State‐of‐the‐art in marketed adjuvants and formulations in Allergen Immunotherapy: A position paper of the European Academy of Allergy and Clinical Immunology (EAACI)

Since the introduction of allergen immunotherapy (AIT) over 100 years ago, focus has been on standardization of allergen extracts, with reliable molecular composition of allergens receiving the highest attention. While adjuvants play a major role in European AIT, they have been less well studied. In this Position Paper, we summarize current unmet needs of adjuvants in AIT citing current evidence. Four adjuvants are used in products marketed in Europe: aluminium hydroxide (Al(OH)3) is the most frequently used adjuvant, with microcrystalline tyrosine (MCT), monophosphoryl lipid A (MPLA) and calcium phosphate (CaP) used less frequently. Recent studies on humans, and using mouse models, have characterized in part the mechanisms of action of adjuvants on pre‐existing immune responses. AIT differs from prophylactic vaccines that provoke immunity to infectious agents, as in allergy the patient is presensitized to the antigen. The intended mode of action of adjuvants is to simultaneously enhance the immunogenicity of the allergen, while precipitating the allergen at the injection site to reduce the risk of anaphylaxis. Contrasting immune effects are seen with different adjuvants. Aluminium hydroxide initially boosts Th2 responses, while the other adjuvants utilized in AIT redirect the Th2 immune response towards Th1 immunity. After varying lengths of time, each of the adjuvants supports tolerance. Further studies of the mechanisms of action of adjuvants may advise shorter treatment periods than the current three‐to‐five‐year regimens, enhancing patient adherence. Improved lead compounds from the adjuvant pipeline are under development and are explored for their capacity to fill this unmet need.

[1]  S. Vieths,et al.  Manufacturing and quality assessment of allergenic extracts for immunotherapy: state of the art. , 2019, Current opinion in allergy and clinical immunology.

[2]  P. Moingeon,et al.  IL‐10 mRNA levels in whole blood cells correlate with house dust mite allergen immunotherapy efficacy , 2019, Allergy.

[3]  E. Fernández‐Caldas,et al.  Alum impairs tolerogenic properties induced by allergoid‐mannan conjugates inhibiting mTOR and metabolic reprogramming in human DCs , 2019, Allergy.

[4]  Zheng Liu,et al.  Allergen immunotherapy improves defective follicular regulatory T cells in patients with allergic rhinitis. , 2019, The Journal of allergy and clinical immunology.

[5]  So Hee Lee,et al.  Factors Associated with Adherence to Allergen Specific Subcutaneous Immunotherapy , 2019, Yonsei medical journal.

[6]  C. Akdis,et al.  Der p 1‐specific regulatory T‐cell response during house dust mite allergen immunotherapy , 2019, Allergy.

[7]  M. Shamji,et al.  Birch pollen allergen‐specific immunotherapy with glutaraldehyde‐modified allergoid induces IL‐10 secretion and protective antibody responses , 2019, Allergy.

[8]  S. Durham,et al.  Role of IL‐35 in sublingual allergen immunotherapy , 2019, The Journal of allergy and clinical immunology.

[9]  S. Durham,et al.  Nasal allergen‐neutralizing IgG4 antibodies block IgE‐mediated responses: Novel biomarker of subcutaneous grass pollen immunotherapy , 2019, The Journal of allergy and clinical immunology.

[10]  C. Akdis,et al.  Role of Der p 1–specific B cells in immune tolerance during 2 years of house dust mite–specific immunotherapy , 2019, The Journal of allergy and clinical immunology.

[11]  S. Vieths,et al.  Understanding differences in allergen immunotherapy products and practices in North America and Europe. , 2019, The Journal of allergy and clinical immunology.

[12]  B. Samoliński,et al.  Efficacy and safety of birch pollen allergoid subcutaneous immunotherapy: A 2‐year double‐blind, placebo‐controlled, randomized trial plus 1‐year open‐label extension , 2019, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[13]  S. Zielen,et al.  Fast up-dosing with a birch allergoid is safe and well tolerated in allergic rhinitis patients with or without asthma. , 2019, Immunotherapy.

[14]  M. Shamji,et al.  Role of IL-35 in sublingual allergen immunotherapy , 2019, Current opinion in allergy and clinical immunology.

[15]  G. Adema,et al.  Adjuvants Enhancing Cross-Presentation by Dendritic Cells: The Key to More Effective Vaccines? , 2018, Front. Immunol..

[16]  M. Ebisawa,et al.  Skin as an immune organ and clinical applications of skin-based immunotherapy , 2018, The World Allergy Organization journal.

