Source data are provided in the Source data file. Combined vaccination against IL-4 and IL-13 protects against chronic asthma in mice We then tested the prophylactic efficacy of these vaccines in a chronic asthma model. feasibility. Subject terms: Interleukins, Asthma, Chronic inflammation, Conjugate vaccines Asthma is usually caused by hyperreactivity to benign antigens, with humoral immunity orchestrated by interleukin-4 (IL-4) and IL-13 being the key etiological factor. Here the authors show, in humanized mouse models, that dual vaccination against IL-4 and IL-13 induces their durable suppression ameliorate experimental asthma, and to hint clinical translation. Introduction Asthma is the most common chronic lung disease, affecting >300 million people worldwide, and with at least 250,000 deaths attributed to the disease each year1. An estimate of 20% of asthma patients suffer from uncontrolled, moderate-to-severe asthma2, presenting with persistent symptoms, with reduced lung functions and recurrent exacerbations, despite the use of high-dose pharmacological therapy3. The heterogeneity of asthma phenotypes represents a challenge for adequate assessment and treatment of the disease4. However, type 2 inflammation characterized by production of interleukin-4 (IL-4) and IL-13 in Boc-NH-PEG2-C2-amido-C4-acid the lung, airway eosinophilia, and high levels of IgE antibodies occurs in ~50% of patients with asthma1,5. Even though IL-4 and IL-13 present comparable structures and share one receptor subunit (IL-4R)6, IL-4 and IL-13 are also thought to have some nonredundant functions in allergy and asthma7. In particular, IL-4 is considered to act predominantly in the early phase of asthma development through its role in regulating T cell proliferation and survival, and IgE synthesis6. In contrast, IL-13 would predominantly be involved in late phases of allergic reactions, such as airway remodeling and mucus hypersecretion6. Phase 3 studies indicated that dupilumaba monoclonal antibody (mAb) against IL-4R that blocks both IL-4 and IL-13 signaling8is usually efficient at decreasing the rate of severe exacerbations, and Boc-NH-PEG2-C2-amido-C4-acid at improving lung function in patients with moderate-to-severe asthma9. Dupilumab was approved in 2018 as an add-on maintenance treatment in moderate-to-severe asthma with type 2 inflammation. However, 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. Therefore, while IL-4 and IL-13 are now clinically validated therapeutic targets for the treatment of asthma, there is a clear need to improve current strategies, with the goal of reaching long-term cost-effective therapeutic effects. Conjugate vaccines called kinoids can elicit an endogenous, long-lasting neutralizing antibody response against a given cytokine10, and could be a favorable alternative to therapeutic mAb administration. Vaccination against mouse IL-4 partially reduced IgE levels and eosinophilia with minor effects on mucus hypersecretion in a mouse asthma model11. A recombinant mouse IL-13 peptide-based virus-like particle vaccine had significant effects on mucus production without, however, affecting IgE levels12. 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 IL-13 alone13C15, we hypothesized that a dual vaccination against IL-4 and IL-13 would be particularly potent at Boc-NH-PEG2-C2-amido-C4-acid reducing the severity of chronic asthma. Here, we design conjugate vaccines against IL-4 and IL-13 rather than IL-4R to minimize the risk that these vaccines may induce antibodies capable of activating this receptor or inducing antibody-dependent cellular toxicity. We show that prophylactic and therapeutic dual vaccination against mouse IL-4 and IL-13 reduces key features of chronic allergic asthma in mice. We also 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-4R. Overall, ZNF346 our results suggest that dual IL-4/IL-13 vaccination is usually a promising long-term therapeutic strategy for allergic asthma, pending further safety and feasibility assessment in additional preclinical models. Results Anti-mouse IL-4 and IL-13 kinoids induce potent and long-lasting neutralizing responses We developed mouse IL-4 and IL-13 kinoids (IL-4-K and IL-13-K),.