Scientific Opinion on development needs for the allergenicity and protein safety assessment of food and feed products derived from biotechnology
2022; Wiley; Volume: 20; Issue: 1 Linguagem: Inglês
10.2903/j.efsa.2022.7044
ISSN1831-4732
AutoresEwen Mullins, Jean‐Louis Bresson, Tamás Dalmay, Ian Crawford Dewhurst, M. Epstein, Leslie George Firbank, Philippe Guerche, Jan Hejátko, Hanspeter Naegeli, Fabien Nogué, Nils Rostoks, Jose Juan Sánchez Serrano, G. Savoini, Eve Veromann, Fabio Veronesi, Antonio Fernández Dumont, F. Javier Moreno,
Tópico(s)Agricultural safety and regulations
ResumoEFSA JournalVolume 20, Issue 1 e07044 Scientific OpinionOpen Access Scientific Opinion on development needs for the allergenicity and protein safety assessment of food and feed products derived from biotechnology EFSA Panel on Genetically Modified Organisms (GMO), Corresponding Author EFSA Panel on Genetically Modified Organisms (GMO) GMO_secretariat_applications@efsa.europa.eu Correspondence:GMO_secretariat_applications@efsa.europa.euSearch for more papers by this authorEwen Mullins, Ewen MullinsSearch for more papers by this authorJean-Louis Bresson, Jean-Louis BressonSearch for more papers by this authorTamas Dalmay, Tamas DalmaySearch for more papers by this authorIan Crawford Dewhurst, Ian Crawford DewhurstSearch for more papers by this authorMichelle M Epstein, Michelle M EpsteinSearch for more papers by this authorLeslie George Firbank, Leslie George FirbankSearch for more papers by this authorPhilippe Guerche, Philippe GuercheSearch for more papers by this authorJan Hejatko, Jan HejatkoSearch for more papers by this authorHanspeter Naegeli, Hanspeter NaegeliSearch for more papers by this authorFabien Nogué, Fabien NoguéSearch for more papers by this authorNils Rostoks, Nils RostoksSearch for more papers by this authorJose Juan Sánchez Serrano, Jose Juan Sánchez SerranoSearch for more papers by this authorGiovanni Savoini, Giovanni SavoiniSearch for more papers by this authorEve Veromann, Eve VeromannSearch for more papers by this authorFabio Veronesi, Fabio VeronesiSearch for more papers by this authorAntonio Fernandez Dumont, Antonio Fernandez DumontSearch for more papers by this authorFrancisco Javier Moreno, Francisco Javier MorenoSearch for more papers by this author EFSA Panel on Genetically Modified Organisms (GMO), Corresponding Author EFSA Panel on Genetically Modified Organisms (GMO) GMO_secretariat_applications@efsa.europa.eu Correspondence:GMO_secretariat_applications@efsa.europa.euSearch for more papers by this authorEwen Mullins, Ewen MullinsSearch for more papers by this authorJean-Louis Bresson, Jean-Louis BressonSearch for more papers by this authorTamas Dalmay, Tamas DalmaySearch for more papers by this authorIan Crawford Dewhurst, Ian Crawford DewhurstSearch for more papers by this authorMichelle M Epstein, Michelle M EpsteinSearch for more papers by this authorLeslie George Firbank, Leslie George FirbankSearch for more papers by this authorPhilippe Guerche, Philippe GuercheSearch for more papers by this authorJan Hejatko, Jan HejatkoSearch for more papers by this authorHanspeter Naegeli, Hanspeter NaegeliSearch for more papers by this authorFabien Nogué, Fabien NoguéSearch for more papers by this authorNils Rostoks, Nils RostoksSearch for more papers by this authorJose Juan Sánchez Serrano, Jose Juan Sánchez SerranoSearch for more papers by this authorGiovanni Savoini, Giovanni SavoiniSearch for more papers by this authorEve Veromann, Eve VeromannSearch for more papers by this authorFabio Veronesi, Fabio VeronesiSearch for more papers by this authorAntonio Fernandez Dumont, Antonio Fernandez DumontSearch for more papers by this authorFrancisco Javier Moreno, Francisco Javier MorenoSearch for more papers by this author First published: 25 January 2022 https://doi.org/10.2903/j.efsa.2022.7044Citations: 1 Requestor: EFSA internal mandate Question number: EFSA-Q-2020-00316 Panel members: Ewen Mullins, Jean-Louis Bresson, Tamas Dalmay, Ian Crawford Dewhurst, Michelle M Epstein, Leslie George Firbank, Philippe Guerche, Jan Hejatko, Francisco Javier Moreno, Hanspeter Naegeli, Fabien Nogué, Nils Rostoks, Jose Juan Sánchez Serrano, Giovanni Savoini, Eve Veromann and Fabio Veronesi. Declarations of interest: The declarations of interest of all scientific experts active in EFSA's work are available at https://ess.efsa.europa.eu/doi/doiweb/doisearch. Acknowledgements: The Panel wishes to thank the members of the Working Group on Allergenicity, the members of the Stakeholder Consultative group 'Focus Group', the hearing experts Clare Mills and Henk van Loveren and the EFSA staff Riccardo Vriz, Anna Lanzoni and Michele Ardizzone for the support provided to this scientific output. Adopted: 2 December 2021 AboutSectionsPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract This Scientific Opinion addresses the formulation of specific development needs, including research requirements for allergenicity assessment and protein safety, in