Experimental therapies for food allergy: Immunotherapy and nonspecific therapies

INTRODUCTION — Food allergy encompasses a variety of immune-mediated adverse reactions to foods that occur in genetically predisposed persons [1]. Management of food allergy consists of strict avoidance of the food allergen and treatment of accidental exposures with medications. Allergies to certain foods, such as hen's egg and cow's milk (CM), tend to be outgrown during childhood, whereas allergies to other foods, such as shellfish and nuts, are much more likely to persist. Several approaches are under investigation for the treatment of food allergy. (See "Management of food allergy: Avoidance" and "Food-induced anaphylaxis" and "Anaphylaxis: Emergency treatment".)

Novel therapeutic approaches to food allergy can be classified as food allergen specific (eg, immunotherapy with native or modified recombinant allergens, or oral desensitization) or food allergen nonspecific (eg, anti-immunoglobulin E [IgE], traditional Chinese medicine [TCM]) (table 1) [2]. The ultimate goal of therapy is to induce permanent tolerance to the food, where the allergy will not recur upon reexposure after a period of abstinence (figure 1 and table 2). However, some therapies in development appear to only temporarily desensitize or protect patients, requiring continued treatment to maintain efficacy. Before these new approaches are applied in routine clinical practice, they must be carefully evaluated for both efficacy and adverse effects, such as acute adverse reactions, toxicity, and overstimulation of T helper type 1 (Th1) immune responses that could prime for autoimmunity.

Investigational food-specific therapies, as well as nonspecific therapies, are reviewed here, with the exception that Chinese herbal therapy for food allergy is discussed separately. Oral immunotherapy (OIT) for food allergy is also reviewed separately. (See "Chinese herbal medicine for the treatment of allergic diseases", section on 'Therapy for food allergy' and "Oral immunotherapy for food allergy".)

TERMINOLOGY — Various terms are used to describe goals and outcomes in patients treated for food allergy (table 2 and figure 1):

●Tolerance – "Tolerance" is a permanent state, which means that there is no recurrence of clinical reactivity upon reintroduction of the food after a period of abstinence.

●Sustained unresponsiveness or remission – Permanent tolerance is difficult to confirm, particularly in a shorter-term clinical trial. Thus, the term "sustained unresponsiveness" (SU) was coined to describe the lack of a reaction to ingestion of a full challenge dose after therapy was discontinued for weeks to months.

●Desensitization – "Desensitization" is a temporary state of protection that requires continued exposure to the allergen to maintain the protective state. Patients can be fully desensitized to a food, such that they can ingest a normal serving size without having a reaction, or partially desensitized, such that the reaction threshold (eliciting dose) is raised but they still react to an amount less than a normal serving size. Partially desensitized patients, in theory, should be less likely to have a reaction to an accidental exposure because of the increased reaction threshold.

●Response – Specific studies may define the "rate of response" or "responders" in a variety of ways. As an example, responders may be subjects who can ingest the full challenge dose or those who are able to ingest a 10-fold-higher dose than they could at baseline.

GOALS OF TREATMENT FOR FOOD ALLERGY — The ultimate goal of treatment for food allergy is to induce permanent tolerance to the food. Important goals for patients and their parents/caregivers are reduction of anxiety related to food allergies and improvement in quality of life. These goals may be accomplished even if the patient does not develop permanent tolerance but rather a temporary state of desensitization or protection from accidental exposures. They may also be accomplished even if dietary restrictions are not lifted by increasing the eliciting dose and thereby reducing the risk of reactions to the food. This enhanced safety often also improves quality of life. Partial reintroduction of the food may have some nutritional value as well. (See "Management of food allergy-related anxiety in children and their parents/caregivers".)

