Adjuvant Strategies to Improve the Efficacy of Allergen Immunotherapy

Introduction

Allergic diseases (such as allergic rhinitis, asthma, eczema and food allergies) are widespread immunological disorders driven by inappropriate Th2 immune responses to otherwise harmless antigens (allergens). These Th2-biased responses lead to excess IgE production and mast cell activation that are in turn responsible for many of the symptoms of allergy.^1,2 Allergen-specific immunotherapy (AIT) is currently the only disease-modifying treatment approved for treatment of IgE-mediated allergies.³ In AIT, patients are repeatedly exposed to small but increasing doses of the allergen with the aim to induce long-term immune tolerance.² Clinical evidence shows that AIT can significantly reduce allergic symptoms and medication needs in allergic rhinitis and asthma⁴ and even decrease the risk of new sensitizations or asthma development in some cases.⁵ Nevertheless, traditional AIT, which is generally delivered via subcutaneous injections, has drawbacks: it requires frequent injections over 3–5 years and carries a risk of systemic allergic reactions, including rare but severe anaphylaxis.^6,7

Mucosal AIT has emerged as an attractive alternative route for allergy therapy. By delivering allergens to mucosal surfaces (sublingual, oral, or intranasal), one can leverage the mucosa-associated lymphoid tissue to induce immune tolerance with fewer systemic side effects.⁸ Indeed, sublingual immunotherapy (SLIT) for inhalant allergies and oral immunotherapy (OIT) for food allergies have demonstrated the ability to induce desensitization, although oral immunotherapy in particular has been associated with higher rates of adverse events and has not consistently been shown to improve quality of life compared with control treatments.⁹ Mucosal routes avoid needles and are more convenient, potentially improving patient adherence. However, mucosal vaccines generally suffer from low immunogenicity as the mucosal mucus barrier tends to prevent allergen penetration and hence may not sufficiently activate the immune system on its own.¹⁰ Adjuvants can be co-administered with an antigen to boost or modulate the resulting immune response (Figure 1) and are being investigated as a means to enhance mucosal AIT.^11,12

Figure 1 Adjuvant classes and functional roles in allergen immunotherapy. Major classes of adjuvants used or under investigation in allergen immunotherapy (AIT) are shown according to their primary mechanisms of action. Carrier and delivery systems (left) enhance allergen stability, uptake, and presentation and include liposomes, virus-like particles, alum, oil-in-water emulsions, and viral carrier peptides (PreS, HIV-TAT). Immunostimulatory carriers (center) combine allergen delivery with innate immune activation, whereas immunostimulatory adjuvants (right), including TLR ligands (flagellin, CpG, MPLA) and carbohydrate-based compounds (QS-21, glycan ligands, mannan), directly activate innate immune pathways. Collectively, these strategies aim to suppress Th2/IgE responses, promote IgG/IgA blocking antibodies, induce regulatory T cells, and establish immune tolerance. This figure is an original conceptual illustration generated with the assistance of artificial intelligence and validated by the authors.

In the context of allergy vaccines, an ideal adjuvant should not only increase the magnitude and durability of the allergen-blocking immune response but also shift the response away from a pathologic Th2/IgE profile toward a protective or tolerant profile, for example, by induction of Th1 cells and/or regulatory T cells (T_reg).^2,13 Unlike vaccines against infections where a strong anti-pathogen immune response is desired, allergy vaccines aim to re-educate the immune system to better tolerate allergens. Thus, adjuvants for allergen immunotherapy should promote production of IgG or IgA “blocking” antibodies and expand T_reg populations, while suppressing IgE production and mast cell activation.² Only a few adjuvants are presently used in licensed injected allergen immunotherapy products, most notably aluminum hydroxide, calcium phosphate, microcrystalline tyrosine, and monophosphoryl lipid A (MPLA), a toll-like receptor-4 agonist.³ These improve the efficacy of injected AIT, inducing higher blocking antibody titers or allowing shorter treatment courses, but each has limitations. For example, aluminum adjuvant induces unwanted Th2 immunity and increases local injection site reactions.¹⁴ As yet, no licensed mucosal AIT contains an adjuvant. As several recent reviews have comprehensively discussed adjuvants in allergen immunotherapy, including delivery systems and mucosal applications, the present review integrates diverse adjuvant classes into a unified, mechanism-based framework with a specific emphasis on mucosal allergen immunotherapy. By explicitly addressing clinical feasibility, safety considerations, translational barriers, and route-specific immune effects, this review aims to provide practical guidance for rational adjuvant selection and “go/no-go” decision-making in the design of next-generation adjuvanted allergy vaccines.

Materials and Methods

This review is based on a structured narrative analysis of the current literature. A comprehensive literature search was conducted using three major biomedical and multidisciplinary databases: PubMed, Scopus, and Web of Science. The search covered publications available in English up to October 2025. Search queries combined controlled vocabulary terms and free-text keywords related to allergen immunotherapy and adjuvant technologies, including but not limited to: “allergen immunotherapy”, “mucosal immunotherapy”, “adjuvants”, “TLR agonists”, “nanoemulsions”, “liposomes”, “virus-like particles”, “polysaccharide adjuvants”, “chitosan”, “delta inulin”, “regulatory T cells”, and “IgG4 blocking antibodies”. Database-specific filters were applied where appropriate to refine results. The initial search yielded a total of 1015 records across the three databases. After removal of 412 duplicate records, the remaining 603 articles were screened based on titles and abstracts for relevance to allergen immunotherapy, adjuvant mechanisms, and mucosal delivery approaches. During this screening step, 358 records were excluded as not relevant. The full texts of 245 articles were then assessed for eligibility. Studies were excluded if they were not related to allergen immunotherapy, did not focus on adjuvant strategies or mucosal delivery routes, or represented editorials or commentaries without original data or substantive mechanistic insight. This resulted in the exclusion of 66 full-text articles. After this combined selection process, a total of 179 references were included in the final narrative synthesis. The overall literature search and study selection process is summarized schematically in Figure 2.

Figure 2 Literature search and study selection strategy.

Mechanisms of Adjuvant-Enhanced Tolerance

AIT works by incrementally retraining the immune system to tolerate allergens. The therapeutic mechanisms of AIT are complex and unfold in phases. In the initial desensitization phase, repeated low-dose allergen exposure rapidly reduces the reactivity of effector cells: mast cells and basophils become less prone to degranulation, including via up-regulation of histamine H2 receptors on basophils that suppress FcεRI-mediated activation.¹⁵ In the subsequent early tolerance phase, there is measurable immune deviation: allergen-specific Th2 cells (sources of IL-4, IL-5, IL-13) are downregulated, while T_reg that secrete IL-10 and TGF-β expand; B cells increasingly favor production of blocking IgG4 and IgA rather than IgE.² With continued therapy, a sustained tolerance phase can develop in which high-affinity IgG4 “blocking” antibodies neutralize allergen before it engages IgE on mast cells and Tregs maintain long-term suppression of allergen-specific Th2 memory such that over time serum IgE levels are suppressed; functional anti-allergen IgG4 activity correlates with clinical response, and persistence of blocking antibodies is associated with long-term tolerance.^16,17 Kinetic studies show that early decreases in basophil sensitivity during AIT can precede—and likely contribute to—sustained clinical unresponsiveness.¹⁸

