Dual vaccination against IL-4 and IL-13 protects against chronic allergic asthma in mice

Eva Conde,Géraldine Grouard-Vogel,Raïssa Houmadi,Noémie Caillot,François Huetz,Aurélie Mougel,David Hardy,Fabien Colaone,Jonathan Bonnefoy,Romain Bertrand,Alexia Loste,Samir Hamdi,John N Snouwaert,Laurent Guilleminault ,Vincent Serra,Nicolas Gaudenzio,Jasper Kamphuis ,Pierre Bruhns,Bianca Balbino,Beverly H Koller,Julien Stackowicz,Laurent L Reber

doi:10.1038/s41467-021-22834-5

Abstract

Allergic asthma is characterized by elevated levels of IgE antibodies, type 2 cytokines such as interleukin-4 (IL-4) and IL-13, airway hyperresponsiveness (AHR), mucus hypersecretion and eosinophilia. Approved therapeutic monoclonal antibodies targeting IgE or IL-4/IL-13 reduce asthma symptoms but require costly lifelong administrations. Here, we develop conjugate vaccines against mouse IL-4 and IL-13, and demonstrate their prophylactic and therapeutic efficacy in reducing IgE levels, AHR, eosinophilia and mucus production in mouse models of asthma analyzed up to 15 weeks after initial vaccination. More importantly, we also test similar vaccines specific for human IL-4/IL-13 in mice expressing human IL-4/IL-13 and the related receptor, IL-4Rα, to find efficient neutralization of both cytokines and reduced IgE levels for at least 11 weeks post-vaccination. Our results imply that dual IL-4/IL-13 vaccination may represent a cost-effective, long-term therapeutic strategy for the treatment of allergic asthma as demonstrated in mouse models, although additional studies are warranted to assess its safety and feasibility.

Highlights

Allergic asthma is characterized by elevated levels of IgE antibodies, type 2 cytokines such as interleukin-4 (IL-4) and IL-13, airway hyperresponsiveness (AHR), mucus hypersecretion and eosinophilia
Based on these partial results, and on the superior clinical efficacy in human asthma of targeting both IL-4 and IL-13 signaling rather than targeting either IL-4 or IL13 alone[13,14,15], we hypothesized that a dual vaccination against IL4 and IL-13 would be potent at reducing the severity of chronic asthma
We demonstrate the immunogenicity of a vaccine targeting human IL-4/IL-13 in a novel mouse strain humanized for IL-4, IL-13, and IL-4Rα

Summary

Introduction

Allergic asthma is characterized by elevated levels of IgE antibodies, type 2 cytokines such as interleukin-4 (IL-4) and IL-13, airway hyperresponsiveness (AHR), mucus hypersecretion and eosinophilia. Dupilumab was approved in 2018 as an add-on maintenance treatment in moderate-to-severe asthma with type 2 inflammation Use of this (or any other) mAb in chronic asthma is limited by high cost and the need to perform injections over years to lifelong. A recombinant mouse IL-13 peptide-based virus-like particle vaccine had significant effects on mucus production without, affecting IgE levels[12] Based on these partial results, and on the superior clinical efficacy in human asthma of targeting both IL-4 and IL-13 signaling (i.e., dupilumab) rather than targeting either IL-4 or IL13 alone[13,14,15], we hypothesized that a dual vaccination against IL4 and IL-13 would be potent at reducing the severity of chronic asthma

Methods

Results

Conclusion