Vaccine-Induced Anti-IgE Antibodies Neutralize Free IgE but Fail to Bind and Activate Mast Cell-Displayed IgE.

Background In Type I hypersensitivity, IgE is the antibody that contributes to the onset of anaphylaxis through the activation of effector cells, causing the release of allergic mediators. Blocking IgE activity with anti-IgE autoantibodies induced by active immunization could potentially offer an efficient and cost-effective method to treat allergic disorders. We recently developed an effective and safe anti-IgE vaccine in mice, but the mechanisms by which the vaccine protects and the explanation for its safety remained largely unknown. Here, our objective was to better understand those mechanisms. Methods CuMVTT-Cε3-Cε4 is a virus-like particles (VLP)-based vaccine designed to target domains 3 and 4 of IgE. Here, we studied the role of FcγRIIb and CD23 in vaccine-mediated protection from allergy using FcγRIIb KO and CD23 KO mice. Moreover, vaccine-induced IgGs were purified for passive immunization studies and for in vitro experiments with murine bone marrow-derived mast cells (BMMCs). Results Immunized mice generated high titers of IgG antibodies specific for IgE that conferred protection against allergic responses, independently of FcγRIIb and CD23. Sera of immunized mice blocked IgE binding to BMMC FcεRI and suppressed degranulation, independent of FcγRIIb. Purified anti-IgE antibodies did not provoke an anaphylactic response when transferred into allergic mice but protected against subsequent allergen challenge. Interestingly, the purified IgG antibodies were unable to recognize receptor-bound IgE in BMMCs, explained by the finding that recognition by these anti-IgEs depends on the same mannose moieties on IgE that are essential for FcεRI binding and thus hidden when receptor-bound. Conclusions In conclusion, the CuMVTT-Cε3-Cε4 vaccine induces high titers of anti-IgE IgGs that confer protection by neutralizing IgE through its glycan epitopes, without causing FcεRI cross-linking. Our results imply that an anti-IgE vaccine may represent a promising therapeutic strategy, offering effective protection while minimizing the risk of adverse reactions similar to the monoclonal antibody omalizumab.