Mucosal adjuvants are intended to facilitate and amplify such tolerance mechanisms when included in an allergy vaccine.^12,13 At a basic level, adjuvants can increase the uptake of allergen by antigen-presenting cells (APCs) and provide innate immune signals that shape the downstream adaptive immune response.^13,19 By activating pattern recognition receptors or causing local inflammation, adjuvants recruit dendritic cells and other APCs to the site of allergen administration and promote their maturation.^13,19 Mature APCs that have captured the allergen then migrate to lymph nodes and efficiently present allergen peptides to T cells, resulting in Th1 response or T_reg differentiation depending on the cytokine milieu induced by the adjuvant.^13,19 For example, an adjuvant that triggers interleukin-12 production by dendritic cells will favor Th1 responses and production of blocking IgG, whereas one that induces IL-10 and TGFβ will foster T_reg development and suppression of IgE-secreting B cells.^20,21 In AIT, the desired outcome is induction of an immune profile that protects against allergic reactions, namely induction of high IgG (and IgA) blocking antibody levels, redirection of T-helper responses from Th2 to Th1, expansion of T_reg and suppression of IgE production, while trying to avoid an early IgE boost effect or excessive inflammation or reactogenicity.²¹

Adjuvants can be categorized by their mode of action (Figure 3). Traditional “first-generation” adjuvants act mainly as delivery systems or depots: they form antigen-adjuvant complexes or particles that prolong antigen residence in tissues and help concentrate antigen in APC-rich environments.^22,23 Aluminum hydroxide (alum), calcium phosphate, and microcrystalline tyrosine (MCT) are examples of adjuvants that adsorb allergens into insoluble aggregates, slowing allergen release and thereby increasing immune exposure time.^23,24 These particulate depots also induce local inflammation with alum crystals activating the NLRP3 inflammasome in macrophages and dendritic cells, releasing cytokines like IL-1β that recruit and activate immune cells.²⁵ The net effect is a stronger antibody response to co-delivered antigens.^13,22 However, depot adjuvants alone may not optimally shape the quality of the response given alum’s unwanted Th2 bias.^22,23

Figure 3 Mechanistic differences between first- and second-generation adjuvants in allergen immunotherapy. Shown are the principal mechanisms of action of traditional first-generation “depot” adjuvants and modern second-generation immunomodulatory adjuvants used in allergen immunotherapy. First-generation adjuvants (A) such as alum, calcium phosphate, and microcrystalline tyrosine (MCT), primarily act as delivery systems by adsorbing allergens into insoluble aggregates that form tissue depots, prolong allergen release, and induce local inflammation, often through NLRP3 inflammasome activation, with a tendency toward Th2-biased immune responses. In contrast, second-generation adjuvants (B) including Toll-like receptor (TLR) agonists such as CpG and MPLA and other pattern-recognition receptor (PRR) ligands, provide defined immunostimulatory signals that activate antigen-presenting cells, induce polarizing cytokines, enhance co-stimulatory molecule expression, and promote Th1 and regulatory T-cell responses. When combined with allergen, these immunomodulatory adjuvants favor IgG/IgA blocking antibody production and the development of immune tolerance.

By contrast, “second-generation” adjuvants are immunomodulatory agents that provide specific activation signals to the immune system.¹⁹ These are often molecules that mimic pathogen-associated molecular patterns (PAMPs) and engage toll-like receptors (TLRs) or other innate immune receptors.²⁶ Upon recognition of these signals, dendritic cells activate gene transcription programs that upregulate co-stimulatory molecules and secrete polarizing cytokines.²⁷ For example, a TLR9 agonist adjuvant like CpG oligonucleotide will drive a dendritic cell to produce IL-12 and type I interferons, thereby skewing the response towards Th1 immunity²⁸ whereas a TLR4 agonist like MPLA will induce a mix of Th1 and regulatory-promoting cytokines.²⁹ When combined with allergen, such immunostimulatory adjuvants ensure that the allergen is presented to T cells in the context of an appropriately activated APC, leading to a strong immune response skewed away from Th2. In essence, delivery adjuvants create a depot to help deliver the allergen to the immune system over a longer time, while immunomodulatory adjuvants instruct the immune system how to better respond to that allergen.¹³ Modern AIT often seeks to employ both adjuvant types to obtain synergy.³⁰

The incorporation of adjuvants into allergen immunotherapy offers several important advantages. Delivery systems such as liposomes, virus-like particles, and emulsions improve allergen stability, prolong tissue residence, and enhance uptake and presentation by antigen-presenting cells. Immunostimulatory adjuvants, including Toll-like receptor ligands and other pattern-recognition receptor agonists, provide defined activation signals that shape adaptive immune responses. By combining allergen delivery with targeted immune modulation, adjuvant-based strategies can suppress pathogenic Th2-driven IgE responses, promote the production of IgG and IgA blocking antibodies, induce regulatory T cells, and accelerate the development of immune tolerance. These approaches also hold the potential to reduce allergen dose requirements and treatment duration, thereby improving safety, efficacy, and patient adherence.

For mucosal AIT, additional mechanistic considerations may come into play. The mucosal immune system possesses unique tolerance-promoting features – for instance, the gut and respiratory mucosa are rich in dendritic cell (DC) subsets that favor T_reg responses via production of IL-10 and TGF-β, a phenomenon known as mucosal tolerance.³¹ Exploiting this existing mucosal bias, adjuvants can further tip the mucosal balance towards immune tolerance. One example of this is cholera toxin B subunit (CTB), a component of cholera toxin that binds GM1 ganglioside receptors on immune cells. CTB is an effective mucosal immune modulator. In mouse models, intranasal or intratracheal administration of CTB with allergen was shown to suppress allergic Th2 responses and inflammation to an inhaled allergen, in part by inducing local IgA production and TGF-β production, a key T_reg and IgA associated cytokine.³² In effect, CTB redirects the response to inhaled allergen from an IgE to an IgA dominant less-pathogenic response with allergen-specific IgA in the airways or gut then blocking allergen uptake and facilitating its safe clearance rather than it being engaged by IgE.³³

Another mechanism of adjuvants in AIT is to induce bystander suppression. Some adjuvants may elicit T_reg networks that extend beyond a specific allergen used. For example, nano-emulsion-based intranasal vaccines have been shown to suppress Th2 responses, not only to the allergen in the vaccine but also to unrelated allergens, via IFN-γ production and dampening of epithelial “alarmin” cytokines that drive allergic inflammation.³⁴ This suggests that Th1-skewing mucosal adjuvants might create an environment in the mucosa that at least temporarily counteracts allergic sensitization. Of course, it will be important to establish just how long such skewing of the immune environment by adjuvants lasts, to know how often mucosal AIT needs to be repeated.

In summary, adjuvants may aid mucosal AIT through multiple synergistic mechanisms: they may improve allergen visibility to the immune system, boost the magnitude of blocking antibody responses allowing lower allergen doses to be effective³⁵) and/or, critically, steer immunity towards non-allergic pathways by increasing blocking IgG and IgA, inducing Th1 cells and T_regs and suppressing Th2 cells and IgE-producing B cells.¹² The following sections will detail various mucosal adjuvant classes and examples.

