Ara h 2–expressing cucumber mosaic virus–like particle (VLP Peanut) induces in vitro tolerogenic cellular responses in peanut-allergic individuals

[Display omitted] Peanut allergy (PA) is one of the most prevalent food allergies with a lack of favorable safety/efficacy treatment. A cucumber mosaic virus–like particle expressing peanut allergen component Ara h 2 (VLP Peanut) has been developed as a novel therapeutic approach for PA. We assessed the tolerogenic properties and reactivity of VLP Peanut. Whole blood and peripheral blood mononuclear cells were collected from 6 peanut-allergic children. Modulation of dendritic cells (DCs), T cells, and B cells, stimulated with VLP Peanut, Ara h 2, and whole peanut extract in vitro, were assessed by quantitative real-time PCR and flow cytometry, respectively. Basophil and skin reactivity in response to VLP Peanut was assessed by basophil activation test and skin prick test, respectively. VLP Peanut showed beneficial biochemical properties, fit for use in clinical studies. VLP Peanut induced IFN-γ+ TH1 (P < .05) while having reduced capacity to elicit proliferation of TH2, allergen-specific TH2, and IL-4+-T follicular helper cells. Moreover, VLP Peanut is associated with upregulation of DC1-associated genes (MX1) compared to Ara h 2 and whole peanut extract. VLP Peanut was the most prominent at inducing IL-10+ regulatory B cells (P < .05). Unbiased clustering analyses identified metaclusters of T and B cells targeted by VLP Peanut. Finally, VLP Peanut had reduced capacity to elicit high- and low-affinity IgE receptor–mediated responses compared to Ara h 2 or whole peanut extract (all P < .05). Finally, in an open-label first-in-human cohort of 6 peanut-allergic adults, administration of increasing concentration of VLP Peanut through skin prick test was tolerated and demonstrated no development of skin reactivity. VLP Peanut displayed tolerogenic properties by modulating DCs, T cells, and B cells in vitro. Preliminary findings of skin reactivity using VLP Peanut in 6 peanut-allergic adults was safe and well tolerated in an open-label phase 1 study. PROTECT, NCT 05476497