Trypanosoma cruzi (Tc) is the causative agent of Chagas disease (CD). With >7 million recorded cases, ~81 million at risk of Tc exposure in Latin America, and large-scale migration from endemic to other countries including the USA where autochthonous transmission of Tc also occurs, CD remains a global health concern. Currently no therapies exist to prophylactically treat adults traveling to endemic countries or those who may already be infected with Tc. The economic burden for chagas cardiomyopathy and heart failure, estimated at ~$10 billion due to healthcare costs and lost productivity by premature deaths, provides a strong rationale for investment in the development of immune therapies against CD. We have already developed a two-component DNA vaccine (TcG2/TcG4) for CD and demonstrated preclinical efficacy of this prototype vaccine in controlling Tc pathogenesis in a mouse model. Vaccine efficacy depends heavily on the induction of a robust TH1 response for the clearance of intracellular pathogens like Tc. Integrin cell adhesion molecules a4ß1 and aLß2 and their ligands, VCAM-1 and ICAM-1, respectively, play an essential role in the activation of adaptive immunity. Prolonged integrin-mediated interactions between T cells and antigen presenting cells (APCs), particularly via the aLß2/ICAM-1 axis, are required for effective T cell priming and long-term T cell mediated memory. Augmenting cell adhesion may facilitate T cell priming and subsequent immune responses. 7HP349 is a clinical- stage, first-in-concept, oral, small-molecule, positive allosteric activator of a4ß1 and aLß2 integrins, which could facilitate endogenous integrin ligand-receptor engagement, promote cell adhesion, and improve T helper function and the effectiveness of CD vaccination. We have demonstrated that 7HP349 augments the effectiveness of the prototype TcG2/TcG4 DNA vaccine in a mouse model of CD. Additionally, 7HP349 has a favorable preclinical safety and pharmacokinetic profile, and was found to be safe and well tolerated in a Phase 1 clinical study in healthy male subjects. In this SBIR grant application, we propose to develop a vaccination regimen for CD consisting of a bicistronic DNA vaccine (BCV)-adjuvant combination with 7HP349 or another integrin activator, 7HP577, demonstrate preclinical efficacy and safety of the BCV-adjuvant combination, and manufacture clinical grade cGMP BCV and adjuvant to support a Phase I/IIa clinical study to assess the safety and tolerability of the vaccine-adjuvant combination, and thereafter to evaluate its immunogenicity in humans. The proposed studies will allow the development of a novel vaccination regimen to prophylactically treat Tc infection and CD.
Public Health Relevance Statement: PROJECT NARRATIVE Chagas disease (CD) is a global health concern, with no existing therapies to prophylactically treat adults traveling to endemic countries or those who may already be infected with Trypanosoma cruzi (Tc). This proposal aims to develop a vaccine-adjuvant combination comprising a DNA vector-based bicistronic vaccine (BCV) and a systemic small-molecule integrin activator adjuvant for the control of Tc infection and CD, and demonstrate preclinical proof-of-concept, efficacy and safety of this vaccine-adjuvant combination in preparation for a Phase I/IIa clinical trial.