Mucosal Routes and Adjuvant Strategies in Allergen Immunotherapy

Mucosal allergen immunotherapy (AIT) aims to exploit the unique immunological properties of mucosal tissues to induce immune tolerance while minimizing systemic reactogenicity. However, each mucosal route presents distinct anatomical, immunological, and translational constraints, which strongly influence the choice and performance of adjuvants. A route-specific evaluation of adjuvant strategies is therefore essential to guide rational vaccine design.³⁶

Oral Allergen Immunotherapy

Oral immunotherapy (OIT) targets the gut-associated lymphoid tissue, where tolerance is actively maintained through regulatory T cells, tolerogenic dendritic cells, and microbiota-derived signals. While OIT can induce desensitization, its clinical application is frequently limited by gastrointestinal adverse events and variable durability of tolerance. To enhance efficacy and safety, several adjuvant strategies have been explored, including nano-emulsions, Toll-like receptor (TLR) agonists, probiotics, and particulate delivery systems that improve antigen stability and uptake by intestinal antigen-presenting cells. Despite promising preclinical results, translation to clinical practice remains challenging due to dose-dependent reactogenicity and incomplete understanding of long-term immunological imprinting in the gut.³⁷

Sublingual Allergen Immunotherapy

Sublingual immunotherapy (SLIT) offers a favorable safety profile and direct access to oral mucosal immune networks but is characterized by limited allergen uptake and relatively weak immunogenicity.³⁸ Adjuvants for SLIT primarily aim to enhance mucosal retention, epithelial transport, and dendritic cell activation. Mucoadhesive polymers such as chitosan, lipid-based nanoparticles, virus-like particles, and mild immunostimulatory agents have been investigated to improve antigen delivery and promote regulatory or Th1-skewed immune responses. While these approaches show potential to enhance SLIT efficacy, careful balancing of immune activation and local tolerability is required.³⁹

Intranasal Allergen Immunotherapy

Intranasal delivery targets the nasal-associated lymphoid tissue, which is highly immunocompetent and capable of inducing both local and systemic immune responses. This route is particularly attractive for respiratory allergies, but it also raises safety considerations related to local inflammation and off-target effects. Adjuvants evaluated for intranasal AIT include CpG oligonucleotides, nanoemulsions, bacterial-derived components, cholera toxin B subunit derivatives, and emerging platforms such as bacterial extracellular vesicles.⁴⁰ These adjuvants can enhance antigen uptake and drive immune deviation away from pathogenic Th2 responses; however, their clinical translation requires stringent safety assessment and optimization of formulation parameters.

Inhaled and Pulmonary Approaches

Pulmonary allergen delivery provides direct access to the lower airways and may induce potent immunomodulatory effects. Nevertheless, the risk of bronchoconstriction and exacerbation of allergic inflammation has limited widespread adoption.⁴¹ Adjuvant strategies for inhaled AIT must therefore prioritize safety and controlled immune activation. To date, this route remains largely experimental, with adjuvant selection constrained by the need to avoid excessive innate immune stimulation in the lung.⁴²

Route-Specific Considerations and Translational Implications

Collectively, these observations highlight that no single adjuvant strategy is universally optimal for mucosal AIT. Instead, adjuvant selection must be tailored to the immunological landscape, epithelial barriers, and safety requirements of each mucosal surface. Delivery systems that enhance antigen stability and uptake often need to be combined with carefully selected immunomodulatory signals to achieve durable tolerance.⁴³ A route-oriented framework for adjuvant evaluation thus provides a clearer basis for translating preclinical advances into clinically viable mucosal allergy vaccines.

Classes of Adjuvants for Allergy Vaccines

Adjuvants can be broadly grouped by their functional characteristics into; (1) particulate delivery systems (depot adjuvants), (2) immune-response modulators (innate pathway activators), and (3) combined systems that accomplish both roles.^44,45 Adjuvant types being studied for improving AIT include traditional depot adjuvants like alum, immuno-stimulators like MPLA, and novel nanoparticle adjuvant systems including liposomes, emulsions, ISCOMS, VLPs, and polymeric particles including delta inulin and chitosan, provide versatile tools to improve allergen vaccines as summarized in Table 1.

Table 1 Summary of Selected Adjuvants in Allergen Immunotherapy, Including Their Category, Mode of Action, and Current Status

Traditional Depot Adjuvants

Aluminum hydroxide (alum) has been used as a vaccine adjuvant for over a century and remains the most common adjuvant in both infectious disease and allergy vaccines.²² Alum particles (often aluminum oxyhydroxide or aluminum phosphate gels) strongly adsorb protein allergens via electrostatic interactions forming a depot at the injection site that slows allergen release.²³ By prolonging allergen presence and uptake by APCs, alum increases the resulting antibody responses.¹³ Many SCIT formulations include alum to enhance immunogenicity and reduce immediate systemic exposure hence lowering anaphylaxis risk.³ Alum has a well-established ability to induce robust IgG responses. However, alum’s mechanism of action also involves triggering innate inflammation with alum crystals causing local cell damage and activating the NLRP3 inflammasome, leading to secretion of IL-1β and IL-18 and recruitment of neutrophils and monocytes.²⁵ This helps boost T-cell activation but can also skew the T-cell response towards IL13 production and Th2 polarization, as observed in animal allergy induction models where alum promotes IL-4 and IgE production towards co-administered allergens.⁹⁹ Indeed, alum is so Th2-biased that it is routinely used in mice to create allergic models.¹⁰⁰ In human use, alum-formulated AIT along with inducing blocking IgG still stimulates some IgE production,² which is not ideal. Other downsides of alum include injection-site reactions with alum causing granulomatous inflammation or nodules in >15% of patients)⁴⁴ and its low biodegradability leading to accumulation in tissues with repeated shots.¹⁰¹ There have also been debates about alum’s potential role in rare immune side effects such as macrophagic myofasciitis.⁴⁴ Hence, while alum might help enhance blocking IgG titers, its tendency to drive Th2/IgE responses and cause local inflammation has led to discontinuation of its use in several AIT products, spurring interest in alternative depot adjuvants for use in AIT.²⁴

Calcium phosphate (CaP) is another inorganic particulate adjuvant with a long history of use. It was introduced in the 1960s and used in some AIT and early childhood vaccines such as diphtheria–tetanus vaccine.⁴⁶ Like alum, calcium phosphate (CaP) forms a depot by adsorbing allergen, but has better biocompatibility since CaP is a natural constituent of bone. CaP nanoparticles are biodegradable and gradually dissolve into calcium and phosphate ions, so they do not persist or accumulate long-term in tissues.⁴⁷ This avoids the longevity of alum deposits. Notably, CaP was found not to induce IgE production upon booster immunizations.⁴⁸ In both animal and human studies vaccines adjuvanted with CaP elicited strong IgG similar to alum but with minimal IgE, making it more appealing for allergy use.⁴⁹ CaP also tends to cause less prolonged local inflammation than alum with injection site reactions resolving faster.⁵⁰ Despite these advantages, CaP adjuvants are no longer marketed in Europe.⁵¹ However, at least one paper suggests CaP nanoparticles may have potential for use in oral vaccines.⁵²