EXPERIMENTAL FOOD ALLERGEN-SPECIFIC THERAPY

Overview of allergen-specific therapy — The aim of allergen-specific immunotherapy is to alter the allergic response to the food allergen so that the patient becomes partially or fully desensitized or, preferably, tolerant to the specific food. Food allergen-specific therapies under investigation include sublingual, epicutaneous, and subcutaneous immunotherapy (SLIT, EPIT, and SCIT). Allergens used for SCIT have been modified to decrease allergenicity while retaining immunogenicity. Oral immunotherapy (OIT) for food allergy is discussed in detail separately. (See "Oral immunotherapy for food allergy".)

Sublingual immunotherapy

Overview of SLIT — One experimental approach to food immunotherapy is SLIT with food extracts. SLIT has been attempted for peanut [3-6], hazelnut [7,8], cow's milk (CM) [9,10], and kiwi [11,12] allergies. Both OIT and SLIT are expected to be safer than subcutaneous administration, with lower rates of systemic reactions reported for SLIT than OIT [3,7,9,11]. However, most studies report higher efficacy of OIT regarding desensitization and induction of tolerance compared with SLIT, although with higher rates of side effects [4,9]. SLIT is used off label by some as it is felt to be a safer alternative to OIT. However, there are no US Food and Drug Administration (FDA) approved products, and the available commercial SLIT food extracts contain very low doses of food protein, raising questions about the efficacy of treatment. (See "Oral immunotherapy for food allergy".)

Mechanisms of action — There are few effector cells, such as mast cells, in the sublingual mucosa [13]. Allergen extracts given sublingually are not systemically absorbed. Rather, they are taken up by dendritic cells in the mucosa and presented to T cells in the draining lymph nodes. Likely mechanisms of action include downregulation of mast cells and activation of T regulatory cells.

Treatment approach in clinical trials — In most clinical trials, patients are started on a very low dose of allergen, and the dose is advanced every week or two to the maintenance dose over several months [3-5,9]. Occasionally, a faster schedule of dose advancement is used (rush schedule) to reach the maintenance dose within a matter of days [7]. The maintenance dose for SLIT is much lower than that used for OIT. As an example, 1.4 to 4 mg versus 2000 mg of peanut protein was used for SLIT and OIT, respectively, in several studies (as a reference, an average-size peanut contains approximately 250 to 280 mg of protein, and 2 tablespoons of peanut butter contains 8 grams) [3-5,14].

Efficacy — In small, randomized trials of SLIT versus placebo, the rate of full desensitization (successfully consumed a normal serving size) ranged from 0 to 42 percent for SLIT compared with approximately 10 percent in the placebo group, and the rate of response (successfully consumed full challenge dose or a 10-fold increase over baseline) ranged from 41 to 70 percent for SLIT compared with 15 percent in the placebo group after four to seven months of maintenance therapy [5-7]. Two peanut SLIT trials reported sustained unresponsiveness (SU) rates of 10 to 21 percent after three to five years of therapy, although 65 percent of the original 40 subjects in one of the trials did not continue therapy during the extended phase of the study [6,15]. A study of peanut OIT reported a modeled median time to loss of clinically significant desensitization (successfully consumed dose >800 mg peanut protein) of 22 weeks [14]. Randomized trials of peanut and CM SLIT versus OIT demonstrated similarly low rates of desensitization (0 to 10 percent) and SU (10 percent) [4,9].

Peanut skin prick test (SPT) wheal, peanut-specific IgE, and basophil activation to peanut decreased significantly compared with baseline values, and peanut-specific immunoglobulin G4 (IgG4) levels increased significantly [14,15].

SLIT trials have generally used the desensitization endpoints defined as ability to ingest a regular serving of food without an allergic reaction, similarly to the OIT trials. This is in contrast with peanut EPIT trials that defined treatment success as a 10-fold increase in the eliciting dose and/or eliciting dose of 1000 mg or greater of peanut protein. When reanalyzing SLIT results according to the EPIT treatment success criteria, SLIT shows a superior efficacy.