[17]  L. Klimek,et al.  Recent developments and highlights in allergen immunotherapy , 2018, Allergy.

[18]  H. Stockinger,et al.  IgG4 drives M2a macrophages to a regulatory M2b‐like phenotype: potential implication in immune tolerance , 2018, Allergy.

[19]  C. Coban,et al.  DAMP-Inducing Adjuvant and PAMP Adjuvants Parallelly Enhance Protective Type-2 and Type-1 Immune Responses to Influenza Split Vaccination , 2018, Front. Immunol..

[20]  D. Larenas-Linnemann,et al.  Intralymphatic Immunotherapy: Update and Unmet Needs , 2018, International Archives of Allergy and Immunology.

[21]  Jennifer D. Oduro,et al.  Aluminium toxicokinetics after intramuscular, subcutaneous, and intravenous injection of Al citrate solution in rats , 2018, Archives of Toxicology.

[22]  A. Avan,et al.  Targeting the death receptor signaling pathway as a potential therapeutic target in the treatment of colorectal cancer , 2018, Journal of cellular physiology.

[23]  P. Lemell,et al.  Clinical efficacy of sublingual immunotherapy is associated with restoration of steady-state serum lipocalin 2 after SLIT: a pilot study , 2018, The World Allergy Organization journal.

[24]  G. Piontek,et al.  Early IL-10 producing B-cells and coinciding Th/Tr17 shifts during three year grass-pollen AIT , 2018, EBioMedicine.

[25]  J. Zubeldia,et al.  Comparative study of adjuvants for allergen-specific immunotherapy in a murine model. , 2018, Immunotherapy.

[26]  M. Akdiş,et al.  Mechanisms of allergen-specific immunotherapy: Diverse mechanisms of immune tolerance to allergens. , 2018, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.

[27]  H. Yamada,et al.  Development of screening method for intranasal influenza vaccine and adjuvant safety in preclinical study. , 2018, Biologicals : journal of the International Association of Biological Standardization.

[28]  C. Janson,et al.  Sublingual grass allergen specific immunotherapy: a retrospective study of clinical outcome and discontinuation , 2018, Clinical and Molecular Allergy.

[29]  A. Sheikh,et al.  EAACI Guidelines on Allergen Immunotherapy: Allergic rhinoconjunctivitis , 2018, Allergy.

[30]  T. Kündig,et al.  Microcrystalline Tyrosine and Aluminum as Adjuvants in Allergen-Specific Immunotherapy Protect from IgE-Mediated Reactivity in Mouse Models and Act Independently of Inflammasome and TLR Signaling , 2018, The Journal of Immunology.

[31]  E. Herrmann,et al.  Long-term effect of monophosphoryl lipid A adjuvanted specific immunotherapy in patients with grass pollen allergy. , 2018, Immunotherapy.

[32]  M. Vogel,et al.  Allergens displayed on virus‐like particles are highly immunogenic but fail to activate human mast cells , 2018, Allergy.

[33]  P. Demoly,et al.  Perspectives in allergen immunotherapy: 2017 and beyond , 2018, Allergy.

[34]  A. Sheikh,et al.  Vaccination and allergy: EAACI position paper, practical aspects , 2017, Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology.

[35]  Y. Shoenfeld,et al.  Debate on vaccines and autoimmunity: Do not attack the author, yet discuss it methodologically. , 2017, Vaccine.

[36]  M. Turner,et al.  AllergoOncology: IgE‐ and IgG4‐mediated immune mechanisms linking allergy with cancer and their translational implications , 2017, The Journal of allergy and clinical immunology.

[37]  M. Bachmann,et al.  Microcrystalline Tyrosine (MCT®): A Depot Adjuvant in Licensed Allergy Immunotherapy Offers New Opportunities in Malaria , 2017, Vaccines.

[38]  R. A. van den Berg,et al.  Cellular and molecular synergy in AS01-adjuvanted vaccines results in an early IFNγ response promoting vaccine immunogenicity , 2017 .

[39]  L. Klimek,et al.  Ultra‐short‐course booster is effective in recurrent grass pollen‐induced allergic rhinoconjunctivitis , 2017, Allergy.

[40]  W. Huisinga,et al.  Towards toxicokinetic modelling of aluminium exposure from adjuvants in medicinal products , 2017, Regulatory toxicology and pharmacology : RTP.

[41]  P Demoly,et al.  Biomarkers for monitoring clinical efficacy of allergen immunotherapy for allergic rhinoconjunctivitis and allergic asthma: an EAACI Position Paper , 2017, Allergy.

