Bruno Iannascoli

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 (CRM ₁₉₇ ) using kinoid technology to raise autoantibodies against a self-antigen by engrafting it onto the highly immunogenic CRM ₁₉₇ 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.

SARS-CoV-2 mRNA vaccination generates protective B cell responses targeting the SARS-CoV-2 spike glycoprotein. Whereas anti-spike memory B cell responses are long lasting, the anti-spike humoral antibody response progressively wanes, making booster vaccinations necessary for maintaining protective immunity. Here, we qualitatively investigated the plasmablast responses by measuring from single cells within hours of sampling the affinity of their secreted antibody for the SARS-CoV-2 spike receptor binding domain (RBD) in cohorts of BNT162b2-vaccinated naive and COVID-19–recovered individuals. Using a droplet microfluidic and imaging approach, we analyzed more than 4,000 single IgG-secreting cells, revealing high interindividual variability in affinity for RBD, with variations over 4 logs. High-affinity plasmablasts were induced by BNT162b2 vaccination against Hu-1 and Omicron RBD but disappeared quickly thereafter, whereas low-affinity plasmablasts represented more than 65% of the plasmablast response at all time points. Our droplet-based method thus proves efficient at fast and qualitative immune monitoring and should be helpful for optimization of vaccination protocols.

Omalizumab is an anti-IgE monoclonal antibody (mAb) approved for the treatment of severe asthma and chronic spontaneous urticaria. Use of omalizumab is associated with reported side effects ranging from local skin inflammation at the injection site to systemic anaphylaxis. To date, the mechanisms through which omalizumab induces adverse reactions are still unknown. Here, we demonstrated that immune complexes formed between omalizumab and IgE can induce both skin inflammation and anaphylaxis through engagement of IgG receptors (FcγRs) in FcγR-humanized mice. We further developed an Fc-engineered mutant version of omalizumab, and demonstrated that this mAb is equally potent as omalizumab at blocking IgE-mediated allergic reactions, but does not induce FcγR-dependent adverse reactions. Overall, our data indicate that omalizumab can induce skin inflammation and anaphylaxis by engaging FcγRs, and demonstrate that Fc-engineered versions of the mAb could be used to reduce such adverse reactions.

Albanesi, M., D. A. Mancardi, L. E. Macdonald, B. Iannascoli, L. Zitvogel, A. J. Murphy, J. H. Leusen, and P. Bruhns. 2012. Cutting Edge: FcγRIII (CD16) and FcγRI (CD64) are responsible for anti-glycoprotein 75 monoclonal antibody TA99 therapy for experimental metastatic B16 melanoma. J. Immunol