Safety — While allergic symptoms with SLIT occur in 5 to 40 percent of doses, they are primarily isolated to the oropharynx [5,6,8,14,15]. Systemic reactions are rare with SLIT, with only one reported reaction that required treatment with epinephrine. No cases of treatment-associated eosinophilic esophagitis (EoE) have been reported for food SLIT, although it has been reported with aeroallergen SLIT [16].

Epicutaneous immunotherapy

Overview of EPIT — The epicutaneous delivery of protein for immunotherapy is under investigation in patients with IgE-mediated CM and peanut allergies and EoE due to CM allergy [17-21] and is in preclinical studies for hen's egg. The epicutaneous delivery system (EDS) solubilizes the allergen by perspiration and disseminates it into the thickness of the stratum corneum [22]. The patches are applied on the upper back in the interscapular area in children ≤11 years of age, and the site of application is rotated daily. In children >11 years, the patches are applied on the inner surface of the arm. The patches are applied to intact skin (eczematous skin is avoided).

Epicutaneous delivery is less invasive than subcutaneous injection and may have a lower risk for systemic reactions than subcutaneous, oral, or sublingual food allergen delivery. Doses are also lower than those used for OIT or SLIT, 250 mcg versus 2 to 4 mg in SLIT and 300 to 2000 mg in OIT. In addition, there is no dose-escalation phase for EPIT compared with OIT or SLIT; the initial dose is the maintenance dose.

Efficacy — Four trials have demonstrated an at least 10-fold increase in the eliciting dose after treatment with peanut EPIT in 35 to 67 percent of patients compared with 12 to 33 percent in the placebo groups [20,21,23-26]. SU to the eliciting dose after 36 months of therapy was found in 7 to 9 percent of patients in two of the trials [24,27]. Desensitization or SU to ingestion of a regular serving of food has not been studied. This therapy appears to be more effective (higher rates of desensitization) in toddlers and young children (response rate difference 33 and 22 percent, respectively) than in older children and adults (no difference in response rate compared with placebo) [20,21,26].

Increased peanut-specific IgG4 levels and IgG4/IgE ratios were detected in patients treated with peanut EPIT, along with trends toward decreased basophil activation and peanut-specific T helper type 2 (Th2) cytokines [20]. Significant increases in peanut- and Ara h2-specific IgG4 observed at week 52 persisted to week 130 [23].

Safety — Most patients report adverse events, primarily mild local skin reactions including localized erythema, eczema, pruritus, and/or urticaria at the site of application [17-21,25]. Mild-to-moderate anaphylaxis has been reported [25-27]. In the toddler peanut EPIT trial, for example, treatment-related anaphylaxis occurred in four infants (1.6 percent) in the active group, with reactions occurring on the first day of application, compared with no similar events in the placebo group. One subject who received CM EPIT had repeated episodes of diarrhea [17]. Adherence is high, and dropout for adverse events is generally low.

Subcutaneous immunotherapy — Early clinical trials with SCIT demonstrated that immunomodulation can be effectively used to induce oral tolerance to peanut but, at the same time, highlighted the serious side effects associated with food allergen immunotherapy [28,29]. Systemic allergic reactions were common both during the build-up phase and with maintenance injections. Subsequent studies have focused on minimizing adverse side effects that are largely IgE mediated. These investigational therapies have been tested in animal models, but most have not been tested in humans.

Chemically modified, alum-adsorbed immunotherapy — A chemically modified, aluminum hydroxide-adsorbed peanut extract given by weekly subcutaneous administration is under evaluation in subjects 5 to 50 years of age with peanut allergy in a safety and tolerability randomized trial [30]. A phase-IIb clinical trial evaluating safety and efficacy of SCIT with alum-adsorbed recombinant fish allergen parvalbumin is completed but not yet published [31,32]. Preliminary results of a small clinical trial evaluating safety and immunomodulation with alum-adsorbed, chemically modified peanut extract found that local and systemic reactions were observed more often in the active group, although no late (more than four hours after therapy) systemic reactions were observed [33].

