Introduction

The increasing trend in food allergy (FA) prevalence over the past few decades is a cause for concern and a public health problem [1]. It is a potentially life-threatening disease increasing anxiety and decreasing quality of life for participants and their caregivers [2]. FA is now estimated to affect between 4–11 % of infants and young children, with peanut allergy affecting about 2 % of children [3, 4]. Although the majority of children outgrow milk (68 %) [5] and egg (79 %) [6] allergies, the likelihood of outgrowing peanut allergy is much lower (27 %)[7]. The current standard of care for the management of FA involves strict elimination of the offending allergen and treating reactions due to accidental exposures with antihistamines and epinephrine. Allergen avoidance is difficult to accomplish because many allergenic foods, such as milk, eggs, and peanuts, are common ingredients in many foods. Accidental ingestion is common and a 10-year follow-up study found that 75 % of individuals with peanut allergy accidentally consumed peanuts, stressing the need for effective treatments [8]. Although not currently FDA-approved for FA, allergen-specific immunotherapy (AIT) has shown promise for treating FA [9].

In AIT, incremental doses of allergen are administered via various routes, such as oral, subcutaneous, sublingual, and epicutaneous [9]. Oral immunotherapy (OIT) and sublingual immunotherapy (SLIT) have been the most common and best researched FA immunotherapies. Subcutaneous immunotherapy has been shown to be efficacious but it is no longer being actively investigated as a treatment for FA because of high adverse reactions [10]. Epicutaneous immunotherapy is a novel mode of FA treatment and preliminary results are promising [11]. The goal of early food immunotherapy trials was to achieve desensitization by increasing antigen threshold to levels that can prevent allergic reactions on accidental ingestion. The ultimate goal of immunotherapy for FA is to enable ingestion of food allergens in amounts that are commonly ingested in diets and to establish a state of permanent desensitization even after periods of discontinuation of allergen ingestion (tolerance). Currently, one of the limitations of immunotherapy for FA is that, in a number of individuals, continued ingestion of allergen appears necessary for maintenance of desensitization. As data on long-term follow up studies of OIT or SLIT is limited and biomarkers for establishing permanent tolerance are not currently available, current studies aim to establish sustained unresponsiveness (SU), defined as a sustained desensitization after a specified period of allergen avoidance [12, 13, 14]. A second limitation of AIT is the long treatment period (months to years), which is further magnified for the 30% of food-allergic individuals who have multiple allergies [3]. These limitations are being addressed by the use of novel adjuvants such as probiotics and anti-IgE antibodies.

Although the exact mechanisms underlying AIT is unclear, studies have indicated that they likely include skewing of T helper (Th) cell responses from a Th2 towards a Th1 cytokine profile, suppression of mast cell and basophil degranulation, upregulation of IL-10-producing regulatory T cells (Tregs) and B regulatory cells (Bregs), decreases in peanut-specific IgE, increases in peanut-specific IgA and IgG4, deletion of antigen-specific T cells, and suppression of late-phase effector cells such as eosinophils. Further details on mechanisms underlying allergic reactions to foods and desensitization with AIT can be obtained from a number of excellent reviews [15, 16, 17, 18, 19]. While OIT introduces allergens to the gastrointestinal tract and activates gut mucosal dendritic cells, SLIT mostly interacts through pro-tolerogenic Langerhans cells in the oral mucosa, and both modalities downregulate allergic responses through immunomodulation of tissue and circulating effector cells [18, 20]. In this review, we compare SLIT and OIT, the most common forms of immunotherapy, for peanut allergy. Tab. 1 summarizes clinical trials of SLIT and OIT trials.