general, which is urgently needed in a world that demands more sustainable food systems. Current allergenicity risk assessment strategies are based on the principles and guidelines of the Codex Alimentarius for the safety assessment of foods derived from 'modern' biotechnology initially published in 2003. The core approach for the safety assessment is based on a 'weight-of-evidence' approach because no single piece of information or experimental method provides sufficient evidence to predict allergenicity. Although the Codex Alimentarius and EFSA guidance documents successfully addressed allergenicity assessments of single/stacked event GM applications, experience gained and new developments in the field call for a modernisation of some key elements of the risk assessment. These should include the consideration of clinical relevance, route of exposure and potential threshold values of food allergens, the update of in silico tools used with more targeted databases and better integration and standardisation of test materials and in vitro/in vivo protocols. Furthermore, more complex future products will likely challenge the overall practical implementation of current guidelines, which were mainly targeted to assess a few newly expressed proteins. Therefore, it is timely to review and clarify the main purpose of the allergenicity risk assessment and the vital role it plays in protecting consumers' health. A roadmap to (re)define the allergenicity safety objectives and risk assessment needs will be required to inform a series of key questions for risk assessors and risk managers such as 'what is the purpose of the allergenicity risk assessment?' or 'what level of confidence is necessary for the predictions?'. Summary This Scientific Opinion addresses the formulation of specific development needs, including research requirements for allergenicity assessment and protein safety, in general, which is urgently needed in a world that demands more sustainable food systems. Current allergenicity risk assessment strategies based on the principles and guidelines of the Codex Alimentarius for the safety assessment of foods derived from 'modern' biotechnology was initially published in 2003. Due to the continuous scientific advances over the last two decades, there is a functional asynchrony between the availability of safety standards and concurrent scientific developments. The European Food Safety Authority (EFSA) has been proactive in this respect and has already invested resources to advance the allergenicity prediction field further. Likewise, EU-funded research programmes, such as the ImpARAS Cost Action, EuroPrevall, iFAAM and AllerScreening projects, among others, also provide insights on the use and improvement of existing and suggested assessment tools in the field of allergenicity assessment of foods. However, important knowledge gaps remain, and the development of novel approaches to deal with allergenicity assessment needs to be pursued further. This Scientific Opinion aims to: (i) define knowledge gaps on allergenicity prediction; (ii) identify specific research needs for improving the allergenicity risk assessment for products derived from biotechnology; (iii) determine how new basic research findings and technological developments can improve the current risk assessment methodology; and (iv) prioritise basic research funding. By considering the complexity and variety of factors involved in food allergy and the current state-of-the-art, it is unrealistic that a single test in the short/medium term will be predictive of the allergenic potential of a protein. Therefore, the 'weight-of-evidence' approach for allergenicity assessment remains valid. However, the evidence needed might differ depending on whether a conventional GMO or another type of new biotech food is being assessed. Although the Codex Alimentarius and EFSA guidance documents successfully addressed allergenicity assessments of single/stacked event GM applications, experience gained and new developments in the field call for a modernisation of some key elements, such as (i) better standardisation on the use of the available knowledge on the source of the gene and the protein itself – context of clinical relevance, route of exposure and potential threshold values of food allergens; (ii) modernisation of in silico tools used with more targeted databases; (iii) better integration of in vitro testing, with clear guidance on how protein stability and digestion informs the assessment and on the use of human sera; and (iv) better clarity on the use of the overall weight-of-evidence approach for protein safety and the aspects needed for expert judgement. Furthermore, more complex future products will challenge the overall practical implementation of such guidelines, mainly targeted to assess few newly expressed proteins. More challenging applications are expected in the future with large numbers of diverse proteins, for instance, derived from new genome techniques and