Peptide immunotherapy — Elimination of IgE binding can be achieved with vaccines consisting of overlapping peptides (protein fragments 10 to 20 amino acids long) that represent the entire sequence of a specific protein. Antigen-presenting cells (APCs) are provided with all possible allergenic epitopes, but mast cells are not activated, because the short peptides are unable to crosslink IgE molecules [34]. Peptide immunotherapy appears to induce T cell unresponsiveness and production of interferon (IFN) gamma in a concentration-dependent manner in human in vitro studies [35].

Although promising in a mouse model of peanut allergy [36], peptide immunotherapy is not a practical option for human therapy, because standardization of a vaccine containing over 100 peptides is extremely difficult. A more refined vaccine containing only the most relevant (tolerogenic) peptides is a more feasible option if these peptides can be determined [37]. A phase-II trial with this type of peptide vaccine for peanut in underway in Australia (NCT05621317).

Intradermal/intramuscular immunotherapy with LAMP-DNA vaccines — A next-generation deoxyribonucleic acid (DNA) vaccine platform has been designed to stimulate an immune response against a particular protein. For food allergy immunotherapy, allergen DNA is combined with the genetic sequences for lysosome-associated membrane proteins (LAMPs) and inserted into plasmid DNA. After vaccine administration, APCs take up the vector, and the DNA is translated into allergen associated with LAMP. This vaccine uses the natural biochemistry of LAMP to intersect with the process that APCs use to internalize, digest, and present exogenously derived antigens to the immune system as part of the lysosomal/major histocompatibility complex (MHC) class II molecules complex and activate CD4+ helper T cells, as well as CD8+ cytotoxic T cells. In a mouse model of cedar allergy, the result was a more complete immune response, including antibody production, cytokine release, and development of critical immunologic memory [38]. This contrasts with the immune response to conventional DNA vaccines, which are processed and primarily presented through MHC I and elicit a cytotoxic CD8+ T cell response. Whether or not these immunologic findings in mice also occur in humans remains to be determined.

A LAMP-DNA vaccine for peanut allergy includes the major peanut allergens, Ara h 1, Ara h 2, and Ara h 3. In peanut-allergic C3H/HeJ mice that were sensitized via oral ingestion of peanut and cholera toxin, intradermal injection of 50 mcg LAMP-peanut vaccine attenuated allergic symptoms during peanut challenge as indicated by lower disease scores and higher body temperature compared with vector control, reduced peanut-specific IgE levels, and increased peanut-specific IgG2a levels. There is an ongoing phase-I randomized trial of intradermal or intramuscular administration of this vaccine in adults and adolescents with peanut allergy to evaluate safety, tolerability, and immune response [39].

Immunotherapy with modified proteins and adjuvants — Generation of "hypoallergenic" recombinant proteins that have lost the ability to interact with IgE antibodies directed against native protein (ie, allergenicity) but retain the ability to interact with T cells (ie, immunogenicity) should improve the safety of immunotherapy because these engineered recombinant proteins should not activate mast cells. The two main techniques are site-directed mutagenesis and polymerization. These modified proteins are more potent when applied together with immunomodulatory adjuvants. Bacteria are potent stimulants of T helper type 1 (Th1) immune responses. Modified bacterial products, such as heat-killed bacteria [40-43] or synthetic immunostimulatory sequences (ISS) [44,45], can be used as adjuvants in immunotherapy. There are no ongoing clinical trials with these approaches, in part due to safety concerns.

NONSPECIFIC THERAPY

Overview of nonspecific therapy — The aim of nonspecific therapies for food allergy is primarily to downregulate the allergic immune response [46]. Some therapies in development have only a transient effect, but others may be curative. Allergen-nonspecific therapies include monoclonal antibodies against IgE (anti-IgE), traditional Chinese medicine (TCM), and blockade of vasoactive mediators (eg, leukotrienes, prostaglandins, bradykinin). Other potential biologic treatments for food allergy include monoclonal antibodies against alarmins (anti-interleukin [IL] 33, anti-thymic stromal lymphopoietin [TSLP]), Bruton tyrosine kinase (BTK) inhibitor (ibrutinib), and Janus kinase (JAK) inhibitors. Additional novel approaches include use of a Toll-like receptor 9 (TLR9) agonist to decrease T helper type 2 (Th2) responses and induce T helper type 1 (Th1) responses [47] and blockade of vasoactive mediators such as platelet-activating factor (PAF) from mast cells and basophils [48].