Microcrystalline tyrosine (MCT) is a newer depot adjuvant designed specifically for AIT. MCT consists of crystalline L-tyrosine, an amino acid, which forms biodegradable particles that serve as an injection depot as an alternative to alum.²⁴ MCT has a short half-life in tissue (~48 hours) before it is naturally metabolized, so it does not accumulate.⁵³ Like alum, MCT adsorbs allergens onto its surface and releases them slowly to immune cells.⁵⁴ However, the immune response with MCT is somewhat different: co-delivery of allergen with MCT in mice produced a broad IgG subclass response with lower IgE and IL-4 production than alum-adjuvanted allergen⁵⁵ consistent with MCT being more Th1-biased than alum.²⁴ Clinically, parenteral MCT-adjuvanted allergy vaccines (often in combination with other immunomodulators) have shown good efficacy and safety.⁵³ For example, pollen allergen injections formulated with MCT yielded high IgG4 levels without significant increases in IgE.⁵⁶ MCT can still cause local reactions (redness, swelling) in some patients, but these are usually mild; and in mouse models MCT caused fewer anaphylactic reactions than alum.⁵⁵ MCT’s adjuvant effect appears independent of TLR signaling,⁵⁵ mostly working as a depot/carrier. MCT is used in the Pollinex Quattro allergy vaccine range, where MCT is combined with MPLA adjuvant to create a potent short-course AIT.^56,57 MCT provides a depot and Th1-biased environment, while the MPLA induces innate immune activation and immunomodulation allowing effective treatment for seasonal rhinitis with only four pre-seasonal injections.⁵⁷ This highlights the potential benefits of combining depot adjuvants with immunomodulatory agents.

Toll-Like Receptor Agonist Adjuvants

Monophosphoryl lipid A (MPLA) is a prime example of a second-generation immunomodulatory adjuvant that has been successfully applied in allergen immunotherapy. MPLA is a detoxified derivative of lipopolysaccharide (LPS) from Salmonella that retains TLR4 agonist activity with markedly reduced toxicity.⁵⁸ It is the first TLR-based adjuvant used in human AIT products.⁵⁹ By engaging TLR4 on dendritic cells, MPLA promotes a Th1-biased response characterized by IL-12 production and downstream NF-κB/TRIF-skewed signaling.²⁹ Parenteral MPLA-adjuvanted allergy vaccines have been shown to increase IgG1 and IgG4 without boosting IgE or directly activating mast cells.⁶⁰ MPLA’s has a favorable safety profile in humans⁶¹ and is a component of licensed parenteral vaccines (AS04 in Cervarix; AS01B in Shingrix).⁴⁵ Notably, intranasal delivery of a TLR4 agonist has been shown to suppress allergic airway inflammation in murine models without provoking anaphylaxis, supporting the feasibility of TLR4-based adjuvants for airway-targeted allergy interventions.⁶²

CpG oligodeoxynucleotides (CpG) are synthetic DNA sequences containing unmethylated CpG motifs that mimic bacterial DNA, acting as potent TLR9 agonists. CpGs have been extensively studied as adjuvants to drive Th1 immunity and suppress allergy.¹⁰² Mechanistically, CpG activates dendritic cells (especially plasmacytoid DCs) to produce interferon-α and IL-12, promoting IgG2a/IgG1 and IFN-γ responses while suppressing IL-4, −5 and −13 and IgE production.²⁸ In murine models of asthma and allergic rhinitis, co-administration of allergen with CpG markedly inhibited Th2 responses and eosinophilic inflammation.⁶⁵ CpG given intratracheally alongside the first allergen exposure in a mouse asthma model prevented airway inflammation and IgE sensitization.⁶⁶ Intranasal CpG therapy has also been shown to attenuate experimental asthma even in absence of TLR9.⁶⁷ CpG has be tested in human allergy trials. CpG1018 conjugated to purified ragweed pollen (Amb a 1) (TOLAMBA™ AIT) delivered a 55% reduction in peak seasonal allergy symptoms after just six injections given weekly.⁶⁹ The improvement persisted through the following year without further dosing suggesting a long-lasting disease-modifying effect. Importantly, CpG-adjuvanted AIT was well tolerated.¹⁰³ Hence addition of CpG achieved tolerance with far fewer doses than traditional AIT.¹⁰⁴ A 2-year Phase 2/3 trial in ~700 ragweed-allergic adults found that TOLAMBA significantly reduced total nasal symptom scores in the second ragweed season by 28.5% relative to placebo⁵¹ with a strong safety profile.⁶⁸ However, a high-dose CpG-adjuvanted AIT given by inhalation in allergic asthma did not show a clear benefit¹⁰⁵ and another Phase IIb trial of a CpG-adjuvanted AIT (CYT003-QbG10) in asthma failed to meet its endpoints.⁹⁵ CpG can be conveniently delivered subcutaneously, intradermally, or intranasally and with its potent ability to suppress Th2 responses remains a promising mucosal AIT adjuvant.¹⁰⁶

Other Toll-like receptor ligands beyond TLR4 and TLR9 may also be of interest as adjuvants for mucosal AIT. Flagellin, a TLR5 agonist derived from bacterial flagella, may help redirect mucosal immunity.⁹⁸ TLR7 agonists such as imiquimod are licensed for topical use in humans for treatment of warts and skin tumors and given their extreme Th1 bias could potentially be used to enhance AIT responses providing excessive inflammation can be avoided.

Carbohydrate-Based Adjuvants

Carbohydrate-based adjuvants such as beta-glucans, delta inulin, chitin, and mannans (which target pattern-recognition receptors like Dectin-1, DC-SIGN or mannose receptors) may also be of interest as adjuvants for parenteral or mucosal AIT.¹⁰⁷ For example, glucans and fructans activate antigen-presenting cells via interaction with C type lectin receptors and may thereby enhance AIT responses. Advax (delta inulin) is a novel carbohydrate-based adjuvant derived from inulin, a natural plant-based polysaccharide¹⁰⁸ that acts as a ligand for DC-SIGN.⁶³ Delta inulin has been shown in animal and human studies to be well tolerated with minimal reactogenicity yet potent ability to enhance vaccine immunogenicity and provide antigen dose-sparing.¹⁰⁹ Notably, the severe eosinophilic pneumonitis caused by vaccines against severe acute respiratory syndrome (SARS) was completely prevented if delta inulin or a particularly a combined delta inulin and CpG adjuvant was used in the vaccines in place of alum adjuvant.⁷⁵ This was shown to be due to an ability of delta inulin to enhance the Th1 response and suppress an excessive Th2 response. Notably, in a human clinical trial of bee venom AIT, delta inulin favorably enhanced AIT immunogenicity, being shown to induce an early and prolonged switch to bee venom specific IgG4.⁶⁴ Delta inulin has similarly been applied to ant venom AIT as an allergen-sparing approach.³⁵ No data is yet available on use of use of delta inulin with or without CpG as adjuvants for mucosal AIT approaches, although they were recently shown to be safe and well tolerated in non-human primates as adjuvants in a mucosal-delivered SARS-CoV-2 vaccine.¹¹⁰