synthetic biology. Therefore, it is timely to review and clarify the main purpose of the allergenicity risk assessment overall and the vital role it plays in protecting consumers' health with existing food allergies and assessing the potential for foods to cause new food allergies. Therefore, a draft of a roadmap that (re)defines the allergenicity safety objectives and risk assessment needs will be needed to address the key questions for risk assessors and risk managers, such as (1) what is the purpose of the allergenicity risk assessment?; (2) what should be assessed in the allergenicity assessment?; (3) what level of confidence is necessary for the predictions?; and (4) what is an unacceptable/acceptable risk in the allergenicity risk assessment?. 1 Introduction 1.1 Background In 2017, the scientific Panel on Genetically Modified Organisms of the European Food Safety Authority (hereafter referred to as the 'GMO Panel') published a supplementary guidance document on allergenicity risk assessment of genetically modified (GM) plants addressing non-IgE-mediated adverse immune reactions to foods, in vitro protein digestibility tests and endogenous allergenicity of plant constituents (EFSA GMO Panel, 2017). The purpose of this guidance document was to incorporate new developments in allergenicity into the risk assessment process. For in vitro protein digestibility, the GMO Panel considered that additional investigations were needed before providing any further recommendations in the form of guidance to applicants. An EFSA external scientific report, where various proteins of plant and animal origin were tested under specific gastrointestinal conditions, was published in 2019 (Mackie et al., 2019). Subsequently, an Ad hoc Allergenicity working group of the GMO Panel was established to address to what extent the in vitro digestion test adds value to the allergenicity risk assessment of GM plants and the protein safety assessment in general, and consequently, published a statement entitled 'in vitro protein digestibility tests in allergenicity and protein safety assessment of genetically modified plants' (EFSA GMO Panel, 2021). The GMO Panel guidance document of 2017 did not consider broader aspects relating to IgE-cross-reactivity and de novo sensitisation prediction. Based on current knowledge, experience gained, and their relevance for the assessment of GMOs and food and feed derived from biotechnology, it is important to address the issue of predicting IgE-cross-reactivity and de novo sensitisation. Therefore, the Ad hoc Allergenicity Working Group was asked to deliver a Scientific Opinion on current gaps and future development needs for the overall allergenicity and protein safety assessment, which is the aim of this document. To support the drafting of this scientific opinion, EFSA organised an Allergenicity Risk Assessment event, entitled 'Workshop on allergenicity assessment – prediction', in June 202111 https://www.efsa.europa.eu/en/events/gmo-workshop-allergenicity-assessment and published an event report (EFSA, 2021). 1.2 Terms of Reference The European Food Safety Authority (EFSA) asked the Panel on Genetically Modified Organisms (GMO Panel) to develop a GMO Panel Scientific Opinion on development needs in allergenicity and protein safety assessment of food and feed derived from biotechnology. No guidelines for applicants are provided in this document as it is not a follow-up of previous guidance documents. 2 Data and methodologies 2.1 Data In delivering this scientific opinion, the EFSA GMO Panel considered information from relevant scientific publications retrieved from the public domain. However, this Scientific Opinion is not intended to be a comprehensive review of the field. The GMO Panel also considered comments raised by a Stakeholder Consultative Group following the activities of the GMO Panel Allergenicity Working Group and the main outcomes of the Allergenicity Risk Assessment Workshop in June 2021, organised by the Allergenicity Working Group of the EFSA GMO Panel in collaboration with the Stakeholder Group. The aim of the workshop was to set the scene on the current state-of-the-art in the science of allergenicity assessment and to define the specific elements of such an assessment to develop to move forward (EFSA, 2021).1 2.2 Methodologies The GMO Panel considered the principles described on allergenicity in its guidance documents, statements, and scientific opinions (EFSA GMO Panel, 2010, 2011, 2017, 2021), Regulation (EU) No 503/2013 and other relevant international guidelines (Codex Alimentarius, 2003–2009). 