Vaccination against Allergy: A Paradigm Shift?
Authors: Martin F. Bachmann, Mona O. Mohsen, Matthias F. Kramer, Matthew D. Heath
Journal: Trends in Molecular Medicine (2020)

Recent advances in the use of virus-like particle (VLP) nanotechnology provides an optimal strategy for the treatment of allergy; eliminating the allergic potential of a vaccine while increasing its ability to trigger strong IgG reactions.Modern approaches to allergen-specific immunotherapy (SIT) exploiting advances in antigen carrier systems such as VLP, aimed at maximizing IgG-mediated inhibition of allergen-induced mast cell activation, present a paradigm shift toward using a classical vaccination approach to treat allergy.The translational potential of VLP technology in allergy may eventually be useful for prophylactic vaccination. Since the discovery that IgE antibodies mediate allergy, decades of research have unraveled complex mechanisms associated with conventional immunotherapy and the vital protagonists that shape 'immune tolerance' to allergens. Debate exists on what should constitute the dominant effector mechanism in driving rational drug designs for next-generation immunotherapies. As vaccine technology continues to advance, the development of novel vaccines in this area of continued medical need might stand on a threshold of breakthrough inspired by experiments by Dunbar on the passive vaccination of allergic animals more than 100 years ago. In this opinion article, we discuss both novel insights into IgG antibodies as the principle effector modality induced by specific immunotherapy and advances in antigen-carrier design that may catapult allergy treatment into our modern world. Since the discovery that IgE antibodies mediate allergy, decades of research have unraveled complex mechanisms associated with conventional immunotherapy and the vital protagonists that shape 'immune tolerance' to allergens. Debate exists on what should constitute the dominant effector mechanism in driving rational drug designs for next-generation immunotherapies. As vaccine technology continues to advance, the development of novel vaccines in this area of continued medical need might stand on a threshold of breakthrough inspired by experiments by Dunbar on the passive vaccination of allergic animals more than 100 years ago. In this opinion article, we discuss both novel insights into IgG antibodies as the principle effector modality induced by specific immunotherapy and advances in antigen-carrier design that may catapult allergy treatment into our modern world. Allergic rhinitis, allergic asthma, and food allergies (see Glossary) are recently burgeoning diseases. The first documented case of hay fever occurred in 1819, when the physician, John Bostock, called the disease catarrhus aestivus (summer catarrh) [1.Elliotson J. On hay fever.Lancet. 1830; ii: 370-373Google Scholar]. Given that Bostock had the disease himself, this first patient was easily found; it took him more than 9 years to find another 28 cases, clearly demonstrating the scarcity of the disease rather than absence of reporting [2.Bostock J. Of the catarrhus aestivus, or summer catarrh.Med. Chir. Trans. 1828; 14: 437-446Crossref PubMed Google Scholar]. This has since dramatically changed and IgE-mediated allergies, such as allergic rhino conjunctivitis and asthma, have reached a worldwide prevalence of 25% [3.Asher M.I. et al.Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys.Lancet. 2006; 368: 733-743Abstract Full Text Full Text PDF PubMed Scopus (2838) Google Scholar], followed by food allergy, with a prevalence of ~10% [4.Gupta R.S. Prevalence and severity of food allergies among US adults.JAMA Netw. 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Update on epigenetics in allergic disease.J. Allergy Clin. Immunol. 2015; 135: 15-24Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar]. There are several ways to treat IgE-mediated allergies. The most accessible and commonly used therapies are symptomatic in nature and block the allergic reactions at the effector stage by inhibiting the action of histamine by using corticosteroids. While these therapies are effective, they usually need daily drug intake, which is not without chronic adverse effects if taken for years, and, most importantly, does not stop progression of the disease toward, for example, asthma. By contrast, allergen-specific immunotherapy (SIT) is the only disease-modifying therapy available [8.Jutel M. et al.International consensus on allergen immunotherapy II: mechanisms, standardization, and pharmacoeconomics.J. Allergy Clin. 