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IgE antibodies play a key role in food allergy and other allergic diseases affecting approximately one-third of the world's population [1]. Upon exposure to an allergen in allergic subjects, such allergen is recognized by allergen-specific IgE bound to their high-affinity receptor FcεRI on the surface of tissue mast cells and blood basophils, which promotes the degranulation of these cells and the release of both preformed and newly synthesized mediators, including histamine [1]. This can even lead to anaphylaxis, a severe and potentially fatal systemic allergic reaction [1]. Omalizumab and other anti-IgE monoclonal antibodies (mAbs) were developed to prevent this reaction and treat IgE-mediated diseases such as allergic asthma, food allergy, and chronic spontaneous urticaria (CSU) [1]. However, the use of these mAbs is still restricted to a minority of patients suffering from the most severe symptoms, as treatment is costly and requires repeated administrations. Our patent covers the use of a therapeutic conjugate vaccine, called IgE “kinoid,” which induces long-term production of neutralizing antibodies able to block binding of IgE to FcεRI for the prevention of anaphylaxis and other IgE-mediated reactions [2]. The IgE kinoid vaccine is produced following the same chemistry we previously used for the development of kinoids targeting IL-4 and IL-13 [3]. Briefly, the Cε3-4 fragment of the heavy chain of human IgE is coupled with a carrier protein such as diphtheria ‘cross-reactive material 197’ (CRM197, a non-toxic mutant of diphtheria toxin used in several approved conjugate vaccines), using a thiol-maleimide conjugation (Figure 1). Importantly, the IgE fragment contains a point mutation at position 335 (G335C) that locks it in a “closed” conformation unable to directly bind FcεRI [4], in order to avoid any potential activation of mast cells at the injection site. In addition, the fragment is produced in a cell system such as HEK293 cells that can induce posttranslational glycosylations which are essential for IgE biology [5]. Upon injection with an adjuvant, the IgE kinoid vaccine will induce an antibody response against the carrier protein, but also against human IgE. It is thus expected to promote beneficial effects in food allergy, CSU and other IgE-mediated pathologies. In particular, it is expected that the vaccine will induce long-term prevention of IgE-mediated anaphylaxis. The development of an anti-IgE therapeutic vaccine has generated a long-time interest in academic research as well as in the pharmaceutical industry. Notably, two peptide-based IgE vaccines were developed by Pfizer, with one peptide selected as a potential sequence recognized by omalizumab and the other one corresponding to part of the FcεRI-binding site. A phase 1 study was conducted in patients with allergic rhinitis (NCT01723254), but little or no lowering of IgE was observed in most patients [6]. We hypothesized that potent neutralization of IgE biological activity would require antibodies recognizing complex conformational epitopes in the Fc portion of IgE. In 2018, we thus decided to develop a conjugate vaccine targeting the full Cε3-4 domains of human IgE with the rationale that such a vaccine would induce neutralizing anti-IgE antibodies with the same protective effects as omalizumab, and could in particular induce long-term prevention of IgE-mediated anaphylaxis. This project was set as a collaboration between the French National Institute of Health and Medical Research (Inserm), the Institut Pasteur, and the French biotech Neovacs specialized in the development of “kinoid” vaccines targeting self-antigens. A kinoid targeting human IgE would be highly immunogenic in mice due to low interspecies similarities of IgE. Thus, we developed and used a novel mouse strain expressing human IgE and human FcεRI in place of the respective mouse proteins. Vaccination of these humanized mice with the IgE kinoid induced potent production of antibodies able to neutralize binding of human IgE to FcεRI. These neutralizing antibodies were still detectable in most mice 1 year after primary immunization with the vaccine. Moreover, vaccination with the IgE kinoid induced a marked reduction in circulating free IgE and IgE at the surface of mast cells. Finally, we demonstrated that both prophylactic and therapeutic vaccination with the IgE kinoid can protect from IgE-mediated systemic anaphylaxis for up to 1 year (the latest time-point we assessed) (Figure 2). We performed in vitro experiments on primary human mast cells to demonstrate that the antibodies present in the serum of vaccinated mice can fully block binding of human IgE to FcεRI expressed on mast cells. These in vitro experiments also highlighted that besides production of neutralizing antibodies, some of the vaccine-induced antibodies were also able to crosslink IgE already bound to FcεRI and thereby induce mast cell degranulation in vitro. We however did not observe any side effect and, in particular, no sign of mast cell degranulation in vivo upon vaccination with the IgE kinoid. We thus speculate that low affinity antibodies generated early after vaccination might even participate in the protective effect of the vaccine by slowly engaging surface IgE without triggering degranulation (although this will require further investigation). Overall, we have demonstrated that our patented IgE vaccine can prevent human IgE-mediated anaphylaxis in preclinical models. Importantly, this effect is long-lasting, which represents a clear benefit over omalizumab or other anti-IgE mAbs for the treatment of chronic IgE-mediated diseases. These findings were published recently [2]. It will now be very important to demonstrate the safety and immunogenicity of this vaccine in clinical trials. Besides the prevention of life-threatening anaphylaxis, we envision that this vaccine could have beneficial effects in many IgE-mediated diseases, including allergic asthma, food allergy, and chronic spontaneous urticaria. V.S. and L.L.R. contributed to the writing and editing of this manuscript. L.L.R. acknowledges support from the European Research Council (ERC)–Seventh Framework Program (ERC-2021-CoG #101043749). This work was supported by grants from the French National Research Agency #ANR-18-ce18-0023 “AllergyVACS” and #ANR-24-ce18-6970 “AllergyVACS2”. V.S. and L.L.R. are inventors on a patent related to this work: WO2022058571 (A1) “Immunogenic product comprising an IgE fragment for treating IgE-mediated inflammatory disorders,” licensed to Neovacs. V.S. and L.L.R. are employees of Neovacs and/or company stock owners. Outside of the submitted work, L.L.R. is or recently was a speaker and/or advisor for and/or has received research funding from Argenx, Novartis, Ceva and CSL Behring. Requests for IgE Kinoids should be addressed to Vincent Serra ([email protected]) and will require an MTA.