3 Assessment The formulation of specific research requirements for allergenicity assessment and protein safety, in general, is urgently needed in a world that demands more sustainable food systems (EFSA, 2019). The European Commission targets food and nutrition security challenges with research and innovation policies designed to future-proof the food systems – to become more sustainable, resilient, responsible, inclusive, diverse and competitive. Consequently, the FOOD 203022 https://fit4food2030.eu/food-2030/ initiative should generate futureproofing of our currently unsustainable food systems supporting alternative proteins and innovative food sources. Before any food or feed derived from biotechnology can be introduced into the EU market, a premarket safety assessment is undertaken to ensure the product's wholesomeness. Evaluating adverse immune reactions to proteins (hereafter referred to as 'allergenicity') is a challenging aspect of this safety assessment. Adverse reactions to foods may involve IgE-mediated hypersensitivity reactions or non-IgE-mediated conditions, such as the T-cell-mediated gluten-sensitive enteropathy, also named coeliac disease (Sampson and Anderson, 2000; Johansson et al., 2001; Mills et al., 2013a; Valenta et al., 2015; Anvari et al., 2019). Current allergenicity risk assessment strategies are based on the principles and guidelines of the Codex Alimentarius for the safety assessment of foods derived from 'modern' biotechnology, which was initially published in 2003 (Codex Alimentarius, 2003–2009). Subsequently, the GMO Panel published Guidance Documents for the allergenicity assessment of GM plants (EFSA GMO Panel, 2011, 2017) that follows the main principles laid down by Codex Alimentarius (2003–2009). As no single piece of information or experimental method provide sufficient evidence to predict allergenicity, the core approach for the safety assessment is based on a 'weight-of-evidence' approach, where information of different nature is considered for the assessment of allergenicity (Codex Alimentarius, 2003–2009; EFSA GMO Panel, 2011, 2017; Regulation (EU) No 503/2013). According to the Codex Alimentarius, each step of the safety assessment aims to provide assurance, in the light of the best available scientific knowledge, that the food does not cause harm when prepared, used and/or eaten according to its intended use. Due to the continuous scientific advances over the last two decades, there is a functional asynchrony between the availability of safety standards and concurrent scientific developments. EFSA and other risk assessment bodies are mandated to mitigate these gaps as much as possible (EFSA, 2021). This is in line with the principles described in the Codex Alimentarius (2003–2009), which states that the safety assessment should be reviewed in the light of new scientific information calling into question the conclusions of the original safety assessment. EFSA has been proactive in this respect and has already invested resources to advance the allergenicity prediction further. A series of EFSA procurements were undertaken, which resulted in several publications representing significant steps forward (Mills et al., 2013a,b; Mackie et al., 2019; Parenti et al., 2019; EFSA GMO Panel, 2017, 2021). Likewise, EU-funded research programmes, such as the ImpARAS Cost Action, EuroPrevall, iFAAM and AllerScreening projects, among others, also provide insights on the use and improvement of existing and suggested assessment tools in the field of allergenicity assessment of foods. However, significant knowledge gaps remain, and the development of novel approaches to deal with allergenicity assessment needs to be pursued further (EFSA, 2021). This Scientific Opinion aims to: (i) define knowledge gaps on allergenicity prediction; (ii) identify specific research needs for improving the allergenicity risk assessment for products derived from biotechnology; (iii) determine how new basic research findings and technological developments can improve the current risk assessment methodology; and (iv) prioritise basic research funding. 3.1 Allergenicity prediction in the safety assessment of foods derived from biotechnology The international consensus on the safety assessment approach of foods derived from biotechnology is based on the principle of a comparative safety assessment, where their equivalence to a conventional counterpart with a history of safe use should be established. Allergenicity risk assessment is part of the information required for the hazard identification and hazard characterisation steps and other aspects such as the molecular characterisation, comparative analysis, potential toxicity or nutritional value of the resulting food. The risk assessment is completed by an exposure assessment and, eventually, by a risk characterisation step, as needed (EFSA GMO Panel, 2011; European Commission, 2013). For the assessment of proteins, the current paradigm builds on classical principles and methodologies developed for assessing small molecules chemicals. However, proteins are large and complex biopolymers that challenge this paradigm and present different hazard and exposure assessments (Fernandez Dumont et al., 2018). Since the human body handles proteins in a very different manner to small molecules, the safety assessment relies on information of a different nature to provide the necessary