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Despite the clinical success of SIT, conventional long-course subcutaneous immunotherapy, typically formulated with an aluminum depot, remains cumbersome (e.g., monthly injections over 3 years) and the mechanisms of action remains unclear. To date, there are no validated and generally accepted candidate biomarkers that are predictive or indicative of the clinical response to conventional SIT [12.Shamji M.H. et al.Biomarkers for monitoring clinical efficacy of allergen immunotherapy for allergic rhinoconjunctivitis and allergic asthma: an EAACI Position Paper.Allergy. 2017; 72: 1156-1173Crossref PubMed Scopus (169) Google Scholar]. It is recommended to explore the use of allergen-specific IgG4 as a biomarker for compliance. Serum IgE/total IgE and IgE-facilitated allergen binding (FAB) are considered as potential surrogate candidate biomarkers, although induction of increased type 1 T helper cells (Th1), in particular regulatory T cells (Tregs), has been postulated to mediate clinical efficacy [12.Shamji M.H. et al.Biomarkers for monitoring clinical efficacy of allergen immunotherapy for allergic rhinoconjunctivitis and allergic asthma: an EAACI Position Paper.Allergy. 2017; 72: 1156-1173Crossref PubMed Scopus (169) Google Scholar]. More recently, additional immune cells, such as innate-like lymphocytes (ILCs) [13.Mohammed-Ali Z. et al.T helper cell IL-4 drives intestinal Th2 priming to oral peanut antigen, under the control of OX40L and independent of innate-like lymphocytes.Mucosal Immunol. 2014; 7: 1395-1404Crossref PubMed Scopus (51) Google Scholar] and regulatory B cells [14.Rosser E.C. Mauri C. 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More than 100 years ago, allergen immunotherapy was described in a way that drew parallels with vaccinology at this time, described as 'a prophylactic vaccination against hay fever' [33.Noon L. Prophylactic inoculation against hay fever.Lancet. 1911; 177: 1572-1573Abstract Scopus (1041) Google Scholar]. Upon the discovery of IgE and research to further elucidate the rather complex interplay of immunological mechanisms that mediate allergy and conventional SIT, those fundamental parallels with vaccinology ('a vaccine against toxins') were somewhat lost and subsequent research focused on the idea that SIT should 'induce tolerance', dampening IgE reactivity [34.Bachmann M.F. Kündig T.M. Allergen-specific immunotherapy: is it vaccination against toxins after all?.Allergy. 2017; 72: 13-23Crossref PubMed Scopus (25) Google Scholar]. However, the design of several new technology platforms has revived the concept that allergens may be viewed as 'protoxins', highlighting the importance and protective umbrella of neutralizing antibodies, which is now considered to be broader than first appreciated [34.Bachmann M.F. Kündig T.M. Allergen-specific immunotherapy: is it vaccination against toxins after all?.Allergy. 2017; 72: 13-23Crossref PubMed Scopus (25) Google Scholar,35.Zha L. et al.An unexpected protective role of low-affinity allergen-specific IgG through the inhibitory receptor FcγRIIb.J. Allergy Clin. Immunol. 2018; 142: 1529-1536Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]. Here, we discuss allergen-specific IgG antibodies, which may be considered a key effector modality in SIT; allergens displayed on VLP, which are highly immunogenic but do not induce anaphylactic reactions; the induction of IgG antibodies against a single allergen combined with VLP nanoparticles to protect against a complex allergen cocktail. The growing evidence in using advanced nanoparticle technology reviewed herein considers a paradigm shift toward a classical vaccination approach to treat allergy (see Clinician's Corner). SIT induces a change in T cell subtypes, mainly Tregs and a shift from type 2 T helper cells (Th2) to Th1 cells [36.Till S. Immunotherapy: readdressing the balance between TH2 and TH1 cells.Clin. Exp. Allergy. 