Chitin and chitosan are other polysaccharides that are naturally derived immunomodulators. Chitin is a polysaccharide from fungal cell walls and insect exoskeletons that can stimulate immune reactions. Some studies show that small chitin fragments can activate macrophages and even drive allergic inflammation by alternative macrophage activation and recruitment of eosinophils,⁷⁶ yet other studies demonstrate that chitin can help suppress allergic responses with the outcome dependent on the context, such as particle size and route.⁷⁷ For example, oral or lower airway administration of chitin was found to down-modulate allergic inflammation in mice.⁷⁸ Chitosan is derived from chitin by deacetylation and is widely studied as a vaccine delivery vehicle. It is a mucoadhesive, biocompatible polymer that can form nanoparticles, gels, or microspheres. Chitosan can transiently open tight junctions in mucosal epithelium, increasing paracellular antigen transport.⁷⁹ It also has its own immunological effects: chitosan particles can activate innate immunity and have been shown to bias toward Th1 responses in some cases.⁸⁰ In a murine dust-mite allergy model, intranasal administration of soluble chitosan during allergen sensitization significantly attenuated subsequent allergic airway inflammation.⁸¹ These observations align with broader work showing that adjuvanted allergen vaccines can shorten treatment and improve disease control in murine models, for example, an ultrashort-regimen Artemisia pollen vaccine demonstrated robust therapeutic benefit in allergic asthma.⁸² In parallel, mannose-conjugated chitosan nanoparticles used for intranasal antigen delivery have shown effective mucosal targeting and protection in vivo, underscoring chitosan’s value as a mannose-receptor–directed carrier.⁸³ Chitin/chitosan have begun to enter human testing: a Phase I/IIa clinical study was initiated using intranasal chitin microparticles in people with allergic rhinitis.⁸⁴ Early human data with intranasal chitin microparticles indicate acceptable tolerability and measurable modulation of nasal inflammatory markers.¹¹¹ Chitosan-based nasal sprays or allergen-nanoparticle vaccines could become a practical reality if they prove effective, with side-effects generally expected to be mild given their biopolymer nature.

Other Adjuvants

Saponin molecules like QS-21 (from Quillaja saponaria) stimulate both Th1 and Th2 responses as well as CD8 T cells and are a component of the powerful Adjuvant System AS01 (used in shingles and malaria vaccines).^96,97 However, one would be cautious about using a saponin adjuvant on mucosal surfaces such as the nasal cavity due to severe irritation from the detergent-like activity.

Cholera toxin B subunit (CTB) and related enterotoxin derivatives can induce IgA and tolerance when given mucosally with antigen⁷⁰ and intranasal administration of CTB conjugated to house dust mite allergen was reported to suppress IgE and airway inflammation in mice.³⁶ Similarly, oral or intranasal co-delivery of CTB with allergens has been shown to reduce allergic sensitization and symptoms in preclinical models.⁷¹ Despite these promising data, clinical use of enterotoxin-based mucosal adjuvants has been hampered by safety concerns: a notable example is the Swiss intranasal influenza vaccine formulated with a mutant E. coli heat-labile enterotoxin, which was associated with cases of facial nerve palsy and subsequently withdrawn.⁷² Even the genetically detoxified LT mutant, LTK63, was linked to transient facial nerve palsy in a clinical trial.⁷³ While further-detoxified derivatives have been engineered; for instance, the isolated A1 subunit of LT (LTA1),⁷⁴ the regulatory hurdles to approval of such products in allergy treatments could prove insurmountable.

Nanoparticles, Emulsions, and Advanced Delivery Systems

Nanoparticle delivery systems are increasingly being applied in the field of adjuvants. Nanoparticles can serve both as carriers (delivering allergen to the right cells) as well as immunomodulators by virtue of their size/structure giving them the ability to activate DC or by incorporating additional immune signaling compounds on their surface.^86,112 Multiple nanoparticle approaches have been explored in allergen immunotherapy. Liposomes are spherical vesicles made of phospholipid bilayers, typically 50–200 nm in diameter. They can encapsulate allergens (inside or intercalated in the membrane) and can also be loaded with adjuvant molecules like TLR ligands. Liposomes by themselves are largely biocompatible. Research in the 1990s showed that encapsulating allergen extracts in liposomes and injecting them into mice led to higher allergen-specific IgG and lower IgE compared with free allergen.⁸⁷ The liposomes are presumed to help more efficient targeting of allergen to antigen presenting cells. Plain liposomes lack inherent immune-stimulating ability.⁸⁸ To address this, composite adjuvant systems have been developed; for example, AS01 adjuvant contains liposomes mixed with MPLA and QS-21 saponin, combining the delivery capacity of liposomes with TLR4 and saponin immune activating signals. In the allergy context, a study of liposome encapsulated ovalbumin (OVA) together with CpG, a TLR9 agonist, significantly reduced allergic airway inflammation and cutaneous anaphylactic reactions in mice, whereas free OVA plus CpG given un-encapsulated was less effective.⁸⁹ The therapeutic effect required MyD88 signaling in DC, suggesting that the co-delivery format enhanced targeting of the CpG to antigen-presenting cells expressing TLR9. Hence, nanoparticle packaging can amplify the benefits of immunostimulatory adjuvants by ensuring spatiotemporal co-localization of allergen and adjuvant within the same APCs. Liposomes are also being explored for sublingual delivery; surface mannosylation and other ligand decorations may further improve dendritic cell targeting in mucosal tissues.

Virus-like particles (VLPs) are essentially the shells of viruses without any genetic material, typically self-assembling protein structures ~20–100 nm in size. They present repetitive, high-density antigen arrays that efficiently cross-link B-cell receptors.⁹⁰ Their size and geometry favor uptake by APCs, and VLP-based vaccines are already licensed for hepatitis B and human papillomavirus virus.⁹¹ Multiple VLP strategies are under exploration for allergy therapy.⁹² These include VLPs displaying allergens on their surface (covalently or by genetic fusion) to elicit blocking IgG, VLPs that package immunostimulatory molecules such as CpG to deliver adjuvant signals to APCs, VLPs that co-display allergen with an immune modulator, for example, IL-10 or TGF-β, to promote tolerance; and empty VLPs administered as an adjuvant alongside the allergen. Diverse VLP constructs have been shown to reduce allergic responses in animal models, reducing mast-cell activation and Th2 cytokines, and increasing blocking IgG.⁹³ The bacteriophage Qβ VLP loaded with CpG (QβG10/CYT003) was evaluated in allergic patients in a Phase I pilot, in combination with alum-adsorbed house-dust-mite extract,⁴⁰ resulting in ~10-fold symptom reduction and significant increases in allergen-specific IgG1, IgG2, and IgG4 during therapy.⁵¹ A larger Phase 2 trial of Qβ-CpG used without allergen, (allergen-independent immunotherapy) produced dose-dependent improvements in symptom-medication scores in dust-mite–allergic adults,⁹⁴ supporting the concept that a VLP with TLR9 activity may modulate allergy even in the absence of co-administered allergen.¹¹³ In allergic asthma, Qβ-CpG was reported to improve asthma control during corticosteroid reduction¹¹⁴ although a subsequent Phase IIb study in persistent moderate-to-severe asthma showed no significant benefit at 12 weeks.⁹⁵ In another VLP approach, cucumber-mosaic-virus VLPs were engineered to display peanut allergen epitopes while naturally carrying RNA as an intrinsic adjuvant.¹¹⁵ In peanut-sensitized mice, VLP displaying single major peanut allergens protected against anaphylaxis upon peanut challenge.¹¹⁶