weight-of-evidence to estimate potential risks. On a case-by-case basis, this information may include in silico bioinformatic analysis, in vitro tests on protein stability, in vivo studies and dietary exposure. However, for the allergenicity assessment, key pieces of knowledge are lacking, including consensus lists of clinically relevant allergens that are structurally well-characterised and have demonstrable potency in eliciting an allergic reaction. The recently published FAO/WHO consultation has identified consensus on reference doses for many major allergenic foods based on published data (Taylor et al., 2002; Ballmer-Weber et al., 2015; Bluemchen and Eiwegger, 2019; Houben et al., 2020; Remington et al., 2020; FAO/WHO, 2021a,b), as shown in Section 3.3.1. However, significant data gaps remain regarding the allergenic potency of other allergenic foods, and there are no clinical data on threshold doses for individual allergenic protein molecules. These gaps in knowledge make it challenging to define strategies that consider the exposure in the risk characterisation step and increase the uncertainty in the overall risk assessment process. The prediction of allergenicity is also challenging because an allergic reaction to a protein depends upon a complex interplay between an individual's immune system and the protein. Allergic disease develops in a process comprising sensitisation to the allergenic food and subsequent elicitation of the allergic reaction. The resulting symptoms occur upon re-exposure to the allergen when administered in sufficient amounts (Renz et al., 2018). The allergenicity risk assessment considers the risks that a newly expressed protein or whole food poses to the existing allergic population by virtue of showing IgE cross-reactivity. Existing methods are available for assessing the allergenic potential of new proteins for cross-reactivity with a reasonable level of confidence. However, there are limited options to assess the hazard and potential risks of new proteins due to de novo sensitisation (Remington et al., 2018; Mazzucchelli et al., 2018). This is because, contrary to other safety assessment areas, such as the toxicity assessment for which well-validated animal models have been in place for years (e.g. OECD protocols for small molecules), no single test or parameter is currently available which provides sufficient evidence to predict de novo sensitisation. Moreover, the methods included in the current weight-of-evidence approach for the allergenicity assessment were designed for the assessment of individual proteins and are not easily applicable to foods developed by introducing traits of many different newly expressed proteins (EFSA GMO Panel, 2022a,b) or to complex mixtures of proteins that often make up whole foods (e.g. insects). The current paradigm, according to Codex Alimentarius (2003–2009), is that potential safety concerns on allergenicity are raised when, for example, (i) reasonable evidence of IgE-mediated oral, respiratory or contact allergy or non-IgE allergy is available on the source of the introduced protein or on the protein itself; (ii) a newly expressed protein has sequence similarities to known allergens higher than 35%; and/or (iii) highly stable proteins leading to resistant fragments following the classical pepsin resistance are separated and visualised by sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS–PAGE). Over the years and following Codex Alimentarius principles (2003–2009), most of the tools used in the allergenicity risk assessment focus on understanding the potential IgE binding properties of allergens, leading to the typical classification of allergens as 'major' (> 50% IgE-binding) and 'minor' (< 50% IgE-binding) (Løwenstein, 1978). However, this classification does not carry any connotation of allergenic potency but rather relates to the proportion of an allergic population that are sensitised to a given molecule (Matricardi et al., 2016). This is because this classification is mainly based on the frequency of IgE-binding in the population, especially detected in vitro, irrespective of clinical impact. Thus, there is a need for a better approach to evaluate the clinical importance of allergens along with prevalence in a population. 