1997; 27: 981-985Crossref PubMed Scopus (11) Google Scholar,37.Benjaponpitakm S. et al.The kinetics of change in cytokine production by CD4 T cells during conventional allergen immunotherapy.J. Allergy Clin. Immunol. 1999; 103: 468-475Abstract Full Text Full Text PDF PubMed Google Scholar]. While induction of Tregs appears to be transient, a reduction in Th2 cell activity is more long-lasting [38.Möbs C. et al.Birch pollen immunotherapy results in long-term loss of Bet v 1-specific TH2 responses, transient TR1 activation, and synthesis of IgE-blocking antibodies.J. Allergy Clin. Immunol. 2012; 130: 1108-1116Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar]. Both Th1 and Tregs are thought to block Th2 cells, causing a nonallergic milieu and depletion of IgE synthesis in the long term (Figure 1A ). In addition to a change in T cells, SIT induces allergen-specific IgE and IgG. Allergen-specific IgG production may often depend on the induction of regulatory B cells, which also secrete immune-suppressive cytokines [14.Rosser E.C. Mauri C. Regulatory B cells: origin, phenotype, and function.Immunity. 2015; 42 (21): 607-612Abstract Full Text Full Text PDF PubMed Scopus (597) Google Scholar,15.Kim A.S. et al.Regulatory B cells and T follicular helper cells are reduced in allergic rhinitis.J. Allergy Clin. Immunol. 2016; 138: 1192-1195Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar]. One million-fold more IgG than IgE (milligrams per milliliter versus nanograms per milliliter) circulate in the bloodstream, and allergens are likely to form complexes with polyclonal IgG antibodies of several specificities before they reach FcƐRI-bound IgE [39.Malbec O. et al.Trans-inhibition of activation and proliferation signals by Fc receptors in mast cells and basophils.Sci. Signal. 2016; 9 (20): ra126Crossref PubMed Scopus (23) Google Scholar]. IgG4, the least-represented human IgG subclass in serum, is an intriguing antibody with unique biological properties, such as the ability to undergo Fab-arm exchange and to limit immune complex formation. The lack of effector functions, such as antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity, is desirable for therapeutic purposes. IgG4 has a protective role in allergy by acting as a blocking antibody (Figure 1A), and inhibiting mast cell degranulation [40.Davies A.M. et al.Human IgG4: a structural perspective.Immunol. Rev. 2015; 268: 139-159Crossref PubMed Scopus (73) Google Scholar] Furthermore, crosslinking of FcγRIIb by the IgG4 subclass redirects proallergic M2a macrophages to an M2b-like immunosuppressive phenotype. This suggests an interplay of macrophages with IgG4 in immune tolerance, likely relevant in allergen immunotherapy [41.Bianchini R. et al.IgG4 drives M2a macrophages to a regulatory M2b-like phenotype: potential implication in immune tolerance.Allergy. 2019; 74: 483-494Crossref PubMed Scopus (26) Google Scholar]. Allergen-specific IgE induction occurs early after treatment and is transient ,while IgG responses are long lasting. Importantly, the increase in IgG is more prominent than the long-term reduction in IgE levels; in addition, a reduction in IgE does not always occur [42.Wachholz P.A. Durham S.R. Mechanisms of immunotherapy: IgG revisited.Curr. Opin. Allergy Clin. Immunol. 2004; 4: 313-318Crossref PubMed Scopus (159) Google Scholar]. Hence, the effector mechanism induced by SIT must be able to block allergic responses despite the presence of allergen-specific IgE. As discussed previously [34.Bachmann M.F. Kündig T.M. Allergen-specific immunotherapy: is it vaccination against toxins after all?.Allergy. 2017; 72: 13-23Crossref PubMed Scopus (25) Google Scholar], this renders Tregs and Th1 cells unlikely candidates mostly for kinetic reasons. Indeed, allergic symptoms in hay fever occur within minutes and, therefore, cannot be blocked by antigen-specific T cells, which are activated by the recognition of allergen-derived peptides presented on MHC class II molecules (Figure 1B). Processing allergens for antigen-presentation requires hours rather than minutes, excluding sufficiently rapid activation of T cells to block IgE-mediated mast cell or basophil activation (Figure 1B). It may be argued that Tregs create a non-inflammatory milieu; however, such a mechanism would not be allergen specific and, therefore, is not compatible with clinical experience [34.Bachmann M.F. Kündig T.M. Allergen-specific immunotherapy: is it vaccination against toxins after all?.Allergy. 