[42]  Qinjian Zhao,et al.  Calcium phosphate nanoparticles as a new generation vaccine adjuvant , 2017, Expert review of vaccines.

[43]  S. Durham,et al.  Novel approaches and perspectives in allergen immunotherapy , 2017, Allergy.

[44]  C. Akdis,et al.  Mechanisms of immune regulation in allergic diseases: the role of regulatory T and B cells , 2017, Immunological reviews.

[45]  J. Bousquet,et al.  Allergen immunotherapy in allergic rhinitis: current use and future trends , 2017, Expert review of clinical immunology.

[46]  M. Bachmann,et al.  Virus-Like Particle (VLP) Plus Microcrystalline Tyrosine (MCT) Adjuvants Enhance Vaccine Efficacy Improving T and B Cell Immunogenicity and Protection against Plasmodium berghei/vivax , 2017, Vaccines.

[47]  N. Silman,et al.  Comparison of a novel microcrystalline tyrosine adjuvant with aluminium hydroxide for enhancing vaccination against seasonal influenza , 2017, BMC Infectious Diseases.

[48]  M. Thibaudon,et al.  Calcium phosphate: a substitute for aluminum adjuvants? , 2017, Expert review of vaccines.

[49]  M. Babina,et al.  The Impact on Allergy-Related Cells of a Birch Pollen Allergoid, with and without Monophosphoryl Lipid A, in Comparison with the Native Equivalent , 2017, International Archives of Allergy and Immunology.

[50]  Y. Shoenfeld,et al.  Autoimmune/inflammatory syndrome induced by adjuvants (Shoenfeld’s syndrome) – An update , 2017, Lupus.

[51]  R. Mösges,et al.  Sublingual versus subcutaneous immunotherapy: patient adherence at a large German allergy center , 2017, Patient preference and adherence.

[52]  M. Akdiş,et al.  Role of regulatory B cells in immune tolerance to allergens and beyond. , 2016, The Journal of allergy and clinical immunology.

[53]  C. Cingi,et al.  New Routes of Allergen Immunotherapy , 2016, American journal of rhinology & allergy.

[54]  H. Park,et al.  Different Responses in Induction of Allergen Specific Immunoglobulin G4 and IgE-Blocking Factors for Three Mite Subcutaneous Immunotherapy Products , 2016, Yonsei medical journal.

[55]  C. Troakes,et al.  The Identification of Aluminum in Human Brain Tissue Using Lumogallion and Fluorescence Microscopy , 2016, Journal of Alzheimer's disease : JAD.

[56]  Paige G. Wickner,et al.  Progestogen Hypersensitivity in 24 Cases: Diagnosis, Management, and Proposed Renaming and Classification. , 2016, The journal of allergy and clinical immunology. In practice.

[57]  S. Boscardin,et al.  Adjuvants: Classification, Modus Operandi, and Licensing , 2016, Journal of immunology research.

[58]  L. James,et al.  Potential Mechanisms for IgG4 Inhibition of Immediate Hypersensitivity Reactions , 2016, Current Allergy and Asthma Reports.

[59]  M. Pallardy,et al.  Changes in markers associated with dendritic cells driving the differentiation of either TH2 cells or regulatory T cells correlate with clinical benefit during allergen immunotherapy. , 2016, The Journal of allergy and clinical immunology.

[60]  P. Heymann,et al.  Alum-Containing Vaccines Increase Total and Food Allergen-Specific IgE, and Cow's Milk Oral Desensitization Increases Bosd4 IgG4 While Peanut Avoidance Increases Arah2 IgE: The Complexity of Today's Child with Food Allergy , 2016 .

[61]  R. Van Ree,et al.  International Consensus on Allergen Immunotherapy II: Mechanisms, standardization, and pharmacoeconomics. , 2016, The Journal of allergy and clinical immunology.

[62]  Stephen J. Galli,et al.  Successful immunotherapy induces previously unidentified allergen-specific CD4+ T-cell subsets , 2016, Proceedings of the National Academy of Sciences.

[63]  R. Schubert,et al.  Induction of Bronchial Tolerance After 1 Cycle of Monophosphoryl-A-Adjuvanted Specific Immunotherapy in Children With Grass Pollen Allergies , 2016, Allergy, asthma & immunology research.

[64]  J. Kalil,et al.  HIV Envelope Trimer Specific Immune Response Is Influenced by Different Adjuvant Formulations and Heterologous Prime-Boost , 2016, PloS one.

[65]  Xiaomin Wei,et al.  Chronic exposure to aluminum and risk of Alzheimer’s disease: A meta-analysis , 2016, Neuroscience Letters.