Tab. 1 Summary of major OIT and SLIT Trials in Peanut Allergy
Full size table

Oral immunotherapy

OIT is a promising treatment option for inducing desensitization in FA and for improving FA-related quality of life. Early studies evaluated safety of OIT with updosing to a maintenance dose of 800 mg of peanut protein (1 peanut contains about 240 [21] to 300 mg of peanut protein) [22]. The goal of these studies was to desensitize individuals and reduce risk of reaction on accidental ingestion. Subsequent studies increased maintenance doses up to 4,000 mg of peanut protein to desensitize individuals to amounts normally ingested in diets. In a peanut-OIT study published in 2009, Hofmann et al. [22] evaluated safety of peanut OIT in peanut-allergic children and found that significant allergic reactions were more likely during the initial escalation day than during the build-up or home dosing phase. Allergic reactions during home dosing were rare with only a 3.5 % risk of reaction (0.7 % of home doses needed treatment). On initial escalation day, 93 % (26/28) experienced symptoms with upper respiratory (79 %) and abdominal (68 %) being the most common symptoms. 71 % completed the study. In a subsequent study of peanut OIT by Jones et al., participants similarly updosed to a maintenance dose of 300 mg peanut protein and continued on this dose until food challenge. The daily maintenance dose was subsequently increased to 1,800 mg in those participants whose peanut IgE remained >2 kU/L after 12 months on maintenance dose. 29 out of the 39 participants completed the protocol and 27 passed OFC of 3,900 mg peanut protein. [21].

The first randomized, double-blind, placebo-controlled study to investigate the safety and effectiveness of peanut OIT in children was reported in 2011 by Varshney et al. After the initial escalation day, participants in the active group were updosed to a much higher maintenance dose (4,000 mg peanut protein) than that of previous studies. Sixteen of the 19 OIT-treated participants completed the 1 year protocol and passed the 5,000 mg OFC, while the 9 placebo-treated participants ingested a much lower dose (median cumulative dose of 280 mg) indicating effectiveness of peanut OIT in inducing desensitization to doses normally ingested in diets. None of the OIT participants required epinephrine or hospitalization [23]. A phase 2 randomized controlled trial (STOP II) of peanut OIT was conducted by Anagnostou et al. in 2014. At the end of 24 weeks, 39 of 49 participants in the active group reached the maintenance dose of 800 mg and 24 successfully completed post-OIT (DBPCFC, double-blind placebo-controlled food challenge); however, 0 of 50 controls achieved desensitization. Participants in the control group who were allergic to peanuts were subsequently offered peanut OIT during a second open-label cross-over phase of the study. At the end of the second phase, 54 % of the participants passed a 1,400 mg food challenge to peanut protein and 91 % tolerated an 800 mg daily dose [24]. A 2017 placebo-controlled study evaluated bronchial hyper-responsiveness (BHR) and airway inflammation as an aspect of peanut OIT safety. In this study, 33 of the 39 OIT-treated participants reached a daily maintenance dose of 4 peanuts and 67 % passed the post treatment OFC of 5,000 mg peanut powder (1255 mg protein) at the 8 month DBPCFC, while none of the 21 controls were desensitized. There was no change in lung function and BHR tended to be alleviated, but the change was not statistically significant. These results indicated that peanut OIT was effective for severe allergy with no harmful effect on BHR or airway inflammation [25].

To assess whether the protective effect of peanut OIT is sustained after stopping treatment, a follow-up study of participants who were successfully desensitized [21] was conducted by Vickery et al. As mentioned earlier, in the study by Jones et al. [21], 29 out of the 39 participants completed the protocol and 27 passed OFC of 3,900 mg peanut protein. These participants were then maintained at a dose of 4,000 mg peanut protein for up to 5 years and then asked to discontinue the maintenance dose for 1 month. In all, 24 participants successfully completed the protocol, and 12 participants passed the food challenge 1 month after OIT discontinuation. This was the first study to demonstrate sustained unresponsiveness (SU) after peanut OIT [26]. In a second study, Vickery further evaluated SU as well as the safety, effectiveness, and feasibility of early peanut OIT in preschool children. Forty peanut-allergic preschool children aged 9–36 months were enrolled in a double-blind, randomized OIT trial and block-randomized 1 : 1 to receive treatment at goal daily maintenance doses of 300 or 3,000 mg peanut protein. SU was assessed 1 month after stopping treatment. Success was reported in suppressing allergic immune responses with both tested doses. Seventeen of 20 children in the low-dose group and 13 of 17 in the high-dose group were desensitized, while 17 of 20 and 12 of 17, respectively, achieved SU [27], indicating that 300 mg/day was as effective as 3,000 mg/day. This has clinical implications as a lower maintenance dose is likely to lead to better long-term compliance. A study by Nagakura et al. [28] evaluated SU in participants with confirmed anaphylactic symptoms. The historical control group consisted of 11 participants with anaphylaxis by OFC who underwent a second OFC after 2 years. Twenty-two Japanese children with peanut allergy, aged 6–18 years, all of whom demonstrated anaphylaxis during a baseline DBPCFC, were enrolled to receive peanut OIT. After the initial rush phase (5–12 days) in hospital, patient administered peanut at home during the long-term build-up phase (0–12 months). Daily ingestion dose was gradually increased to a maintenance dose of 795 mg of peanut protein. By 8 months, all participants were desensitized, which was defined as being able to consume 795 mg peanut protein without symptoms after stopping premedication. All participants completed the protocol. Fifteen out of 22 participants passed the second OFC after 2 weeks of peanut elimination and achieved SU. In the control group, only 2 of 11 participants passed OFC.