2017; 72: 13-23Crossref PubMed Scopus (25) Google Scholar,43.Wagenmann M. et al.Randomized immunotherapy trial in dual-allergic patients using 'active allergen placebo' as control.Allergy. 2019; 74: 1480-1489PubMed Google Scholar,44.Ellis A.K. et al.Lack of effect of Timothy grass pollen sublingual immunotherapy tablet on birch pollen-induced allergic rhinoconjunctivitis in an environmental exposure unit.Ann. Allergy Asthma Immunol. 2018; 120: 495-503Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar]. In addition, depletion of Tregs in a murine model of cat allergy did not abrogate protection induced by SIT [45.Schmitz N. et al.Displaying Fel d1 on virus-like particles prevents reactogenicity despite greatly enhanced immunogenicity: a novel therapy for cat allergy.J. Exp. Med. 2009; 206: 1941-1955Crossref PubMed Scopus (80) Google Scholar]. In contrast to slowly activated allergen-specific T cells, allergen-specific IgG may be able to block allergen-induced cellular activation within seconds (Figure 1B). It is well established that SIT induces allergen-neutralizing IgG antibodies [38.Möbs C. et al.Birch pollen immunotherapy results in long-term loss of Bet v 1-specific TH2 responses, transient TR1 activation, and synthesis of IgE-blocking antibodies.J. Allergy Clin. Immunol. 2012; 130: 1108-1116Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar,42.Wachholz P.A. Durham S.R. Mechanisms of immunotherapy: IgG revisited.Curr. Opin. Allergy Clin. Immunol. 2004; 4: 313-318Crossref PubMed Scopus (159) Google Scholar] and that these antibodies are able to block IgE-mediated antigen presentation. Even though induction of IgG does not always correlate with clinical efficacy [12.Shamji M.H. et al.Biomarkers for monitoring clinical efficacy of allergen immunotherapy for allergic rhinoconjunctivitis and allergic asthma: an EAACI Position Paper.Allergy. 2017; 72: 1156-1173Crossref PubMed Scopus (169) Google Scholar], the IgE:IgG ratio might be the more important parameter yielding better correlations or, indeed, considerations related to the affinity and/or avidity of IgG4 and ELISA-based approaches to establish a meaningful correlation [12.Shamji M.H. et al.Biomarkers for monitoring clinical efficacy of allergen immunotherapy for allergic rhinoconjunctivitis and allergic asthma: an EAACI Position Paper.Allergy. 2017; 72: 1156-1173Crossref PubMed Scopus (169) Google Scholar]. In a classical experiment, immune sera from patients after but not before SIT were able neutralize allergens in a skin-prick test, directly demonstrating the therapeutic potential of allergen-specific IgG [46.Cooke R.A. et al.Serological evidence of immunity with coexisting sensitization in a type of human allergy (hay fever).J. Exp. Med. 1935; 62: 733-750Crossref PubMed Scopus (239) Google Scholar]. Furthermore, it has been shown in murine models of cat and peanut allergies that the transfer of allergen-specific IgG resulted protection against local and systemic allergen challenge [35.Zha L. et al.An unexpected protective role of low-affinity allergen-specific IgG through the inhibitory receptor FcγRIIb.J. Allergy Clin. Immunol. 2018; 142: 1529-1536Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar,47.Storni, F. et al. Vaccine against peanut allergy based on engineered Virus-Like-Particles and single major peanut allergens. J. Allergy Clin. Immunol. Published online December 19, 2019. http://dx.doi.org/10.1016/j.jaci.2019.12.007Google Scholar]. An important piece of evidence for a protective role of allergen-specific IgG was recently provided in a clinical study that demonstrated that passive vaccination with monoclonal antibodies (mAbs) against Fel d 1, the major allergen in cats, protected humans against allergic symptoms [48.Orengo J.M. et al.Treating cat allergy with monoclonal IgG antibodies that bind allergen and prevent IgE engagement.Nat. Commun. 2018; 9 (12): 1421Crossref PubMed Scopus (84) Google Scholar]. Thus, such evidence resuscitates the concept from the early 20th century developed by the American physician Dunbar using antibody-based immunotherapy [49.Dunbar W.P. Zur Ursache und spec. Heil. des Heufiebers.Dtsch. Med. Wochenschr. 