Vaccination against helminth IL-33 modulators permits immune-mediated parasite ejection

The murine intestinal nematode Heligmosomoides polygyrus bakeri (Hpb) modulates the host immune response via the Hpb alarmin release inhibitor (HpARI) family (HpARI1/2/3), which acts on interleukin (IL)-33, and the Hpb binds alarmin receptor and inhibits (HpBARI) family (HpBARI and HpBARI_Hom2), which acts on the IL-33 receptor ST2. Here, we find that this immunomodulation is evident only in the first week of infection and affects local and distal tissues. Vaccination with HpARI or HpBARI proteins raises antibody responses that block their immunomodulatory activities: HpARI2 vaccination results in significantly increased type 2 innate lymphoid cells (ILC2s), T helper (Th)2, and serum IL-4 and IL-5 responses, while HpBARI + HpBARI_Hom2 vaccination reverses infection-mediated ST2 suppression and increases Th2 immunity. A cocktail of HpARI2 + HpBARI + HpBARI_Hom2 gives robust protection against infection, associated with stunting of adult parasites, reduced egg burden, increased type 2 immune responses, and intestinal goblet cell expansion. Therefore, vaccination with immunomodulatory proteins can protect the host against infection and can be used as a tool for blocking the effects of specific parasite-derived proteins.