Objective

New insights into mechanisms should enable strategic improvement of allergen immunotherapy, aiming to make it safer, faster, more effective, and able to induce long-term tolerance. We review novel approaches with potential to translate into clinical use.
Data Sources

Database searches were conducted in PubMed, Scopus, and Google Scholar.
Study Selections

Search terms were based on current and novel approaches in immunotherapy. Literature was selected primarily from recent randomized double-blinded placebo-controlled trials and meta-analyses.
Results

Alum, microcrystalline tyrosine, and calcium phosphate are adjuvants in current use. Toll-like receptor-4 agonists combined with allergen have potential to shorten duration of treatment. Other novel adjuvants, nanoparticles, and virus-like particles in combination with allergen have shown early promise. Omalizumab lessens systemic side effects but does not improve efficacy. Intralymphatic immunotherapy for aeroallergens, epicutaneous immunotherapy for food allergens, and use of modified allergens (allergoids), recombinant allergens (and hypoallergenic variants), and T- and B-cell peptide approaches have shown evidence of efficacy and permitted shortened courses but have only rarely been compared with conventional extracts.
Conclusion

Novel routes of immunotherapy, use of modified allergens, and combination of allergens with immunostimulatory adjuvants or immune modifiers have been developed to augment downregulation of T-helper cell type 2 immunity and/or induce “protective” blocking antibodies. Although these strategies have permitted shortened courses, confirmatory phase 3 trials are required to confirm efficacy and safety and head-to-head trials are required for comparative efficacy. Currently, subcutaneous and sublingual immunotherapies using in-house standardized crude extracts remain the only approaches proved to induce long-term tolerance.