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Wise et al.

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Aggregate Grade of Evidence for cat: B (Level 1b: 5 studies).

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• Aggregate Grade of Evidence for birch: Indeterminate, based on only 1 Level 1b study. • Aggregate Grade of Evidence for ragweed: B (Level 1b: 1 study; Level 2b: 1 study). Allergoids and polymerized allergens. Allergoids are chemically modified allergens which were developed for improved immunotherapy protocols via accelerated dosing and decreased side effects. Initial attempts at development of an allergoid by partial denaturing of the allergenic moiety with formalin resulted in reduced allergenicity; however, concurrent reduction in the immunogenicity of the allergoids, as defined by IgG antibody production, was seen. 1590 Studies using a glutaraldehyde-linked polymerization of allergens for grass and ragweed allergens demonstrated efficacy and tolerability. 1591,1592 However, standardization criteria and production factors negatively impacted regulatory approval in the United States. Clinical trials for allergoids employing ragweed, grass, and HDM allergens have been reported. Promising early results are seen for these allergoids. In addition, more recent work has focused on depigmented allergoid constructs, which are currently in use in Europe 1593,1594 (Table IX.D.2-2). • Aggregate Grade of Evidence for ragweed: B (Level 1b: 1 study; Level 2b: 1 study). • Aggregate Grade of Evidence for grass: B (Level 1b: 7 studies). • Aggregate Grade of Evidence for HDM: Indeterminate, based on only 1 Level 2b study. • Allergoid or polymerized allergen products have been approved in Europe but none has received FDA approval. Adjuvant constructs.: The addition of molecules (adjuvants) to the native allergen has been attempted to improve desensitization protocols. Alum was the first adjuvant to gain acceptance in AIT. Early studies with alum-precipitated extracts demonstrated an augmented immunologic response. However, alum induced an initial IgE immune response which hindered its therapeutic application. 1595 Clinical trials with adjuvants have been reports for ragweed, grass, and HDM allergens (Table IX.D.2-2). Creticos reported the proof-of-concept study for using bacterial DNA (CpG oligonucleotide synthetically derived from Mycobacterium bovis ) to upregulate an immunostimulatory response to allergen through the corresponding ligand (TLR ligand) on a specific class of regulatory dendritic cells. 1596 The TLR-9 agonist was administered in a 2-year double-blind placebo-controlled study of ragweed-allergic subjects immunized with a 6-injection regimen administered prior to the initial ragweed season. A similar magnitude of effect vs placebo was observed over both ragweed seasons indicating that the vaccine conferred meaningful long-term efficacy (clinical and immune tolerance) over 2 ragweed seasons. 1596 Subsequent large-scale multicenter trials were not able to satisfy regulatory approval requirements and

Int Forum Allergy Rhinol . Author manuscript; available in PMC 2020 June 10.