Anti-IgE

Overview of anti-IgE — Anti-IgE therapy alone is not a cure, and protection requires administration at regular intervals indefinitely. However, its appeal is that it should be effective for allergy to any food. It may have a role in pretreatment before oral immunotherapy (OIT) and has been shown to decrease the rate of adverse events during single and multifood OIT. Prior to clinical application, further studies are necessary to confirm and optimize the protective effect of anti-IgE against food allergy, establish a safety profile in young children, and identify markers for selecting patients who are most likely to benefit from anti-IgE therapy. (See "The biology of IgE" and "Oral immunotherapy for food allergy", section on 'OIT plus anti-IgE' and "Anti-IgE therapy".)

Mechanisms of action — Allergen-specific IgE antibodies play an important role in the pathophysiology of food allergy. IgE antibodies bind to high-affinity receptors (Fc-epsilon-RI) on the surface of mast cells and basophils. Crosslinking of IgE molecules on the surface of mast cells by allergen leads to the release of preformed mast cell mediators (the early phase of an allergic reaction) as well as synthesis of proinflammatory cytokines and chemokines that result in late-phase reaction [49]. Humanized monoclonal anti-IgE antibodies (anti-IgE) bind to IgE molecules, preventing them from binding to IgE receptors; downregulate the expression of the high-affinity IgE receptor on mast cells; and decrease basophil histamine release [50].

Efficacy — Studies suggest that anti-IgE monotherapy can alter the reaction threshold for many treated patients, but additional studies on safety and efficacy are needed. Cost may also be an issue since long-term monotherapy would be required. An alternative approach is using anti-IgE as pretreatment or concomitant treatment with OIT, with the goal of improving both safety and efficacy of OIT. (See "Oral immunotherapy for food allergy", section on 'OIT plus anti-IgE'.)

●Talizumab – One clinical trial using anti-IgE antibody as monotherapy for peanut allergy demonstrated an increase in mean baseline threshold of sensitivity in all groups with an apparent dose response that was only significant in the 450 mg group (increased from 178 to 2805 mg, or half a peanut to nearly nine peanuts, an effect that should provide protection against most accidental ingestion) [51]. However, even at the highest dose of talizumab, approximately 25 percent were not protected.

●Omalizumab – Omalizumab is another anti-IgE humanized IgG1 antibody that has no formal indication for food allergy. However, accumulating clinical trial results and real-world experience support benefits for patients with food allergy who are treated with omalizumab monotherapy for asthma or chronic urticaria. A systematic review and meta-analysis of clinical trials and observational studies concluded that omalizumab monotherapy (compared with pretreatment) was associated with a significant increase in the tolerated dose of multiple foods, cow's milk (CM), hen's egg, wheat, and CM in baked foods; improvement in quality of life; and a reduced rate of allergic reactions [52]. The dosing is determined by the approved indication for which omalizumab is prescribed. In clinical trials for food allergy, dosing is based upon the dosing schedule for asthma, incorporating body weight and total IgE. Omalizumab also has proven benefits (reduced adverse events, shortened time to maintenance) when used in combination with OIT, as pretreatment, and/or as a concomitant therapy [53]. Use of omalizumab in combination with OIT is discussed in greater detail separately. (See "Oral immunotherapy for food allergy", section on 'OIT plus anti-IgE'.)

