Experimental vaccine protects against anaphylaxis in mice

Researchers led by the Institut Pasteur, Université Paris, have developed a vaccine that elicits anti-Immunoglobulin E antibodies in humanized mice, protects against Immunoglobulin E-mediated anaphylaxis, and shows no detectable adverse reaction over one year of observation.

Allergy and anaphylaxis create major patient discomfort and potentially life-threatening conditions. Immunoglobulin E (IgE) is at the core of anaphylaxis biology, particularly in reactions against foods. Allergens crosslink onto IgE while it is bound to its high-affinity receptor FcεRI on the surface of mast cells and basophils, causing those cells to release substances that then cause allergy symptoms, including anaphylaxis.

Omalizumab, an approved monoclonal antibody therapy, blocks IgE from binding FcεRI, reduces free IgE, and down-regulates FcεRI expression. First approval came for asthma, and more recently, omalizumab received US Food and Drug Administration approval for food allergy.

In a recent study of individuals with food allergies, one-third did not meet the clinical end point for omalizumab. Questions also remain about financial feasibility and adherence, since monoclonal antibody therapies are expensive and injections are required every few weeks, potentially over a lifetime.

An idea first developed in the early 1990s has reentered the conversation. Instead of administering therapeutic antibodies, the host might be prompted to make endogenous, omalizumab-like antibodies by immunizing against IgE.

Antibodies against IgE face important constraints. Antibodies that bind IgE outside the FcεRI-binding domain can still crosslink IgE molecules on the surface of mast cells and basophils and potentially trigger a clinical reaction. Any such approach also needs to overcome immune tolerance and induce antibodies against self-IgE in sufficient titers to block FcεRI binding over the long term.

Designing an IgE locking vaccine

In the study, “A vaccine targeting human IgE induces long-term protection against anaphylaxis in humanized mice,” published in Science Translational Medicine, researchers designed a conjugate vaccine to induce high-avidity antibodies that coerce free IgE into a closed state that cannot bind FcεRI.

Vaccine design drew on the crystal structure of omalizumab binding to IgE. Structural work showed that IgE toggles between open and closed states. FcεRI binding is accessible only in the open state, and omalizumab functions by locking IgE in the closed state so that FcεRI cannot engage.

Using that structural map, the team engineered a target antigen composed of a fragment of IgE with the domains required to bind FcεRI and introduced a point mutation, G335C, that permanently locks this fragment into the closed state.

Researchers attached the mutated IgE fragment to a highly immunogenic but nontoxic mutant of diphtheria toxin to create the vaccine and IgE-humanized mice received IgE-K immunization.

IgE-humanized mice that received the vaccine (IgE-K) produced anti–human IgE antibodies. Serum collected from these vaccinated animals blocked IgE binding to FcεRI in vitro, showing that vaccination generated antibodies capable of interfering with that interaction.

Testing protection

Humanized mice carrying both human IgE and human FcεRI then received the IgE-K vaccine before passive transfer of human IgE specific for the model antigen NP.

In a local skin reaction test, vaccinated animals showed reduced extravasation and reduced mast-cell degranulation (release of histamines and enzymes) in the skin compared with controls after antigen challenge.

In a systemic model, vaccinated mice did not develop signs of anaphylaxis and showed reduced systemic mast cell activation compared with controls after systemic administration of human IgE and antigen.

Peanut-allergic humanized mice that received IgE-K after sensitization showed greatly reduced signs of anaphylaxis after a high dose of polyclonal anti-IgE.

Taken together, these experiments show that IgE-K vaccination controlled IgE-mediated anaphylaxis in these settings. Findings indicate that IgE-K might be able to overcome tolerance and establish long-term anti-IgE reservoirs in this setting.

Balancing safety and immune defense

IgE-K–vaccinated hIgE-hFcεRI mice had no detectable adverse reaction to IgE-K immunization. Findings may indicate that, for some unknown reason, crosslinking was not meaningfully induced in vivo.

Another possibility is that the progressive increase in anti-IgE that emerged after immunization softly triggered mast cells over time and effectively desensitized them. Any subsequent IgE antibodies would have been blocked from binding FcεRI, leaving the mice unable to respond to later challenges.

Mast cells play pathogenic roles in atopic disease and also participate in protection against parasitic infection. In a nematode infection model that does not require IgE for protection, IgE-K–vaccinated mice and control mice showed similar mast cell numbers, similar mast cell activation, and similar parasite clearance.

Findings indicate that mast cells in vaccinated mice remained functional. A suggested next step is evaluation of IgE-K in a model of multicellular parasitic infection cleared by both IgE and mast cells.

Long-term IgE production may arise from long-lived IgE plasma cells or from IgG+ type 2-polarized memory B cells capable of generating IgE-secreting plasma cells upon allergen exposure. Ligation of the B cell receptor on IgE-secreting plasma cells induces apoptosis, a feature that suggests anti-IgE antibodies generated during IgE-K vaccination could further deplete IgE titers through this mechanism.

Strong suppression of anaphylaxis in the absence of adverse events makes the IgE-K vaccine a very enticing therapeutic candidate if results can translate to humans.

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