1903; 9: 24-28Google Scholar,50.Dunbar W.P. Zur Frage betreffend der spezifischen Heilung des Heufiebers.Berl Klin Wochenschrift. 1903; 40: 569Google Scholar]. IgG antibodies may block mast cell and/or basophil activation via three pathways: direct allergen neutralization (Figure 2A ); engagement of the inhibitory FcγRIIb (Figure 2B) [51.Ravetch J.V. et al.IgG Fc receptors.Annu. Rev. Immunol. 2001; 19: 275-290Crossref PubMed Scopus (1303) Google Scholar]; and co-internalization of IgE by mast cells (Figure 2C) [52.Uermösi C. et al.IgG-mediated down-regulation of IgE bound to mast cells: a potential novel mechanism of allergen-specific desensitization.Allergy. 2014; 69: 338-347Crossref PubMed Scopus (37) Google Scholar]. Direct allergen neutralization is the most straightforward mechanism, because it simply blocks the access of the allergen to IgE bound to the high-affinity FcƐRI (Figure 2A). However, allergen neutralization is demanding since the antibodies essentially need to block all epitopes recognized by IgE. It was recently shown that only high-affinity antibodies are able to mediate allergen neutralization [35.Zha L. et al.An unexpected protective role of low-affinity allergen-specific IgG through the inhibitory receptor FcγRIIb.J. Allergy Clin. Immunol. 2018; 142: 1529-1536Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]. By contrast, engagement of the inhibitory receptor FcγRIIb by an IgG-allergen immune complex is sufficient to block cellular activation. Hence, this mechanism is less demanding because not all epitopes need to be targeted. Furthermore, and rather unexpectedly, antibodies with affinities as low as 10–7 M effectively shut down mast cell activation [35.Zha L. et al.An unexpected protective role of low-affinity allergen-specific IgG through the inhibitory receptor FcγRIIb.J. Allergy Clin. Immunol. 2018; 142: 1529-1536Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]. Hence, in contrast to neutralizing antibodies, FcγRIIb-engaging IgG antibodies can be of low affinity. Engagement of FcγRIIb causes its internalization and it was recently shown that co-engaged IgE is co-internalized [52.Uermösi C. et al.IgG-mediated down-regulation of IgE bound to mast cells: a potential novel mechanism of allergen-specific desensitization.Allergy. 2014; 69: 338-347Crossref PubMed Scopus (37) Google Scholar]. Hence, co-exposure to allergen and specific IgG causes the removal of IgE from the surface of mast cells. 'Trans-inhibition', a previously unreported regulatory mechanism by which antibodies can energize mast cells and basophils when engaging Fc receptors, operates in normal primary mast cells and basophils, whether of murine or human origin, and human FcγRIIb induces trans-inhibition similarly to murine FcγRIIb. Trans-inhibition dampened all IgE-induced mast cell secretory responses, including the release of all mediators that account for anaphylaxis. Interestingly, whereas all ITIM-containing receptors can inhibit activation signals in cis, FcγRIIb, but not other ITIM-containing receptors, can inhibit signaling in trans [39.Malbec O. et al.Trans-inhibition of activation and proliferation signals by Fc receptors in mast cells and basophils.Sci. Signal. 2016; 9 (20): ra126Crossref PubMed Scopus (23) Google Scholar]. IgG4 antibodies exhibit blocking activity, as might IgG1 antibodies [53.Hussain R. et al.Predominant localization of blocking antibody to the IgG4 subclass.J. Immunol. 1992; 148 (1): 2731-2737PubMed Google Scholar]. Thus, the ability of mAbs of the IgG1 and IgG4 isotypes to neutralize allergens and to engage FcγRIIb should be further investigated. Using recombinantly produced murine antibodies, it was recently shown in mice that IgG1 and IgG2a antibodies of the same specificity were equally potent at inhibiting the allergic reaction [52.Uermösi C. et al.IgG-mediated down-regulation of IgE bound to mast cells: a potential novel mechanism of allergen-specific desensitization.Allergy. 2014; 69: 338-347Crossref PubMed Scopus (37) Google Scholar]. In summary, these observations clearly illustrate the potential of allergen-specific IgG antibodies to protect against allergic symptoms. While these results do not exclude a potential role for T cells in SIT, they demonstrate that induction of IgG alone may be sufficient for clinical efficacy. Thus, it is reason