Emulsion adjuvants are mixtures of water and oil that create micron- or nanometer-sized particles that can be used as vaccine adjuvants. They act as both a depot and an immune activator. MF59, a squalene-based emulsion recruits immune cells to the injection site and facilitates antigen uptake by APCs resulting in enhanced antibody production with mixed Th1/Th2 features.¹¹⁷ A nano-emulsion (NE) formulated with soybean oil W805EC was tested intranasally to formulate a peanut allergen vaccine for mice where it induced potent Th1/Th17 responses and protected against a subsequent peanut challenge.⁸⁵ Emulsions can also be applied to sublingual immunotherapy to potentially increase antigen uptake through the oral mucosa. That said, Pandemrix, a pandemic influenza vaccine with AS03 squalene emulsion was associated with increased narcolepsy risk in some populations.¹¹⁸ An emulsion adjuvant could allow less allergen to be used while helping to skew the allergen response away from Th2.¹¹⁹

Immunostimulatory complexes (ISCOMs) are cage-like nanoparticles (~40 nm) formed by self-assembly of cholesterol, phospholipid, and Quillaja saponins (eg., Quil-A) that package (or co-mix with) antigen.¹²⁰ By destabilizing endosomal membranes, ISCOMs deliver antigen into the cytosol of antigen-presenting cells, enabling efficient cross-presentation and robust CD8⁺ T-cell priming alongside strong antibody responses.^121,122 Although CD8⁺ responses are not the principal goal in allergy, the same cross-presentation and dendritic-cell activation can favor Th1/IFN-γ skewing and high-titer IgG that competes with IgE. In preclinical studies, saponin-based ISCOM adjuvant formulations have enhanced IgG responses to aeroallergens.^123,124 From a formulation perspective, ISCOMs are “empty” adjuvant particles (saponin–cholesterol–phospholipid) that are mixed with soluble antigens at the time of vaccination.^116,119 ISCOMs have shown strong adjuvant activity after intranasal administration, inducing durable secretory IgA and systemic responses in animal models.¹²⁵ A caveat is that saponins are highly reactogenic when applied to the mucosa causing severe epithelial irritation.¹²⁶

Adjuvanted Allergen Peptides

Human trials have tested adjuvants with synthetic allergen peptides to avoid IgE cross-linking. A cat allergen peptide vaccine (VACCAT study) used a mixture of Fel d 1 peptides combined with IL-12 as an adjuvant but was too reactogenic whereas the peptides alone were insufficiently immunogenic.¹²⁷

Probiotics and Vitamin D

Some clinical trials have evaluated administering immune-modulatory supplements alongside administration of AIT. A randomized study of children receiving grass SLIT plus oral vitamin D reported better clinical outcomes and immunologic signals of tolerance (higher IL-10 and increased CD4⁺CD25⁺FoxP3⁺ T cells) than those on grass SLIT alone.¹²⁸ A related pediatric study linked higher serum 25(OH)D levels during AIT with greater FoxP3 induction and a steroid-sparing effect, supporting a role for vitamin D in optimizing T_reg responses.¹²⁹ In another human trial a Lactobacillus rhamnosus probiotic was co-administered with peanut oral immunotherapy with a claim of higher rates of sustained peanut allergen unresponsiveness versus a placebo control, raising the question of whether a probiotic might have an adjuvant effect on gut-mucosal tolerance.¹³⁰ However, the absence of subsequent independent confirmation of these results question whether the effect was real or due to some form of confounding or bias in the trial design.

Anti-IgE–Facilitated AIT

Adding an anti-IgE monoclonal antibody such as omalizumab to AIT is a- strategy to rapidly lower free IgE and down-regulate FcεRI on effector cells to improve AIT safety and accelerate allergen dose escalation, reducing acute reactions during up-dosing and permitting higher maintenance doses.¹³¹ In peanut oral immunotherapy (OIT), randomized trials show that a short lead-in with omalizumab enables rapid escalation to multi-gram peanut doses with favorable tolerability, and many participants sustain higher challenge thresholds even after omalizumab is stopped.¹³² Similar facilitation has been demonstrated for rush SCIT in seasonal rhinitis, where omalizumab pretreatment cut the risk of anaphylaxis and improved outcomes.¹³³ Complementary to this approach, passive intranasal delivery of allergen-specific IgG has emerged as a mucosal “shield”: in a mouse model of mugwort allergy, with intranasal anti-Art v 1 monoclonal IgG markedly suppressing nasal and airway inflammation without altering IgE, suggesting a practical adjunct to protect patients during peak exposure periods or during early AIT dose escalation.¹³⁴

Bacterial Extracellular Vesicles

Bacterial extracellular vesicles, including outer membrane vesicles (OMVs), have recently gained attention as potential immunomodulatory platforms for the diagnosis and treatment of allergic diseases.¹³⁵ OMVs are nanoscale vesicles naturally released by bacteria and contain a complex repertoire of pathogen-associated molecular patterns, proteins, lipids, and nucleic acids capable of engaging innate immune receptors. Recent preclinical studies suggest that OMVs may modulate allergic inflammation by influencing antigen presentation, shaping T helper cell polarization, and promoting regulatory immune responses.¹³⁶ Their intrinsic adjuvant-like properties and capacity for mucosal interaction make them conceptually attractive for allergen immunotherapy. However, current evidence is largely limited to experimental models, and important challenges related to safety, standardization, and translational applicability remain to be addressed before clinical implementation.

Challenges in Developing Mucosal Adjuvant Vaccines

Collectively, the above studies underline a few key points. Adjuvants can substantially improve the efficacy of allergen immunotherapy, with potential to reduce years of desensitization therapy down to just a few vaccine doses.⁶⁹ New adjuvants are now available including MPLA, delta-inulin, CpG, and nano-emulsions, that have shown safety and efficacy in human trials, in the context of parenteral vaccine approaches, and may also be suitable for testing in mucosal AIT approaches. However, the failure of some late-stage allergy programs, for example, Cytos’s CYT003 asthma and Circassia’s cat-peptide program^95,137 highlight the challenges and risks with developing new allergy treatments. While the potential for adjuvants to improve mucosal AIT is high, there are ongoing challenges and considerations that must still be addressed. Adjuvants work by activating the immune system and thereby walk the line between therapeutic immune modulation and inducing pathological inflammation. Any new mucosal adjuvant must be rigorously tested for local tolerability with the intranasal route warranting caution because of the demonstrated potential for nose-to-brain transport via the olfactory pathway.¹³⁸ Regulators therefore expect robust evaluation of neurologic risk for novel intranasal products and large, well-controlled safety studies in this space. Additionally, strongly inflammatory adjuvants such as MPLA might trigger local airway inflammation or systemic cytokine toxicity.^106,139 Reassuringly, CpG¹⁴⁰ and MPLA¹⁴¹ have shown acceptable safety profiles in human AIT trials. Alternatively, newer adjuvants that work via activation of non-inflammatory immune receptors, for example, delta inulin may offer better mucosal alternatives. Delta inulin works as a ligand of DC-SIGN, a non-inflammatory receptor expressed on dendritic cells that acts to enhance their ability to prime antigen-specific T cells.⁶³ This thereby avoids the risk of excess inflammation, while still obtaining benefits of enhanced adaptive immune responses and antigen-sparing.

