The goal of this project is to utilize cytomegalovirus (CMV) vectors to develop a therapeutic vaccine againstTrypanosoma cruzi, the causative agent of Chagas disease. Although the most common transmission route isby a triatomine bug vector known as the ?kissing bug?, Chagas disease is also spread vertically from mother tochild and along blood born routes such as organ transplant and transfusion. While the acute phase of infectionmay last a couple of months, it is generally asymptomatic and self-limiting. However, chronic parasitepersistence in 30 ? 40% of patients can give rise to severe cardiac and gastrointestinal disorders presumed tobe a result of an inadequate host immune response. Severe long-term chronic disease can lead to cardiacmanifestations such as arrhythmias, aneurysms, thromboembolic events, and heart failure resulting in suddendeath. Current efforts to control disease is focused on the use of anti-trypanosomal drugs which arecontraindicated in pregnancy, advanced kidney or liver disease, and are of questionable efficacy for those whocan tolerate treatment. An effective therapeutic vaccine has the potential to ameliorate the complications of theestimated 40,000 new cases of Chagas and prevent 10,000 or more deaths annually. Vaccine studies indicateprotective immune responses are linked to T. cruzi specific CD8 T-cell induction. CMV vectors are uniquelyqualified for this task due to their ability to induce lifelong, high frequency effector memory T cell (TEM)responses. The TEM cell population is maintained by persistent, low level antigen presentation. In non-humanprimate models, TEM induced by CMV-vectored vaccines have functionally cured SIV. CMV-vectors arecurrently being developed for prophylactic and therapeutic vaccines against HIV by TomegaVax, Inc. Unliketraditional viral vectors, CMV vectors can be used repeatedly, without loss of immunogenicity or efficacy.Importantly, spread-deficient CMV vectors maintain the same level of TEM stimulation as wild-type vectors,providing safety for immunocompromised recipients. The feasibility of CMV vectors for Chagas, will beevaluated in murine CMV vectors expressing T. cruzi antigens in a well-established murine model. Usingbacterial artificial chromosome technology, we will construct CMV vectors expressing selected antigens,characterize the induced immune responses, and determine their prophylactic and therapeutic efficacy againstchallenge with T. cruzi. This phase I study will enable the selection of protective antigens for insertion intospread-deficient human CMV vectors. Phase II of this program will then focus on IND-enabling studies tomanufacture and test HCMV-vectored Chagas vaccines. The ultimate product of this research program will bea recombinant therapeutic vaccine providing lifelong protection.
Currently there is no approved vaccine for Trypanasoma cruzi; the infectious agent in Chagasdisease. While primarily affecting Central and South Americans living in poor quality housingwhere the ?kissing bug? vector is less well controlled; the vertical transmission from mother tochild and the globalization of Chagas into border nations like the United States is cause forgreat concern. To address this issue we propose development of a therapeutic vaccine basedon recombinant; spread deficient cytomegalovirus vectors that elicit high levels of T-lymphocytes against their target antigens.