[66]  S. Hewings,et al.  The adsorption of allergoids and 3-O-desacyl-4'-monophosphoryl lipid A (MPL®) to microcrystalline tyrosine (MCT) in formulations for use in allergy immunotherapy. , 2015, Journal of inorganic biochemistry.

[67]  R. Van Ree,et al.  International consensus on allergy immunotherapy. , 2015, The Journal of allergy and clinical immunology.

[68]  Cezmi A Akdis,et al.  Mechanisms of allergen-specific immunotherapy and immune tolerance to allergens , 2015, The World Allergy Organization journal.

[69]  E. Jensen‐Jarolim.  Aluminium in Allergies and Allergen immunotherapy , 2015, The World Allergy Organization journal.

[70]  E. Maggi,et al.  Perspectives in vaccine adjuvants for allergen-specific immunotherapy. , 2014, Immunology letters.

[71]  D. Krewski,et al.  Systematic review of potential health risks posed by pharmaceutical, occupational and consumer exposures to metallic and nanoscale aluminum, aluminum oxides, aluminum hydroxide and its soluble salts , 2014, Critical reviews in toxicology.

[72]  J. Coote,et al.  Protein coated microcrystals formulated with model antigens and modified with calcium phosphate exhibit enhanced phagocytosis and immunogenicity☆ , 2014, Vaccine.

[73]  S. Holgate,et al.  A New Era of Targeting the Ancient Gatekeepers of the Immune System: Toll-Like Agonists in the Treatment of Allergic Rhinitis and Asthma , 2014, International Archives of Allergy and Immunology.

[74]  P. Patel,et al.  Efficacy of a short course of specific immunotherapy in patients with allergic rhinoconjunctivitis to ragweed pollen. , 2014, The Journal of allergy and clinical immunology.

[75]  N. Scichilone,et al.  Allergen sensitizations in southern Italy: a 5-year retrospective study in allergic respiratory patients. , 2013, European annals of allergy and clinical immunology.

[76]  S. Zielen,et al.  Pollinex Quattro: An innovative four injections immunotherapy In allergic rhinitis , 2013, Human vaccines & immunotherapeutics.

[77]  D. Larenas-Linnemann,et al.  Adjuvants for immunotherapy , 2012, Current opinion in allergy and clinical immunology.

[78]  P. Moingeon.  Adjuvants for allergy vaccines , 2012, Human vaccines & immunotherapeutics.

[79]  W. Hop,et al.  Real-life compliance and persistence among users of subcutaneous and sublingual allergen immunotherapy. , 2012, The Journal of allergy and clinical immunology.

[80]  H. Golding,et al.  Use of human MonoMac6 cells for development of in vitro assay predictive of adjuvant safety in vivo. , 2012, Vaccine.

[81]  S. Durham,et al.  Long-term clinical and immunological effects of allergen immunotherapy , 2011, Current opinion in allergy and clinical immunology.

[82]  C. Hong,et al.  Optimization of Allergen Standardization , 2011, Yonsei medical journal.

[83]  R. Mösges,et al.  Medication persistence with long-term, specific grass pollen immunotherapy measured by prescription renewal rates , 2011, Current medical research and opinion.

[84]  M. Calderón,et al.  Subcutaneous specific immunotherapy for seasonal allergic rhinitis: a review of treatment practices in the US and Europe , 2010, Current medical research and opinion.

[85]  K. Hörmann,et al.  Sublingual Allergen-Specific Immunotherapy Adjuvanted with Monophosphoryl Lipid A: A Phase I/IIa Study , 2010, International Archives of Allergy and Immunology.

[86]  E. Agger,et al.  T‐helper 1 and T‐helper 2 adjuvants induce distinct differences in the magnitude, quality and kinetics of the early inflammatory response at the site of injection , 2010, Immunology.

[87]  Arnaud M. Didierlaurent,et al.  AS04, an Aluminum Salt- and TLR4 Agonist-Based Adjuvant System, Induces a Transient Localized Innate Immune Response Leading to Enhanced Adaptive Immunity1 , 2009, The Journal of Immunology.

[88]  A. Riemer,et al.  Aluminium per se and in the anti‐acid drug sucralfate promotes sensitization via the oral route , 2009, Allergy.

[89]  J. Björk,et al.  There is an association between contact allergy to aluminium and persistent subcutaneous nodules in children undergoing hyposensitization therapy , 2009, Contact dermatitis.

[90]  H. Hammad,et al.  Cutting Edge: Alum Adjuvant Stimulates Inflammatory Dendritic Cells through Activation of the NALP3 Inflammasome , 2008, The Journal of Immunology.