3.1.1 Clinical relevance of food allergens The characterisation of an allergen involves from the analysis of its IgE antibody binding capacity to the demonstration of clinical relevance. Moreover, the characterisation of all allergens is a challenging and comprehensive process that also includes physicochemical properties, biological function and structure determination (Caraballo et al., 2020). An allergen becomes clinically relevant when it causes symptoms and is corroborated by medical history and/or provocation testing (Worm et al., 2021). The clinical relevance of individual food allergens should be a key driver for developing new strategies and tools for allergenicity risk assessment (EFSA, 2021). To achieve this goal, it is necessary to rely on clinical data of good quality and to determine criteria for describing the allergenicity of single proteins. However, the factors that may determine a convincing history of an IgE-mediated allergic reaction to a specific food are still controversial. Likewise, it is challenging to define 'minimal criteria' for food allergy (Asai et al., 2020). It is well accepted that individuals are often sensitised to a food or allergen molecule but are still able to consume food without experiencing an allergic reaction, and is one reason why double-blind placebo-controlled oral food challenges (DBPCFC) are considered the gold standard for a diagnosis of food allergy (Sicherer and Sampson, 2018). Consequently, criteria have been developed to identify allergenic foods of public health importance where oral food challenges play a crucial role in demonstrating clinical relevance, i.e. the capacity of a food to elicit an allergic reaction in an allergic individual (Björkstén et al., 2008; Chung et al., 2012). Thus, although sensitisation is a predisposing risk factor for IgE-mediated food allergy, neither a quantitative positive specific IgE test result nor a positive skin prick test can prove the clinical relevance of a food extract or purified molecule. The ultimate means of determining the clinical relevance of an allergen molecule would be to perform a provocation test with a purified allergen molecule, as is undertaken with inhalant allergens used for immunotherapy. However, data from such studies are lacking, and new alternatives are required. Therefore, there is a need for consensus definitions of clinically relevant allergens, and these should build on data available for component-resolved diagnostics in allergic patients, with some initiatives being recently proposed (Caraballo et al., 2020, 2021). A crucial aspect of such definitions relates to the source and quality of the diagnosis of the allergic population used to define an allergen. The clinical relevance of allergens could include criteria such as (i) the severity (i.e. the proportion of severe objective allergic symptoms to the potential allergen); (ii) the potency (i.e. the amount of the potential allergen required to cause objective symptoms); (iii) the prevalence of immune-mediated hypersensitivity to the potential allergen source; and iv) the exposure route that the allergen presents to the immune system and the level of exposure. Recently, an Ad hoc Joint FAO/WHO Expert Consultation on Risk Assessment of Food Allergens reviewed and validated the Codex priority allergen list based on systematic and thorough assessments using prevalence, severity and potency as key criteria (FAO/WHO, 2021a). In addition, the definition of a set of non/low-allergenic (control) proteins is needed. One initiative has been proposed by Krutz et al. (2019). Briefly, the main principle assumes that proteins to which humans are known to have significant exposure (such as proteins from spinach, corn, potato, rice, tomato or wheat), but that are not (or only rarely) associated with allergy, can be classified as having low (or even absent) sensitising potential. Finally, in the last years, allergic diseases in animals have gained great prominence in veterinary practice. However, very few studies are currently available (mainly in dogs and horses), which provide evidence of the allergens involved, but it is unclear whether these allergens are similar to those in humans (Mueller et al., 2018). Furthermore, the prevalence of food allergy in animals is largely unknown, and additional efforts in this field are needed (Pali-Scholl et al., 2017, 2019). 3.1.2 Determinants of food protein allergenicity 3.1.2.1 Intrinsic and extrinsic properties of food allergens Despite many approaches aimed at understanding what makes a food protein an allergen (Huby et al., 2000; Helm, 2001; Bannon, 2004; Scheurer et al., 2015; Costa et al., 2020, 2021), the underlying reasons why proteins or peptides become allergenic in susceptible individuals is not fully understood (EFSA GMO Panel, 2010, 2011, 2017; EFSA NDA Panel, 2014). The molecular determinants of allergenicity depend on the protein sequence with contributions from protein structure and dynamics (James et al., 2018). It has long been recognised that food and pollen allergens belong to a limited number of protein superfamilies (Jenkins et al., 2005; Radauer and Breiteneder 2006; Jenkins et al., 2007; Radauer et al., 2008). Although these protein family scaffolds are associated with allergenicity, there are no single common structural causes, features or sequence motifs identified that contribute to their overall allergenicity. However, not all members of a certain protein family are allergens, and many allergens do not exhibit any known physicochemical, functional or structural properties that account for their allergenicity (Scheurer et al., 2015; Costa et al., 2020, 2021). Inter
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