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.

Database searches were conducted in Pubmed, Scopus and Google Scholar.

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

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, nano-particles and virus-like particles in combination with allergen have shown early promise. Omalizumab reduces systemic side effects, however does not improve efficacy. Intralymphatic immunotherapy for aeroallergens and epicutaneous immunotherapy for food allergens, 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

Novel routes of immunotherapy, the use of modified allergens and the combination of allergens with immunostimulatory adjuvants, or immune modifiers have been developed to augment down-regulation of Th2 immunity and/or induce ‘protective’ blocking antibodies. Whereas these strategies have permitted shortened courses, confirmatory phase III trials are required to confirm efficacy and safety, and head-to-head trials for comparative efficacy. At present, subcutaneous and sublingual immunotherapy using in-house standardised crude extracts remain the only approaches proven to induce long-term tolerance.