Each different mucosal surface has practical nuances. Oral delivery can lead to allergen degradation in the stomach and primarily engages oral tolerance, but high doses may induce gastrointestinal adverse effects including oesophageal eosinophilia.¹⁴² Sublingual delivery is convenient, but absorption of adjuvants through the oral mucosa may be limited, and the oral cavity lacks organized inductive lymphoid tissue.¹⁴³ Intranasal delivery engages a rich immune network in nasal-associated lymphoid tissue (NALT), but formulations (spray, drops, powder) must be optimized for consistent dosing, early innate activation can transiently aggravate rhinitis symptoms¹⁰⁶ and the potential for neurological toxicity must be excluded. Aerosolized, inhaled delivery can reach the bronchi but requires caution in patients with airway hyperreactivity, as bronchospasm is a recognized risk. Intralymphatic ultrasound-guided AIT administration is an innovative route that dramatically reduces the dose needed¹⁴⁴ although the approach is invasive.¹⁴⁵

Balancing Efficacy vs Tolerance

The goal in allergy vaccines is to induce tolerance, not merely immunity. Overly strong adjuvants can overshoot and drive robust inflammation with unwanted effector responses. For example, complete Freund’s adjuvant, a highly potent Th1-skewing adjuvant, can suppress Th2 activity but at the cost of marked tissue inflammation and potential Th1-mediated damage.¹⁴⁶ Achieving the optimal balance is challenging because patients vary widely (eg., highly Th2-skewed vs mixed Th2/Th17 phenotypes), suggesting that future personalization using biomarkers (eg., baseline interferon or IL-10 signatures) may guide adjuvant selection.

Regulatory Hurdles

Introducing new adjuvants into human vaccines is notoriously slow because of stringent safety requirements. The European Medicines Agency and the U.S. FDA expect extensive nonclinical (toxicology) programs before first-in-human testing, and regulators emphasize that adjuvants must be evaluated within their final vaccine formulations.^147,148 Historically, very few adjuvants have gained approval; for allergy products, additional complexity arises because many AITs are regulated as therapeutic products rather than classic prophylactic vaccines, meaning that each distinct allergen-adjuvant combination can be treated as a new product requiring full clinical development. The absence of standardized correlates of protection further complicates early efficacy assessment, IgG4 rises alone are insufficient, so field studies across pollen seasons, controlled exposure chamber studies, or food challenges are often needed. These scientific and regulatory barriers increase costs and risk, limiting innovation largely to research settings or to a few well-resourced developers.

Public Perception and Acceptance

One advantage of mucosal AIT is better acceptance. For example, many patients prefer sublingual immunotherapy (SLIT) over injections despite its daily dosing.⁸ Educating patients that transient immune stimulation (eg., fever or injection-site redness) can be normal and offset by long-term benefit is part of the challenge. Using the term “allergy vaccine” may also trigger hesitancy in some. Any safety concerns or adverse events could amplify skepticism, so robust pharmacovigilance and transparent safety monitoring will be essential during early rollouts.

Disease Heterogeneity

Allergic diseases span from mild intermittent rhinitis to severe, chronic asthma or eczema, and adjuvant-aided immunotherapy may perform differently across this spectrum. Atopic dermatitis is characterized by barrier defects and mixed Th2/Th22 inflammation and it remains uncertain whether mucosal vaccines can meaningfully impact skin disease. Food allergy poses additional challenges: while OIT relies on daily oral dosing, vaccine-style regimens (eg., limited injections or sublingual courses with adjuvant) could theoretically accelerate desensitization but require validation.

Manufacturing and Formulation

Some next-generation adjuvants, particularly VLPs and nanoparticles/liposomes pose nontrivial manufacturing and formulation challenges. VLP platforms face issues of process scalability, particle homogeneity, and stability that often require platform-specific solutions and excipients.¹⁴⁹ Allergens (extracts or recombinant proteins) add another layer: their stability and release profiles can shift when combined with adjuvants or novel dose forms, necessitating careful selection of drying technologies (eg., lyophilization, spray-drying) and tablet architectures for SLIT to ensure reproducible delivery.^150,151 Oil-in-water emulsions (MF59/AS03) are generally robust but have well-defined manufacturing windows and handling constraints (sensitivity to freezing, oxidation and pH), requiring tight in-process controls to maintain droplet size and composition.^152,153 For liposomes, co-loading allergen with immunostimulants (CpG) can improve co-delivery but raises batch-to-batch consistency questions (encapsulation efficiency, antigen-adjuvant ratios, release kinetics) that must be locked down for good manufacturing practice (GMP) production.¹⁵⁴ Finally, allergen extract stability (shelf life/expiry, temperature excursions) remains a regulatory focal point and can be affected by the addition of adjuvants or new device formats.¹⁵⁵

Despite these challenges, the field is steadily advancing. Knowledge from both successful and failed trials refines our understanding. For example, the failure of intranasal LT in influenza vaccination prompted researchers to further detoxify toxins or avoid intranasal use of such adjuvants. The success of CpG in allergy suggests it might be combined with other strategies (for instance, CpG plus an IL-10–inducing component to bias toward tolerance). Combining multiple adjuvants may yield synergistic effects as seen with tyrosine plus MPLA in ultra-short AIT⁵⁶ or with liposome-packaged CpG that co-delivers immune-stimulation with allergen,⁷² but it also complicates manufacturing and regulatory approval. Nonetheless, precisely formulated combination adjuvants such as, for example, the AS01 liposomal formulation containing MPL and QS-21, have set a precedent showing that such products can be licensed in vaccines.^71,156

Future Directions and Perspectives

The landscape of mucosal adjuvants for allergy vaccines is dynamic and full of possibility. Going forward, several key strategies and research directions are likely to shape the field. We anticipate a focused effort to engineer adjuvants that preferentially drive regulatory immunity such as agents such as retinoic acid that condition dendritic cells to produce IL-10 and/or amplify TGF-β signaling, thereby favoring FoxP3⁺ T-regulatory cell induction.¹⁵⁷ Other strategies might include use of exogenous immunoregulatory cues, such as specific probiotic strains that elicit IL-10–producing Tregs via DC reprogramming and helminth-derived immunomodulators (for example, ES-62) that dampen type-2 inflammation and remodel effector pathways.¹⁵⁸ With deeper patient profiling (cytokine signatures, transcriptomics, specific IgE/IgG patterns), adjuvant selection and dosing could be tailored to immune phenotype. For example, in an IL-5–dominant eosinophilic profile, a Th1-promoting adjuvant might be prioritized; if IgG4 induction is weak, a depot system that enhances antibody production could be favored. Practical tools such as the basophil activation test (BAT) and early immunologic biomarkers are needed to predict AIT responders and to monitor on-treatment immunomodulation, supporting a move toward precision medicine in AIT.¹⁵⁹

Combination of Biologicals with Vaccines

A growing body of evidence supports pairing biologics with AIT/OIT to improve safety and accelerate desensitization. For example, omalizumab used as a short lead-in to peanut OIT enables faster, safer dose escalation and higher tolerated doses, with many patients maintaining protection after omalizumab discontinuation. Beyond anti-IgE, dupilumab (anti-IL-4Rα) as an adjunct to peanut OIT has shown modest incremental efficacy (but without preventing OIT-related reactions), informing how to time and dose combination regimens.¹⁶⁰ In respiratory allergy, tezepelumab (anti-TSLP) combined with SCIT improved clinical and mechanistic outcomes versus SCIT alone in a randomized trial, illustrating that upstream cytokine blockade can potentiate AIT.¹⁶¹ These data align with the strategy you describe: a time-limited biologic “reset,” followed by vaccine-driven durable tolerance.