●Ligelizumab – Another humanized IgG1 anti-IgE molecule, ligelizumab, has significantly higher potency of binding to the high-affinity IgE type I receptor (Fc-epsilon-RI) on the surface of basophils and mast cells, but not to low-affinity IgE receptor type II (Fc-epsilon-RII, CD23), compared with omalizumab. Ligelizumab is more efficacious versus omalizumab in chronic spontaneous urticaria but less efficacious in asthma [54]. Assessment of ligelizumab safety and clinical efficacy in 486 participants ages 6 to 55 years with peanut allergy is underway in a multicenter phase-III clinical trial (NCT04984876).

●Quilizumab – Quilizumab is an anti-IgE monoclonal humanized IgG1 molecule specifically targeting the M1 prime epitope of cell membrane-bound IgE. In randomized trials for allergic asthma and chronic spontaneous urticaria, it was found to decrease IgE levels but did not improve clinical parameters [55,56]. It has not been studied for the treatment of food allergy.

Safety — Anti-IgE molecules are generally well tolerated. Rare adverse effects include hypersensitivity reactions, injection-site reactions, and serum sickness. The adverse effects of anti-IgE are discussed in greater detail separately. (See "Anti-IgE therapy", section on 'Adverse effects'.)

Anti-IL-4 — Dupilumab is a fully human monoclonal antibody that binds to the alpha subunit of the interleukin (IL) 4 receptor and inhibits downstream signaling of IL-4 and IL-13, cytokines of type 2 helper T lymphocytes (Th2) that are believed to play a key role in atopic diseases. It is indicated for the treatment of moderate-to-severe atopic dermatitis, moderate-to-severe asthma with eosinophilic phenotype, eosinophilic esophagitis (EoE), and chronic rhinosinusitis with nasal polyposis. Ongoing clinical trials are evaluating efficacy and safety of dupilumab as monotherapy (NCT03793608) or with OIT (NCT03682770) [57]. The monotherapy trial was an open-label study that enrolled 24 participants. Following 24 weeks of dupilumab dosing every two weeks (dose of 200 or 300 mg subcutaneously based on body weight), 8.3 percent (95% CI, 1.03-27.00) of the participants met the primary endpoint of passing a double-blind placebo-controlled food challenge (DBPCFC) with at least 444 mg (cumulative) peanut protein. This disappointing result led to discontinuation of investigation into dupilumab monotherapy for peanut allergy. Use of dupilumab in combination with OIT is discussed in greater detail separately. (See "Oral immunotherapy for food allergy", section on 'OIT plus dupilumab'.)

Monoclonal antibodies targeting alarmins — Etokimab, a monoclonal antibody against the alarmin IL-33 (anti-IL-33), was evaluated in a six-week placebo-controlled phase-IIa study in 20 adults with peanut allergy assigned 3:1 to treatment or placebo, with inconclusive results [58].

Small molecule inhibitors — Acalabrutinib, a small molecule inhibitor of BTK, which is critical to B cell signaling and cytokine pathways, is under study for prevention of anaphylaxis in adults with allergy to peanut and/or tree nuts (NCT05038904). Abrocitinib, an inhibitor of JAK, which plays a critical role in the modulation of immune system function including T cells and cytokine receptors, is under investigation for the treatment of food allergy in adults with a history of eczema (NCT05069831).

Fecal microbiota transplantation — Environmental factors such as imbalance intestinal microbiome may play a role in the development of food allergy. Study of oral encapsulated fecal microbiota transplantation (FMT) in adults with peanut allergy is ongoing (NCT02960074).

Traditional Chinese medicine — Herbs have been used in Asia for centuries for treatment of various ailments, including asthma and environmental allergies. TCM attracted interest because of its reported effectiveness, favorable safety profile, and low cost [59,60]. The mechanism of action of TCM is largely unknown despite extensive clinical experience with TCM in Asia. One double-blind, placebo-controlled multicenter clinical trial evaluated the safety and efficacy of enhanced, butanol-purified food allergy herbal formula 2 (E-B-FAHF-2) for inducing remission in patients undergoing omalizumab-facilitated multiallergen OIT [61]. Omalizumab-facilitated multifood OIT was safe and effective, and remission was achieved in approximately one-quarter of subjects. However, outcomes were not improved by addition of E-B-FAHF-2. At this time, TCM has no proven role in treatment of food allergy.

