The goal of this project is to utilize cytomegalovirus (CMV) vectors to develop a therapeutic vaccine against Trypanosoma cruzi, the causative agent of Chagas disease. Although the most common transmission route is by a triatomine bug vector known as the kissing bug, Chagas disease is also spread vertically from mother to child and along blood born routes such as organ transplant and transfusion. While the acute phase of infection may last a couple of months, it is generally asymptomatic and self-limiting. However, chronic parasite persistence in 30 40% of patients can give rise to severe cardiac and gastrointestinal disorders presumed to be a result of an inadequate host immune response. Severe long-term chronic disease can lead to cardiac manifestations such as arrhythmias, aneurysms, thromboembolic events, and heart failure resulting in sudden death. Current efforts to control disease is focused on the use of anti-trypanosomal drugs which are contraindicated in pregnancy, advanced kidney or liver disease, and are of questionable efficacy for those who can tolerate treatment. An effective therapeutic vaccine has the potential to ameliorate the complications of the estimated 40,000 new cases of Chagas and prevent 10,000 or more deaths annually. Vaccine studies indicate protective immune responses are linked to T. cruzi specific CD8 T-cell induction. CMV vectors are uniquely qualified 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-human primate models, TEM induced by CMV-vectored vaccines have functionally cured SIV. CMV-vectors are currently being developed for prophylactic and therapeutic vaccines against HIV by TomegaVax, Inc. Unlike traditional 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 be evaluated in murine CMV vectors expressing T. cruzi antigens in a well-established murine model. Using bacterial artificial chromosome technology, we will construct CMV vectors expressing selected antigens, characterize the induced immune responses, and determine their prophylactic and therapeutic efficacy against challenge with T. cruzi. This phase I study will enable the selection of protective antigens for insertion into spread-deficient human CMV vectors. Phase II of this program will then focus on IND-enabling studies to manufacture and test HCMV-vectored Chagas vaccines. The ultimate product of this research program will be a recombinant therapeutic vaccine providing lifelong protection.
Public Health Relevance Statement: 8. Project Narrative Currently there is no approved vaccine for Trypanasoma cruzi, the infectious agent in Chagas disease. While primarily affecting Central and South Americans living in poor quality housing where the kissing bug vector is less well controlled, the vertical transmission from mother to child and the globalization of Chagas into border nations like the United States is cause for great concern. To address this issue we propose development of a therapeutic vaccine based on recombinant, spread deficient cytomegalovirus vectors that elicit high levels of T- lymphocytes against their target antigens.
Project Terms: abstracting; Acute; Address; Affect; Americas; Aneurysm; Antigen Presentation; Antigen Targeting; Antigens; Arrhythmia; Bacterial Artificial Chromosomes; base; Blood; Businesses; Cardiac; CD8B1 gene; Central American; Cessation of life; Chagas Disease; Characteristics; Child; Chronic; Chronic Disease; college; cytokine; Cytomegalovirus; Cytomegalovirus Vaccines; Development; Disease; disorder control; Drug or chemical Tissue Distribution; Engineering; Epitopes; Essential Genes; Event; exhaustion; expression vector; Frequencies; Gastrointestinal Diseases; Genes; Goals; Heart; Heart Diseases; Heart failure; HIV; Housing; Human; Immune; Immune response; Immunity; Immunocompromised Host; immunogenicity; Immunotherapy; Individual; Infection; Infectious Agent; innovation; Kidney Diseases; Lead; Life; Link; Liver diseases; LY6E gene; Modeling; Monitor; Mothers; mouse model; mucosal site; Murid herpesvirus 1; Mus; nonhuman primate; Organ Transplantation; Parasites; pathogen; Patients; Peptides; Pharmaceutical Preparations; Phase; phase 1 study; Population; Pregnancy; prevent; programs; prophylactic; protective efficacy; Proteins; Qualifying; Recombinants; Research; response; Rights; Route; Safety; Site; SIV; small molecule; South American; Specificity; Splenocyte; Sudden Death; System; T cell response; T cell therapy; T memory cell; T-Lymphocyte; Tacrolimus Binding Proteins; Technology; terminally differentiated effector memory (TEM) T cells; Testing; Therapeutic; Therapeutic Uses; therapeutic vaccine; Tissues; tool; Transfusion; Transgenes; transmission process; Treatment Efficacy; Trypanosoma cruzi; United States; vaccine trial; Vaccines; vector; vector vaccine; vector-based vaccine; vector-induced; Vertebral column; Vertical Disease Transmission; Viral Vector; Work