Peanut OIT protocols and peanut allergen doses have as yet not been standardized among studies, which have variably used whole peanuts, peanut flour, protein, or powder. AR101 is a peanut product developed by Aimmune. It consists of defatted lightly roasted peanut flour with the relative antigen potency of Ara h1, Ara h2, and Ara h6 kept uniform. In 2017, Bird et al. [29] published the first randomized, double-blind, placebo-controlled phase 2 clinical trial to assess the safety and efficacy of AR101 in peanut OIT. Fifty-five participants aged 4 to 26 years were enrolled at 8 US centers, with 29 participants receiving AR101 and 26 receiving placebo. Eighteen of 29 AR101-treated and 0 of 26 placebo-treated participants tolerated 1,043 mg peanut protein, respectively, at exit DBPCFC. Compared with placebo, AR101 significantly reduced symptom severity during exit DBPCFCs.

Oral immunotherapy with adjuvants

As mentioned earlier, some of the limitations of OIT are the recurrence of peanut sensitization after a period of peanut avoidance or elimination and the lengthy treatment period. To address these limitations, adjuvants such as probiotics and other biologics have been evaluated in clinical trials. Tang et al. co-administrated a probiotic (Lactobacillus rhamnosus CGMCC 1.3724) with peanut OIT (PPOIT) in a randomized, double-blind, placebo-controlled trial. Sixty-two peanut-allergic children aged 1–10 years were randomized 1 : 1 into a treatment or placebo group and underwent PPOIT for 18 months. The active group received a fixed daily dose of probiotic together with OIT, while the placebo group received placebo only. DBPCFC of 4,000 mg peanut protein was performed at the last day of treatment and at 2 or more weeks after stopping treatment. SU was achieved in 23 of 28 treated participants and 1 of 28 placebo-treated participant [30]. The study concluded PPOIT was effective at inducing SU compared with placebo [30]. A 4-year long-term follow-up study of treatment cessation of eligible participants from the PPOIT study was recently published. The study found that participants from the PPOIT group were significantly more likely than those from the placebo group to have continued eating peanut (16 out of 24 vs 1 out of 24, respectively) and attain 8 week SU (7 of 12 vs 1 of 15 from the placebo group, respectively) but less likely to have allergic reactions (4 out of 24 vs 6 out of 24, respectively). None of the participants had anaphylactic reactions. These results indicate that PPOIT provides long-term SU after cessation of treatment. A drawback of the study was a lack of a probiotic group (without OIT) to clarify the relative contributions of probiotics versus OIT [31].

Omalizumab (Xolair, Genentech), a monoclonal anti-IgE antibody approved for treatment of asthma, has had success as an adjuvant to OIT. It reduces the concentration of circulating IgE and mast cell activation and potentially alleviates allergic reactions [32]. In 2013, Schneider et al. published a pilot study of omalizumab in high-risk peanut-allergic participants. Thirteen participants aged 7 to 15 years received omalizumab for 12 weeks prior to onset of OIT. A cumulative dose of 992 mg peanut flour (about 496 peanut protein; peanut flour contains about 50 % peanut protein) was administered over a period of 6 h during the rush desensitization. Updosing escalation phase began with 500 mg peanut flour the next day and increased gradually over time until the daily maintenance dose of 4,000 mg peanut flour was reached. Twelve weeks after omalizumab withdrawal, 92 % (12/13) tolerated oral food challenge with 8,000 mg peanut flour and achieved desensitization [33], indicating a rapid decrease in time to desensitization. A major limitation of the study was the small sample size and the absence of a placebo group. However, the data from the study provides preliminary evidence regarding the safety and efficacy of adjunct omalizumab. MacGinnitie et al. also reported in a phase 2 double-blind, placebo-controlled trial that omalizumab facilitates rapid oral desensitization. A total of 37 peanut-allergic participants aged 6–19 years were enrolled and randomized in a 3.5 : 1 ratio with 29 participants receiving omalizumab and 8 receiving placebo. OIT began 12 weeks after the first dose of omalizumab. Omalizumab was administered till week 19 to participants who tolerated 1625 mg peanut protein. There were 8 participants including 2 from active group and 6 from control who could not tolerate 250 mg of peanut protein after 8 weeks of desensitization, and thereby received open-label omalizumab, while initial therapy remained blinded. Daily maintenance dose was 2000 mg of peanut protein. Six weeks after withdrawal of omalizumab, 73.9 % of the omalizumab group, 12.5 % of the placebo group, and 100 % of the open-label group reached desensitization to 2,000 mg of peanut protein. Twelve weeks after withdrawal of omalizumab, 79 % of the active group and 12.5 % of the placebo group achieved desensitization to 4,000 mg of peanut protein [34]. These studies indicate that adjuvant omalizumab with OIT leads to faster desensitization as it allows participants to start at a higher initial dose than conventional OIT and reduces the number of allergen doses needed to reach the target maintenance dose.