New Routes and Devices

Epicutaneous immunotherapy has advanced with the Viaskin peanut patch.¹⁶² Microneedle patches are emerging as a painless, skin-targeted platform for co-delivery of allergen and adjuvant.¹⁶³ Pulmonary delivery is being explored using inhaled TLR9 agonists; early human studies showed interferon responses and acceptable safety, but later trials reported mixed clinical efficacy in asthma.¹⁶⁴ Intradermal delivery leveraging skin dendritic cells has yielded inconsistent results in allergic rhinitis, underscoring the need for optimized dosing/formulations.¹⁶⁵ Strategically combining routes (a limited number of injections to induce systemic IgG plus mucosal doses to drive local IgA/Tregs) remains a rational direction as devices and formulations mature.

Multi-Allergen Vaccines

Many patients are polysensitized (eg., pollens, dust mites, molds), and mucosal adjuvants could enable broader-spectrum immunotherapy. One strategy is a multi-allergen cocktail although component dominance and uneven immunogenicity may occur.¹⁶⁶ Another concept is bystander suppression, in which adjuvanted therapy directed at one allergen dampens responses to others; in murine models, an intranasal nano-emulsion vaccine suppressed Th2 responses to multiple unrelated food allergens via IFN-γ induction and reduced epithelial alarmins. Collectively, these approaches support the hypothesis that well-chosen mucosal adjuvants might shift the broader atopic milieu, potentially benefiting polysensitized patients and, if validated clinically, helping to interrupt the “atopic march”.

Preventive Vaccination

A forward-looking strategy is primary prevention of allergy through early-life induction of mucosal tolerance in infants at elevated risk (eg., strong family history, severe eczema). Proof-of-concept already exists: the LEAP randomized trial showed that introducing peanut exposure early in infancy markedly reduced subsequent peanut allergy, with follow-up work confirming durability of protection into adolescence.¹⁶⁷ Likewise, the EAT trial tested early introduction of multiple allergenic foods in breast-fed infants and demonstrated reduced food allergy for per-protocol adherers, supporting the feasibility of proactive tolerance induction to several allergens.¹⁶⁸ These data underpin clinical guidance recommending early peanut introduction in infants at risk, a public-health shift toward prevention over treatment.¹⁶⁹ Extending this paradigm, prophylactic mucosal vaccines that pair very low-dose allergen(s) with tolerogenic adjuvants could, in principle, amplify IgG4 and regulatory T-cell programs with minimal dosing, enabling safe, scalable prevention of common food and aeroallergen sensitizations. Ethically and practically, such approaches would require careful selection of candidates, but if validated, they could help blunt the trajectory of the atopic march.

Integration with Microbiome Science

The intestinal and airway microbiota shape allergic sensitization and tolerance, creating opportunities to use microbiome-derived cues as functional adjuvants. Short-chain fatty acids (SCFAs), especially butyrate, promote regulatory T-cell programs and IL-10 production, suggesting that postbiotics or fiber-based formulations could be paired with oral immunotherapy to bias toward tolerance.^170,171 Adjunctive probiotic + OIT regimens (eg., Lactobacillus rhamnosus with peanut OIT) have produced higher rates of sustained unresponsiveness in children, suggesting microbiome modulation may enhance clinical outcomes.¹⁷² Beyond the gut, topical/nasal probiotics are being tested to tune local immunity in hay fever; early human studies of intranasal probiotic treatments suggest acceptable safety and signals of symptomatic benefit, supporting further development of nasal microbiome adjuvant therapy.^173,174 Next-generation approaches include defined bacterial consortia and metabolite delivery (postbiotic) to rationally co-administer with allergen therapy as tolerogenic “environment shapers.”.¹⁷⁵

Next-Generation Cytokine or Checkpoint Modulators

A promising direction is to design adjuvants that actively bias dendritic cells (DCs) and allergen-specific T cells toward tolerance rather than effector activation. Pharmacologic strategies that enhance PD-1/PD-L1 signaling on DCs, for example, could favor regulatory T-cell (Treg) induction.¹⁷⁶ This is the opposite of their use in oncology where they are used to block T cell regulation.¹⁷⁷ Metabolic-sensor pathways such as the aryl hydrocarbon receptor (AhR) offer other tolerogenic levers. AhR ligands (including host- or microbiota-derived tryptophan metabolites) can drive Treg differentiation and restrain type-2 inflammation, providing a tractable target for mucosal “tolerogenic adjuvants”.¹⁷⁸ Mechanistically, the IDO-kynurenine-AhR axis integrates tryptophan catabolism with AhR signaling to skew toward immune regulation, suggesting that AhR agonists or approaches that elevate endogenous kynurenines in a controlled fashion, could be paired with allergens to stabilize tolerance.¹⁷⁹

Limitations of Adjuvant-Based Approaches in Allergen Immunotherapy

Despite their promise, adjuvant-based approaches in allergen immunotherapy have inherent limitations. The immunological effects of many adjuvants are context-dependent and may vary according to allergen type, formulation, route of administration, and patient-specific immune profiles. As a result, findings from one allergen or delivery route may not be directly generalizable to others. In addition, precise control of immune polarization remains challenging. While immunostimulatory adjuvants aim to suppress Th2-driven IgE responses and promote regulatory or Th1-biased immunity, excessive or inappropriate activation may increase the risk of unwanted inflammation. Furthermore, predictive biomarkers that reliably identify responders or guide adjuvant selection are still lacking, complicating patient stratification and individualized treatment strategies.

Conclusions

The field is moving toward more precise and potent allergy vaccines enabled by advances in adjuvant design. Over the next decade, several of the concepts discussed above, including the use of novel mucosal adjuvants, are expected to progress toward clinical application in allergic diseases. This could make mucosal AIT a more practical and widely adopted solution, rather than a niche option. The armamentarium of potential mucosal adjuvants spans biodegradable depot carriers, innate immune receptor ligands, nano-emulsions, and nano particles that can co-deliver allergen and immunomodulators to the same antigen-presenting cells.

Key challenges remain, including achieving maximal efficacy without provoking local or systemic reactogenicity, scaling GMP-compliant manufacturing of complex formulations, harmonizing regulatory pathways, and accounting for disease heterogeneity. Progress will hinge on rational adjuvant design (favoring IL-10/TGF-β–linked tolerance pathways), route-appropriate formulations for sublingual, oral, intranasal, or intradermal delivery, and the integration of biomarkers (basophil activation, mucosal IgA, transcriptional signatures) to personalize adjuvant choice and dose. Synergistic strategies including brief use of biologics to “reset” the inflammatory milieu, microbiome-informed adjuncts, and next-generation devices (patches, microneedles, aerosols), offer additional levers to enhance efficacy, safety and durability. Future progress in the field will depend on the rational selection of adjuvants, improved understanding of their mechanisms of action, and carefully designed clinical studies that balance efficacy with safety.