Table 1. Immunopotentiators for allergy vaccines.

Immunopotentiators	Status	Route	Allergen	Comments
Mineral adjuvants	Clinical	Subcutaneous	Various commercial vaccines	Aluminum hydroxide and calcium phosphate are commonly used for subcutaneous allergy vaccines in Europe. Mechanisms involved include both a depot effect (ie slow release of the allergen, formulation of the allergen as particles to target APCs) as well as interaction with the innate immune system (e.g., activation of the inflammasome).
Probiotics	Clinical (stand alone) or preclinical (adjuvant)	Mucosal	OVA, Bet v 1	Mucosal (ie intranasal or sublingual) administration of commensal bacteria such as Lactococcus lactis, Lactobacillus plantarum or Bifidobacterium bifidum in various murine models together with the allergen(s) induces Th1 and/or regulatory T cells as well as asthma improvement. Tolerogenic IL10 inducing probiotics interact with DCSign3 and exhibit specific forms of teichoid acids in their wall composition. Selected probiotics used as a stand alone therapy protect children against eczema, following the induction of Th1 responses. or asthma after intradermal administration.
Attenuated Mycobacteria, bacterial products	Clinical (stand alone) or preclinical (adjuvant)	Systemic / mucosal	Mite, grass pollen	In mice, heat-killed Mycobacterium vaccae induces Treg cells secreting IL-10 and TGFβ, and decreases airway inflammation. Genetically detoxified cholera toxin (CT) and lymphotoxin (LT) (or B subunits without ADP ribosyl transferase activity) induce strong seric and mucosal IgAs responses. The allergen can be mixed, fused, or chemically conjuged with the toxin moiety. Sublingual administration of the allergen conjugated to CTB enhances tolerance induction in murine models. M vaccae and BCG exhibit some clinical efficacy in children with atopic dermatitis or asthma after intradermal administration.
TLR ligands	Clinical (for CpGs and MPL), preclinical (others)	Subcutaneous, intradermal / sublingual	OVA, Amb a 1, grass pollen	Ligands for TLR2 (including lipopeptides, Pam3Csk4), TLR4 (MPL, RC 529, OM294-BA-MP), TLR7 (imidazoquinolines), TLR9 (CpGs) have some efficacy in murine asthma models (decrease of both airway inflammation and Th2 responses, with induction of Th1 and/or T Reg responses). Intradermal immunization with Amb a 1 fused to CpG oligonucleotides prevents allergen-induced hyperresponsiveness in mice.    A conjugate Amb a 1-CpG vaccine has been tested in ragweed allergic humans through the subcutaneous route, with some level of clinical efficacy, and induction of Th1 responses and CD25+ T Reg cells. In humans, the TLR4 ligand monophosphoryl lipid A (MPL) with or without tyrosine-absorbed grass pollen allergens induces a strong production of IgG1 and IgG4 antibodies through the subcutaneous route. Following SLIT in grass pollen allergic patients, MPL enhanced specific IgG responses and decreased reactivity to nasal allergen challenge.
Small synthetic molecules	Clinical (fluticasone), preclinical (others)	Systemic, sublingual	OVA, grass pollen	Dihydroxyvitamin D3 plus glucocorticoids, calcineurin inhibitors (cyclosporin A, FK 506), rapamycin, aspirin and mycophenolate mofetil enhance IL10 production by CD4+ T cells. Dexamethasone plus dihydroxy vit D3 enhance SLIT efficacy in a murine asthma model. No synergy between fluticasone and SLIT was observed in humans when using distinct administration routes.