Sublingual immunotherapy

SLIT is a well-studied method of immunotherapy in individuals with allergic rhinitis [20]. Allergens, in the form of drops or tablets are held under the tongue and the immunogenic properties of the oral mucosa are invoked, leading to desensitization over time [20]. The primary indication for SLIT continues to be allergic rhinoconjunctivitis; however, it is being actively explored in the treatment of FA [20, 35], and since the first reported trials in 2003 for FA to kiwi fruit [36], there have been many clinical trials showing promise for several foods, including peanut.

Since 2011, there have been two randomized, DBPCFC trials for peanut SLIT [37, 38]. The first study, by Kim et al. [37], enrolled 18 peanut-allergic children (ages 1–11 years) who were either randomized to peanut SLIT (n = 11) or placebo (n = 7). The dose of SLIT was kept under the tongue for 2 min and then swallowed. Over the next 6 months, during the escalation phase, the participants in the active group reached a dose of 2.5 mg of peanut protein and continued for an additional 6 months in the maintenance phase and then underwent DBPCFC. All 11 children in the active group were able to complete the desensitization protocol. The median dose of the posttreatment OFC was 1,710 mg, which was more than 20 times the amount achieved in the placebo group (85 mg). There were minimal safety concerns in the study with dosing side effects mainly involving oropharyngeal symptoms which generally did not require treatment.

Two years later, Fleischer et al. [38], published the results of the first multicenter, randomized, double-blind placebo-controlled clinical trial involving peanut SLIT. The study included 40 participants (ages 12–37 years), who were treated with peanut SLIT or placebo. Participants performed an initial peanut DBPCFC for inclusion in the study, with a median successfully consumed dose of 46 mg. At the end of phase 1 of the trial (44 weeks; goal dose of 1.386 mg peanut protein per day), 14 out of 20 (70 %) participants were considered “responders” and able to tolerate either 5,000 mg of peanut powder (about 2,500 mg of peanut protein) or a 10-fold higher amount than their baseline challenge. The median successfully tolerated dose increased from 3.5 to 496 mg. During the second phase of the study (unblinded), the active peanut-SLIT group continued on maintenance therapy for an additional 24 weeks (total 68 weeks), and the placebo group crossed over to a higher active peanut SLIT dose (3.696 mg of peanut protein daily). After 68 weeks of therapy, the median tolerated dose of peanut increased to 996 mg in the original active peanut-SLIT group. For the participants in the crossover group (original placebo group), who received 44 weeks of active peanut-SLIT, 7 of 16 participants (35 %) were considered to be “responders”, and the median successfully consumed dose was up to 496 mg from a baseline of 21 mg. Based on these results, the authors concluded that the longer duration of treatment was more efficacious than the higher dose. The safety profile was again found to be very reassuring. Of the 10,855 peanut-SLIT doses over 44 weeks, 63.1 % of participants were symptom free. On excluding oropharyngeal symptoms, 95.2 % of participants were found to be symptom free [38].

The study continued for 3 additional years over an open-label period of active peanut SLIT along with yearly DBPCFCs. At 3 years, participants who passed DBPCFC to 10,000 mg (about 5,000 mg peanut protein) discontinued peanut maintenance doses and SU was assessed 8 weeks later by another DBPCFC to 10 g peanut powder and an open feeding of peanut butter. Only 4 of the original 40 participants (11%) achieved SU. There were no notable differences between the group on 1,386 vs. 3,695 mg of daily peanut protein. The safety profile was excellent; however the authors concluded that peanut SLIT induces only a modest level of desensitization [39].