Investigational Chinese herbal formula for food allergy is reviewed in greater detail separately. (See "Chinese herbal medicine for the treatment of allergic diseases".)

SUMMARY AND RECOMMENDATIONS

●Overview – Management of food allergy consists of strict avoidance of the food allergen and treatment of accidental exposures with medications. The ultimate goal of therapy for food allergy is to induce tolerance, which means the patient can consume the food ad libitum without symptoms or fear of a reaction. However, a reduction in the risk of allergic reactions through desensitization, even if the food cannot be fully reintroduced into the diet, may be a sufficient outcome for many patients (figure 1 and table 2). Novel therapeutic approaches to food allergy can be classified as food allergen-specific or food allergen-nonspecific (table 1). (See 'Introduction' above and 'Terminology' above and 'Goals of treatment for food allergy' above.)

●Experimental food allergen-specific therapy – The aim of allergen-specific immunotherapy is to alter the allergic response to the food allergen so that the patient becomes partially or fully desensitized or, preferably, tolerant to the specific food. We suggest not routinely using any of these interventions (Grade 2C) until further data are available that confirm a favorable balance of efficacy and safety:

•Sublingual immunotherapy (SLIT) – Most patients are at least partially desensitized, but persistent tolerance after discontinuation of therapy is uncommon. Systemic reactions are rare and generally mild. (See 'Sublingual immunotherapy' above.)

•Epicutaneous immunotherapy (EPIT) – EPIT is safe and well tolerated, induces modest desensitization, and may be more efficacious when initiated in younger children.

•Peptide immunotherapy – This approach minimizes the risk of immunoglobulin E (IgE) mediated reactions because the peptides are too small to bind to and crosslink IgE. Standardization issues make this option less viable. There are no human studies in food allergy. (See 'Peptide immunotherapy' above.)

•Lysosome-associated membrane protein (LAMP) deoxyribonucleic acid (DNA) vaccines – This next-generation plasmid DNA vaccine results in a more complete immune response in animal models than conventional DNA vaccines and is under investigation for the treatment of peanut allergy.

•Immunotherapy with modified proteins and adjuvants – Modified bacterial products, such as heat-killed Escherichia coli (HKE), are used as immunomodulatory adjuvants. A human trial with rectally administered HKE producing recombinant hypoallergenic peanut proteins was unsuccessful. (See 'Immunotherapy with modified proteins and adjuvants' above.)

●Experimental nonspecific therapy – The primary aim of nonspecific therapies for food allergy is to downregulate the allergic immune response. We suggest not routinely using any of these interventions (Grade 2C) until further data are available that confirm a favorable balance of efficacy and safety:

•Anti-IgE – Anti-IgE monoclonal antibody (anti-IgE) can be used for any food allergen, but it is not curative, and protection is not uniform. Anti-IgE monotherapy is being studied in conjunction with oral immunotherapy (OIT). (See 'Anti-IgE' above and "Oral immunotherapy for food allergy", section on 'OIT plus anti-IgE'.)

•Anti-interleukin (IL) 4/IL-13 – Anti-IL-4/IL-13 receptor monoclonal antibody is under investigation for the treatment of eosinophilic esophagitis (EoE) and for IgE-mediated peanut allergy as monotherapy and as adjunctive therapy to peanut OIT. (See 'Anti-IL-4' above.)

•Traditional Chinese medicine (TCM) – The exact mechanism(s) of this herbal therapy is unclear. Preclinical studies in a murine model of peanut-induced anaphylaxis demonstrate a protective effect that may be prolonged. However, human efficacy trials did not show a benefit. (See 'Traditional Chinese medicine' above and "Chinese herbal medicine for the treatment of allergic diseases".)