A vaccine targeting human IgE induces long-term protection against anaphylaxis in humanized mice.

Abstract

Immunoglobulin E (IgE) antibodies play a key role in allergy and its most dangerous and life-threatening manifestation, anaphylaxis. Anti-IgE monoclonal antibodies (mAbs) have been developed to treat IgE-dependent diseases such as allergic asthma, food allergy, and chronic spontaneous urticaria. However, their use is still restricted to a minority of patients suffering from the most severe symptoms because treatment is costly and requires repeated administration. Therefore, we developed a conjugate vaccine against human IgE as a potential alternative therapy for long-term protection from IgE-dependent diseases. The IgE conjugate vaccine was generated by coupling a mutated fragment containing the Cε3-4 domains of human IgE with the carrier protein diphtheria cross-reactive material 197 (CRM₁₉₇) using kinoid technology to raise autoantibodies against a self-antigen by engrafting it onto the highly immunogenic CRM₁₉₇ carrier. To assess the efficacy of IgE-kinoid (IgE-K) vaccination, we generated a mouse model humanized for IgE and its high-affinity receptor FcεRI. IgE-K vaccination induced long-term production of anti-human IgE neutralizing antibodies without any detectable adverse effect. Anti-IgE antibodies were detected in the sera of IgE-K-immunized mice for up to 12 months postvaccination with a similar avidity as the approved anti-IgE mAb omalizumab. Furthermore, IgE-K vaccination protected against both IgE-mediated cutaneous and severe systemic anaphylaxis in IgE/FcεRI-humanized mice. Our results demonstrate that long-term reduction in IgE activity can be achieved through vaccination with human kinoids and can protect against anaphylaxis in humanized mice. This may represent a cost-effective, long-term therapeutic strategy for the treatment of IgE-mediated diseases.