[91]  P. McNamara,et al.  Aluminium toxicokinetics: an updated minireview. , 2001, Pharmacology & toxicology.

[92]  C. Leclercq,et al.  Safety of aluminium from dietary intake - Scientific Opinion of the Panel on Food Additives, Flavourings, Processing Aids and Food Contact Materials (AFC). , 2008, EFSA journal. European Food Safety Authority.

[93]  Henk C. Hoogsteden,et al.  Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells , 2008, The Journal of experimental medicine.

[94]  N. Skovgaard.  Safety evaluation of certain contaminants in food , 2007 .

[95]  A. Sheikh,et al.  Allergen injection immunotherapy for seasonal allergic rhinitis. , 2007, The Cochrane database of systematic reviews.

[96]  Allergen products , 2006 .

[97]  Christopher Exley,et al.  Comment on "the biological behaviour and bioavailability of aluminium in man" by N. D. Priest, JEM, 2004, 6, 375. , 2005, Journal of environmental monitoring : JEM.

[98]  N. Priest.  Reply to the ‘Comment on “The biological behaviour and bioavailability of aluminium in man”’ by C. Exley, JEM, 2005, 7, DOI: 10.1039/b504226g , 2005 .

[99]  S. Durham,et al.  Adjuvants for allergen immunotherapy: experimental results and clinical perspectives , 2004, Current opinion in allergy and clinical immunology.

[100]  Y. Shoenfeld,et al.  Vaccination and allergy , 2004, Current opinion in otolaryngology & head and neck surgery.

[101]  N D Priest,et al.  The biological behaviour and bioavailability of aluminium in man, with special reference to studies employing aluminium-26 as a tracer: review and study update. , 2004, Journal of environmental monitoring : JEM.

[102]  B. Björkstén,et al.  Do early childhood immunizations influence the development of atopy and do they cause allergic reactions? , 2001, Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology.

[103]  C. Traube,et al.  Immunotherapy with a calcium phosphate‐adsorbed five‐grass‐pollen extract in seasonal rhinoconjunctivitis: a double‐blind, placebo‐controlled study , 2001, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[104]  A. Kapp,et al.  Aluminium‐induced granulomas after inaccurate intradermal hyposensitization injections of aluminium‐adsorbed depot preparations , 2000, Allergy.

[105]  M. Suckow,et al.  In vivo absorption of aluminium-containing vaccine adjuvants using 26Al. , 1997, Vaccine.

[106]  C. Carda,et al.  Aluminium allergy in patients hyposensitized with aluminium‐precipitated antigen extracts , 1994, Contact dermatitis.

[107]  R. Yokel,et al.  Toxicity of gestational aluminum exposure to the maternal rabbit and offspring. , 1985, Toxicology and applied pharmacology.

[108]  Tetsuya Hayashi,et al.  Current status, problems and future prospects of microbial testing Application of the Next-generation Sequencer in the Clinical Microbiological Laboratory: Perspective , 2016 .

[109]  A. Fusi,et al.  A case of anaphylaxis to Pollinex® Quattro MPL-4. , 2014, European annals of allergy and clinical immunology.

[110]  J. Björk,et al.  Does allergen-specific immunotherapy induce contact allergy to aluminium? , 2013, Acta dermato-venereologica.

[111]  C. Cluff.  Monophosphoryl lipid A (MPL) as an adjuvant for anti-cancer vaccines: clinical results. , 2010, Advances in experimental medicine and biology.

[112]  No risk of Alzheimer ' s disease from aluminium in consumer products , 2010 .

[113]  J. V. Lenteren.  Evaluation of pest risk assessments and risk management options prepared to justify requests for phytosanitary measures under Council Directive 2000/29/EC: Guidance of the Panel on Plant Health , 2009 .

[114]  Kelly Boyer Sagert.  Safety evaluation of certain contaminants in food. Prepared by the Sixty-fourth meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA). , 2006, FAO food and nutrition paper.

[115]  B. Wüthrich,et al.  Safety and efficacy of specific immunotherapy with standardized allergenic extracts adsorbed on aluminium hydroxide. , 2001, Journal of investigational allergology & clinical immunology.

[116]  R. Gupta,et al.  Adjuvants for human vaccines--current status, problems and future prospects. , 1995, Vaccine.

[117]  J. L. Greger.  Aluminum metabolism. , 1993, Annual review of nutrition.

[118]  S. Ott,et al.  Indirect methods for the diagnosis of aluminum bone disease: plasma aluminum, the desferrioxamine infusion test, and serum iPTH. , 1986, Kidney international. Supplement.