Sublingual immunotherapy versus oral immunotherapy

Only one study to date has directly compared OIT and SLIT in a randomized double-blind placebo-controlled clinical trial while another study has performed a retrospective comparison. In 2013, Chin et al. performed a retrospective comparison of peanut OIT vs. SLIT using data from previous published SLIT and OIT protocols for peanut [23, 37]. In these studies, 27 subjects underwent peanut SLIT on a dose of 2 mg/day of peanut protein, and 18 subjects were treated with an OIT dose of 4,000 mg/day of peanut protein. DBPCFC were performed after 12 months of therapy to 2,500 mg in the SLIT group and 5,000 mg in the OIT group. Although there were differences among the DBPCFC protocols, participants in the SLIT group reacted at lower eliciting dose thresholds than the participants in the OIT group. Subjects in the OIT group were 3 times more likely to pass the 12-month DBPCFC than the subjects in the SLIT group. The authors concluded that OIT was more efficacious than SLIT in inducing desensitization to peanut protein.

Two years later, Narisety et al. published the results of a randomized double-blind, placebo controlled pilot study exploring the differences between SLIT and OIT for peanut allergy [40]. The study included 21 children (between 7–13 years) who were randomized to receive active SLIT vs placebo OIT or active OIT vs. placebo SLIT. The doses were escalated to 3.7 mg in the SLIT group or 2,000 mg in the OIT group, and the participants were challenged after 6 and 12 months of treatment. After the 12-month challenge the participants were unblinded, therapy was modified and participants were offered an additional 16 months of therapy. The participants who passed OFCs at 12 or 18 months (for those with extended therapy), discontinued therapy for 4 weeks and were rechallenged. In all, 63.3 % of the participants in the active OIT group and 70 % in the active SLIT group completed the 12-month double-blind phase and had a greater than 10-fold increase in challenge threshold compared to baseline. However, the threshold was significantly larger in the OIT group (141-fold) vs. the SLIT group (22-fold). At the end of the study 1 participant from the SLIT group and 3 from the OIT group successfully demonstrated SU. OIT appeared to be far more efficacious than SLIT for the treatment of peanut allergy. Notably, adverse reactions were more common with OIT, including moderate reactions, doses requiring treatment and study discontinuation due to gastrointestinal symptoms.

Discussion

OIT is a well-investigated approach to treat FA and has been studied in many clinical trials for over a decade. More recently, studies using adjuvants such as omalizumab and probiotics with OIT have shown promise and appear to reduce the rate of recurrence of peanut sensitization after a period of peanut avoidance or elimination as well as the lengthy treatment period. Adjuvant omalizumab with OIT has also been shown to be safe and effective in those with multiple food allergies (including peanuts) [41]. Clinical evidence has been accumulated substantially more in OIT than in SLIT. Although there are a relatively fewer number of SLIT clinical trials targeting peanut allergy, the efficacy and safety of SLIT has been demonstrated in allergic rhinitis and other FA. It is not surprising to see that SLIT of which the treatment dose is log-fold lower than OIT, is associated with fewer adverse reactions and symptom-related early study withdrawal. Current evidence shows that significantly greater immunologic changes are seen in OIT than in SLIT, specifically, changes in skin test results, peanut-specific IgE, IgG4, and IgE/IgG4 ratio, and basophil activation. OIT tends to have a higher and less variable eliciting threshold in OFC than SLIT. It has been difficult to maintain SU after treatment in most participants with either modality. It is noteworthy that combination of the two modalities could induce significant increases in challenge thresholds and protection against adverse reactions. In its current state SLIT may be useful as a bridging technique before initiating OIT in highly sensitive individuals or it may be coupled with adjuvants to make it more effective and be used as stand-alone therapy.

Further investigation is needed to define the optimal dosing strategy and administration protocol in both approaches, and the potential for combination of the two treatment methods remains to be explored. More randomized, double-blinded, placebo-controlled, head-to-head clinical trials are necessary for a direct comparison. More data is needed for the long-term outcome as well, since very little is known about the effects of even brief lapses in exposures, after many years of therapy.