placebo in the 4 peak pollen weeks (p = 0.0038).[94] "More significant benefits over placebo were observed in subjects with severe symptoms (17.1%; p = 0.0023), in those who had a history of allergic rhinoconjunctivitis for up to 35 years (up to 37.2%; p = 0.0059) and at sites with a higher burden of disease (38.3%; p < 0.0001)".[94]

Other novel immunotherapy approaches have shown promise for injection therapy utilizing currently available allergen extracts. A study that compared the combination of SCIT in the build-up phase followed by SLIT in the maintenance phase with SCIT or SLIT alone found similar improvement in asthma attacks and inhaled corticosteroid use in the two SCIT groups but significant improvement in rhinitis scores only in the SCIT plus SLIT group.[95] An open-label study compared the efficacy of 3 years of conventional SCIT with three low-dose intralymphatic injections administered over 2 months.[96] At 3 years, there was no difference between the groups in terms of clinical efficacy, despite the intralymphatic group having received only 8 weeks of treatment.

These investigations suggest that, in the future, SCIT may involve short courses with modified extracts or be used in combination with or replaced by other SIT routes deemed more effective, convenient and/or safe.

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