Revisiting Oral Tolerance to Peanut Allergens

The complexities associated with food allergens were recently heightened in a proposed pharmaceutical agent. Purportedly, this agent would allow those with peanut allergies to consume this nut, possibly without adverse events such as gastrointestinal symptoms, respiratory distress, rhinitis, or some forms of dermatitis. Peanut allergy is among the most common food allergies; it impacts nearly 5% of school-age children, according to a 2014 report (Bunyavanich, Rifas-Shiman, Platts-Mills, et al. 2014).

Several reports over the past decade question the prospects of developing an oral tolerance to or immunotherapy for peanut allergens. The current standard of care is elimination or avoidance of peanuts in the diet (Sampson 2013). Unfortunately, not all foods and food safety practices at home and in restaurants consider that even the smallest amount of peanut or peanut powder could trigger a life-threatening adverse event.

The current evidence suggests the prevalence of peanut allergy continues to increase. While many mechanisms exist for this apparent rise in peanut allergic reactions, the complexities associated with these reactions challenge even the strongest advocates of oral immunotherapy (OIT or oral tolerance). Several recent comprehensive reviews suggest there is insufficient, and certainly inconsistent, evidence that OIT for peanuts, and perhaps even fruit, is safe and effective, and therefore it requires additional appropriate investigations (Nurmatov, Venderbosch, Devereux, Simons, and Sheikh 2012) (Yepes-Nuñez, Zhang, Roqué, et al. 2015).

One of many challenges within the global food industry and among international consumers is the inconsistency of allergen declaration. Within the United States, there are the basic eight—milk, eggs, fish, crustacean shellfish, tree nuts, peanuts, wheat, and soybean—which cover about 90% of food allergic reactions. In Canada, there are additional required allergen declarations that include sesame seeds, mollusks (more than just crustaceans), triticale (a hybrid of wheat and rye grains), and mustard. Within the European market, there are 14 mandated food allergen declarations, which include those required within the United States and Canada plus cereals with gluten, celery, sulphites and sulphur dioxide (>10 ppm), and lupin. If one were to step back to gain a global perspective on this topic, the cluster of food allergens to be declared include those mentioned plus buckwheat, bee pollen/propolis, royal jelly, mango, tomato, and latex (natural rubber) and many of those on the GSO voluntary list. The voluntary recommendations include abalone, mackerel, squid, salmon, salmon roe, cashew, walnut, matsutake mushroom, sesame, soybean, yam, apple, banana, kiwifruit, orange, peach, beef, chicken, gelatin, and pork among 28 GSO nations of the Gulf Cooperation Council, including Saudi Arabia, United Arab Emirates, Kuwait, Bahrain, Oman, Qatar, and Yemen.

As a reminder, when studying pharmaceutical agents (and often when evaluating potential food bioactives), there are several basic clinical assessment phases. These phases are preceded by appropriate discovery evaluations and animal trials to evaluate possible mechanism(s) of action, toxicology, and safety considerations, which are often referred to as preclinical studies (or phase 0). Then there are phases I, II, III, and IV, with results of the earlier phase contributing to the design of subsequent study phases. In phase II, a modest number of subjects (based on phase I) are used to further evaluate the safety (including any adverse events) and efficacy of the substance under investigation. Then, in phase III, a large study population is used to further evaluate the safety (including adverse events) and efficacy of potential therapeutic doses (American Cancer Society 2017).

In phase II of an oral immunotherapy trial, the safety and efficacy of a novel medication to potentially reduce or eliminate adverse events when consuming peanuts were evaluated (Bird, Spergel, Jones, et al. 2018). Evidence from this study among a small group of individuals (4–29 years old) sensitized to peanuts from eight centers within the United States indicated ≥443 mg and 1,043 mg of peanut protein at exit were tolerated. The primary adverse event was the presentation of gastrointestinal symptoms, which led to the withdrawal of six subjects in the intervention group. The authors contended that these results justified further research (phase III) with a larger population, including children, adolescents, and young adults.

In a phase III trial, 4- to 55-year-old subjects with clinically diagnosed peanut protein allergy were subjects of a double-blind, placebo-controlled food challenge (PALISADE Group 2018). The study protocol and monitoring of adverse events were similar to those implemented and assessed by Burks, Jones, Wood, et al. (2012), who studied oral immunotherapy among children who presented egg allergy. The most frequent adverse events among children with peanut allergy include rhinitis, gastrointestinal symptoms, and systemic reactions (Virkud, Burks, Steele, et al. 2017).

Results from the peanut trial indicated 67.2% of those who received active treatment, as compared with 4.0% who received placebo, were able to ingest a dose of 600 mg or more of peanut protein, without dose-limiting symptoms following the food challenge at the end of the study. However, it is important to note that more than 90% of the participants, regardless of group assignments, presented with adverse events during the intervention period. As with any clinical study, subjects from both groups (intervention and control) withdrew from the study because of adverse events.

Importantly, the U.S. Food and Drug Administration will consider these studies and the spectrum of evidence on the OIT as appropriate for medical management of peanut allergy. The limitations of these studies and the propensity of consumers to exceed recommended amounts of peanuts in a single setting could jeopardize the health of sensitized individuals. Some ideal treatment for peanut allergy would provide safe and efficacious tolerance, defined by the sustained absence of symptoms after allergen ingestion even after periods of prolonged avoidance, and we must acknowledge that desensitization is certainly not the panacea. It is, however, sufficiently intriguing and promising that more research is justified in order to fully understand the immunologic changes that occur with the various forms of food immunotherapy. A greater understanding of these mechanisms could potentially lead to the discovery of useful biomarkers to track success of treatment. Additional work is needed toward investigation of the ability of adjuvants and other adjunctive therapies to promote long-lasting tolerance as well as safety.

The longer-term side effects of sustained consumption of an allergen to which the body has produced IgE antibodies remain unknown. Legal issues may also ultimately be a concern in terms of how peanut flour is characterized by regulatory frameworks and agencies.

Roger Clemens, DrPH, CFS, Contributing Editor
Adjunct Professor, Univ. of Southern California’s School of Pharmacy, Los Angeles, Calif.
[email protected]

Peter Pressman, MD, is director, The Daedalus Foundation ([email protected]).