Project Terms: Adult; 21+ years old; Adult Human; adulthood; Alleles; Allelomorphs; Antigen-Presenting Cells; accessory cell; Epitopes; Antigenic Determinants; Binding Determinants; Antigens; immunogen; Biological Assay; Assay; Bioassay; Biologic Assays; Biological Availability; Bioavailability; Biologic Availability; Physiologic Availability; capsule; Capsules; Cell Adhesion; Cellular Adhesion; Cell Adhesion Molecules; Adhesion Molecule; Cell Adhesion Molecule Gene; cell adhesion protein; cell motility; Cell Locomotion; Cell Migration; Cell Movement; Cellular Migration; Cellular Motility; Motility; Clinical Research; Clinical Study; Clinical Trials; Codon Nucleotides; Codon; Cessation of life; Death; DNA; Deoxyribonucleic Acid; Canis familiaris; Canine Species; Dogs; Dogs Mammals; canine; domestic dog; Female; Future; Heart failure; cardiac failure; Human; Modern Man; Hypersensitivity; Allergy; Immunoglobulin G; 7S Gamma Globulin; IgG; Immunity; Immunization; Immunologic Sensitization; Immunologic Stimulation; Immunological Sensitization; Immunological Stimulation; Immunostimulation; Immunotherapy; Immune mediated therapy; Immunologically Directed Therapy; immune therapeutic approach; immune therapeutic interventions; immune therapeutic regimens; immune therapeutic strategy; immune therapy; immune-based therapies; immune-based treatments; immuno therapy; In Vitro; Infection; Intramuscular Injections; intramuscular drug administration; Integrins; Integrins Extracellular Matrix; Investments; Latin America; Lead; Pb element; heavy metal Pb; heavy metal lead; Ligands; Lipids; male; Memory; Mus; Mice; Mice Mammals; Murine; Mycobacterium tuberculosis; M tb; M tuberculosis; M. tb; M. tuberculosis; mtb; NIH; National Institutes of Health; United States National Institutes of Health; Parasites; Pharmacokinetics; Drug Kinetics; Phenotype; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Plasma; Play; Production; Productivity; Research; Risk; social role; Role; Safety; T-Cells; thymus derived lymphocyte; T-Lymphocyte; Cell-Mediated Lympholytic Cells; Cytolytic T-Cell; Cytotoxic T Cell; killer T cell; Cytotoxic T-Lymphocytes; Testing; Tissues; Body Tissues; Travel; Trypanosoma cruzi; American trypanosome; T cruzi; T. cruzi; Chagas Disease; American Trypanosomiasis; South American Trypanosomiasis; Vaccination; Vaccines; Work; aluminum sulfate; Alum Adjuvant; alum; Intercellular adhesion molecule 1; CD54 Antigens; ICAM-1; Vascular Cell Adhesion Molecule-1; CD106; CD106 Antigens; INCAM-110; Inducible Cell Adhesion Molecule 110; VCAM; VCAM-1; Vascular Cell Adhesion Molecule; cytokine; Health Care Costs; Health Costs; Healthcare Costs; Mediating; base; Blood specimen; Blood Sample; improved; Acute; Chronic; Clinical; premature; prematurity; Phase; Biological; biologic; Antigen Presentation; Collaborations; Immunological response; host response; immune system response; immunoresponse; Immune response; Therapeutic; Naked DNA Vaccines; Recombinant DNA Vaccines; DNA Vaccines; Investigation; Immunes; Immune; Oral; prophylactic; Country; Adverse reactions; Receptor Protein; receptor; develop a vaccine; develop vaccines; development of a vaccine; vaccine development; expression vector; Animal Models and Related Studies; model of animal; model organism; Animal Model; novel; Study Subject; memory T lymphocyte; T memory cell; Pathogenesis; Modeling; response; Pathogenicity; Bio-Informatics; Bioinformatics; T cell differentiation; T-Cell Activation; evaluate vaccines; vaccine screening; vaccine testing; vaccine evaluation; Effectiveness; small molecule; Dose; global health; Biological Testing; Economic Burden; Grant Proposals; Applications Grants; Interruption; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Vaccine Design; Vaccine Production; produce vaccines; Monitor; transmission process; Transmission; Preparation; Adjuvant; Development; developmental; pre-clinical; preclinical; preclinical study; pre-clinical study; vector; vaccine efficacy; immunogenicity; design; designing; vaccine safety; efficacy evaluation; efficacy analysis; efficacy assessment; efficacy examination; evaluate efficacy; examine efficacy; Biodistribution; Treatment Efficacy; intervention efficacy; therapeutic efficacy; therapy efficacy; pathogen; migration; mouse model; murine model; prototype; commercialization; product development; preclinical efficacy; pre-clinical efficacy; preclinical safety; pre-clinical safety; vaccine candidate; Regimen; T cell response; adaptive immunity; Antibody Response; Formulation; chagasic cardiomyopathy; Cardiomyopathy in Chagas' Disease; Cardiovascular Trypanosomiasis; Chagas Cardiomyopathy; efficacy study; Innate Immune Response
