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Wise et al.

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this specific product is not going forward in development. 1597 However, the field of adjuvant approaches to immunization is moving forward. A TLR-4 adjuvant is also currently in clinical development. This construct is comprised of monophosphoryl lipid A, derived from detoxified lipopolysaccharide of gram-negative bacterium ( Salmonella minnesota , a TLR-4 inducing adjuvant), and formulated with pollen allergoids absorbed onto microcrystalline tyrosine. This compound reduces IgE-mediated allergenicity but preserves immunogenicity. A large grass study showed significant improvement in symptom and medication scores vs placebo with subgroup analysis showing greater benefit in patients with more severe symptoms. 1598 An abbreviated ragweed trial showed clinical effect in the primary endpoint vs placebo. 1066 These studies of adjuvant-modified extracts demonstrate potential for improved immunotherapy protocols; however, several challenges remain. Each of the modified extracts requires robust clinical outcomes data to demonstrate short and long-term improvement in both efficacy and safety over conventional allergenic extracts. • Aggregate Grade of Evidence for ragweed: B (Level 1b: 3 studies). • Aggregate Grade of Evidence for grass: B (Level 1b: 2 studies). • Aggregate Grade of Evidence for HDM: Indeterminate, based on only 1 Level 2b study. In summary, a wide variety of immunotherapeutic agents are currently undergoing clinical development with the goal of improving safety and achieving immune tolerance with long lasting therapeutic efficacy. This new generation of vaccines includes recombinant allergens, peptide constructs, allergoids/polymerized allergens, and adjuvant constructs—each of which must undergo rigorous clinical evaluation to demonstrate acceptable safety and meaningful clinical outcomes that meet regulatory guidelines for approval. For some of the studied preparations, there appears to be improvement over placebo and comparable outcomes to native allergens. The TLR-9 agonist trial showed 2 years of efficacy post discontinuation of drug. However, some peptide molecules demonstrated increased late reactions as well as mixed clinical outcomes depending on the preparation. Allergoids, adjuvants, and peptides have also shown efficacy in multiyear clinical trials. There is insufficient evidence to make recommendations based on the low number of studies for each preparation and lack of long-term outcomes, as no study has examined outcomes for longer than a 2-year period. IX.D.3. Subcutaneous immunotherapy (SCIT)— AIT is a treatment for IgE mediated sensitivity to environmental allergens. 101,1613,1614 SCIT involves the injection of increasing doses of an extract of the allergen in question, followed by repeated injections of the top or maintenance dose for periods of 3 to 5 years, to reduce symptoms on exposure to that allergen. SCIT has been practiced for over a century using aqueous extracts of the naturally occurring allergens. 1615 SCIT has been shown to be effective for AR, allergic asthma, and sensitivity to hymenoptera venom, along with demonstrated benefit in selected patients with AD. Although meta-analyses conclude that AIT is effective, this positive judgment of efficacy (and safety) should be limited to products tested in the clinical trials. It

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