LEISHDNAVAX

Preclinical and preparation of early clinical testing of a new vaccine candidate against cutaneous leishmaniasis

Background

Leishmaniases are vector-borne protozoal diseases with clinical manifestations ranging from self-healing or chronic cutaneous leishmaniasis (CL), disfiguring mucocutaneous leishmaniasis (MCL) to fatal visceral leishmaniasis (VL). Causative agents are parasites of the genus Leishmania that are transmitted by female sand flies to mammalian hosts where they infect and proliferate inside phagocytes, especially macrophages. Treatment options are limited to a few drugs, with high costs, significant adverse effects and, in some areas, increasing parasite drug resistance. So far, preventative measures are restricted to vector control with bed nets and indoor residual spraying, of limited effect, and insecticides, which raises environmental issues.

The use of vaccines in therapy of leishmaniasis has been a long-term aim, however, there is no licensed vaccine against human leishmaniasis. Several candidates have been proposed and are at different stages of development.

Based on a pentavalent DNA vaccine coding for optimized and T cell epitope-enriched antigens of Leishmania, the present partnership seeks to establish a new vaccine principle for leishmaniasis with a special focus on the induction of cell-mediated immunity, including the potential of the LEISHDNAVAX vaccine candidate to protect against cutaneous leishmaniasis in a preclinical animal model.

Moreover, we will prepare a Phase I clinical trial for the evaluation of the safety and immunogenicity of the vaccine candidate.

Objectives

LEISHDNAVAX is a candidate DNA vaccine against leishmaniasis that has been successfully tested for antigenicity in humans in ex vivo studies, and for efficacy in a mouse model for visceral leishmaniasis. We aim to complete the preclinical development with tests for cutaneous leishmaniasis and to prepare a clinical Phase I trial. At the end of the project we will have fulfilled the prerequisites for a clinical Phase I trial to test safety and immunogenicity of the vaccine.

The project comprises the preclinical evaluation of the immunogenicity, prophylactic and therapeutic efficacy of the DNA leishmaniasis vaccine LEISHDNAVAX in mouse models of cutaneous leishmaniasis (CL). In addition, we will prepare the evaluation of the vaccine candidate in a clinical Phase I trial. To achieve this goal, the project is divided in four specific objectives:

Objective 1: To test the preclinical efficacy of a preventive vaccine, we will examine T cell immune responses in mice, before and after infection. Several Leishmania species that are endemic in different regions of the world will be used and different immunization schemes will be tested.

Objective 2: Based on previous experience with L. donovani infection models in mice, we will study the therapeutic effect of the vaccine candidate alone and in combination with known anti-leishmanial drugs against CL.

Objective 3: The vaccine production process will be established at the site of a Contract Manufacturing Organisation (CMO) and the vaccine material for the clinical Phase I trial will be produced.

Objective 4: Under this objective we will prepare a future clinical Phase I trial to evaluate safety, tolerability and immunogenicity of the vaccine candidate in human volunteers.

References

Riede, O. et al. Preclinical safety and tolerability of a repeatedly administered human leishmaniasis DNA vaccine. Gene Ther. 22, 628–635 (2015).

Seifert, K., Juhls, C., Salguero, F. J. & Croft, S. L. Sequential Chemoimmunotherapy of Experimental Visceral Leishmaniasis Using a Single Low Dose of Liposomal Amphotericin B and a Novel DNA Vaccine Candidate. Antimicrob. Agents Chemother. 59, 5819–5823 (2015).