Therapeutic CD8+ T cell-biased vaccines for human visceral leishmaniasis.

Visceral leishmaniasis (VL) causes an estimated 250,000 deaths annually. Resistance against existing treatments is high or developing. Affordable second line treatments are not available, making the development of new preventative and/or therapeutic measures a major international research priority. CD4+ T cell-biased vaccines have so far failed to deliver significant levels of protective immunity in man. Hence, we propose a novel therapeutic vaccine for VL, targeting the induction / re-activation of CD8+ T cells. We have selected two candidate antigens for which experimental data are most compelling, and two viral delivery systems with proven ability to induce CD8+ T cell responses in man. We have assembled an international team of investigators, integrating scientists / clinicians working in the area of greatest disease burden (Bihar, India), and developed forward-looking strategies for the rapid evaluation of vaccine efficacy in Phase IIb trials. Our aims in this proposal are to: i) confirm antigen/vector selection, based on efficacy studies in mice, and analysis of pre-existing anti-vector immunity and antigen polymorphism (m1); ii) produce a single vaccine to GMP and gain regulatory approvals (m2); and iii) conduct a Phase I study in UK volunteers, demonstrating safety of a novel CD8+ T cell -biased vaccine for VL (m3).