Human trichuriasis (whipworm infection caused by Trichuris trichiura), is one of the most prevalent and serious neglected tropical diseases, and a major cause of colitis and inflammatory bowel disease, affecting ~450 million people in the world's poorest countries. The current approach for intestinal helminth control, namely annual mass treatment with either albendazole or mebendazole, is much less effective for whipworm (only 28- 36% cure rate) than for other intestinal worms, and that reinfection is not prevented post-treatment. A trichuriasis vaccine would represent an important technological advance as a complementary approach for global intestinal helminth control and elimination. To develop and test the whipworm vaccine, we have established a surrogate murine model for Trichuris infection, and have cloned and expressed a major protective antigen candidate, known as Whey Acidic Protein (Tm-WAP49) that is believed to facilitate parasite mucosal invasion in the colon. Mice immunized subcutaneously with adjuvanted Tm-WAP exhibit Th2 immune responses and 48% worm reduction after challenge with T. muris infective eggs. Since intestinal tissues are the main sites of Trichuris infection and pathology, mucosal immunization may better educate immune cells to target and persist at mucosal surfaces. We hypothesize that the mucosal route of immunization with rTm- WAP49 adjuvanted with OCH, a sphingosine truncated analog of the synthetic glycolipid alpha- galactosylceramide, can harness important innate immune functions that will be effective in eliciting potent mucosal and systemic antigen-specific Th2 immune responses for superior efficacy against trichuriasis.
In Aim 1, the vaccine formulation will be administered to AKR mice either orally, intranasally or sublingually, prior to oral challenge with T. muris eggs. Once the optimal route-of-administration has been determined, we will conduct a dosing study of the antigen to further optimize protection.
For Aim 2 we will identify immune correlates of protective efficacy induced by the vaccine in the mouse gut: serum and mucosal levels of IgG1 & 2a, IgA, and IgE, phenotype and functions of CD4+ and CD8+ T lymphocytes, as well as myeloid cells. We will also monitor memory immunity responses post-vaccination as well as recall immunity. We will specifically analyze for IL-4 and IL-13 as these cytokines are implicated in efficient worm expulsion. As a specific outcome, we aim to develop a successful mucosal immunization regimen against murine trichuriasis that will ultimately be translated to humans with T. trichiura WAP protein-based vaccine. A key innovation for this project is the evaluation of vaccine delivery via a non-injectable, mucosal route that allows administration by community healthcare workers who currently administer chemotherapeutic drugs in resource-poor settings.
Trichuriasis or human whipworm infection constitutes a severe peril to public health and leading global cause of colitis (inflammatory bowel disease) for the world's poorest children. The project proposed here will address this problem through systematic analyses of the immunogenicity and protective efficacy of an innovative and safe vaccine candidate via needle-free practical administration strategy to protect the public from this continuing threat.
