Virus like particle displaying the major allergen Der p 1 as a vaccine candidate against house dust mite allergy

Abstract

House dust mite (HDM) represents one of the most important allergenic sources worldwide. HDM allergens trigger in atopic patients potent Th2-biased inflammatory responses leading to the development of allergic rhinitis/asthma and atopic dermatitis. The HDM allergic response is mediated mainly by the allergen-specific Th2 cells and IgE. Der p 1, a papain-like cysteine protease, is a major HDM allergen from the Dermatophagoides pteronyssinus species, inducing allergic sensitizations in around 80 percent of HDM allergic populations. Allergen-specific immunotherapy (AIT) represents a unique specific treatment capable to revert the house dust mite (HDM) allergic response into immune tolerance through repetitive subcutaneous or sublingual administrations of mite allergen extracts. However, the AIT duration (minimum 2-3 years), efficacy issues, and side-effect developments could explain the poor adherence of the HDM allergic patients to conventional AIT. As successful AIT was shown to be correlated with the levels of blocking IgG antibodies inhibiting allergen-IgE interactions, new generations of immunotherapies, aimed to boost such blocking of IgE responses, could be more effective than conventional allergen extract-based AIT. Virus-like particles (VLP) are well-known to elicit potent antibody responses, the goal of the present study was to design VLPs displaying a recombinant form of Der p 1 zymogen (ProDer p 1, PD1) and to test the allergenicity and immunogenicity of these chimeric particles. AP205 bacteriophage-based VLPs were decorated with PD1 using the split-protein (SpyTag/SpyCatcher) conjugation technology. To get successful conjugation of PD1 to SpyCatcher-VLP, we had to express SpyTagged-PD1C34A (mutation of the active site cysteine residue of Der p 1). Competitive ELISA IgE assays evidenced that VLP-PD1 has a much lower IgE reactivity in comparison with natural Der p 1 (nDer p 1). Remarkably, PD1 multimerization prevented basophil degranulation. Unadjuvanted VLP-PD1 elicited strong anti-nDer p 1 IgG responses but no specific IgE. Specific IgG induced by VLP-PD1 could inhibit the binding of human IgE to nDer p 1 as well as nDer p 1-specific basophil activation. Finally, lymphoproliferative assays showed that VLP-PD1 triggered allergen-specific Th1 cells as shown by the potent production of IFN-g. In conclusion, VLP decorated with PD1 was hypoallergenic and induced potent blocking IgG antibody response. Such chimeric VLPs could represent a promising vaccine candidate for HDM-specific immunoprophylaxis and immunotherapy.