Introduction and Background of the Project

Introduction

Over 12 million people are currently affected by leishmaniasis, and approximately 2 million new cases occur annually, making it a global health problem and a WHO-classified Neglected Tropical Disease (NTD) (www.who.int). Cutaneous leishmaniasis (CL) manifests as localized skin lesions that can become chronic, leading to significant tissue destruction and disfigurement. Other forms include mucosal leishmaniasis (ML). Visceral leishmaniasis (VL) is a life-threatening, second-deadliest parasitic disease, after malaria, and is characterized by the spread of parasites to the liver, spleen, and bone marrow. The zoonotic potential of leishmaniasis has also been escalating with the increased incidence of canine infections worldwide. It is well documented that the majority of patients with leishmaniasis (both CL and VL) develop a long-term protective immunity after cure, either spontaneously or after treatment, which indicates that the development of an effective vaccine against leishmaniasis should be possible. However, currently, there are no prophylactic or therapeutic vaccines available for leishmaniasis. During the previous funding period, this team successfully developed and produced a GLP-grade LmCen-/- vaccine under cGMP conditions, which demonstrated excellent safety and efficacy in preventing both CL and VL in preclinical studies. In the current project, the project team will undertake Phase I clinical trials to test the safety and immunogenicity of a cGMP-grade LmCen-/- vaccine (currently under production) in healthy individuals living in leishmaniasis-endemic regions where the vaccine will be ultimately deployed.

Project objective

Objective 1: Conduct a Phase I clinical trial to evaluate the safety and immunogenicity of the LmCen-/- vaccine in healthy volunteers in Brazil (New World)

Objective 2: Conduct a Phase I clinical trial to evaluate the safety and immunogenicity of the LmCen-/- vaccine in healthy volunteers in Kenya (Old World)

Project design

This project is a continuation of the GHIT-funded project G2018-201 to advance clinical development of the LmCen-/- vaccine.  During the previous funding period, the project team successfully accomplished the goals of the project by:

1) Validate the safety and efficacy of a GLP-grade LmCen-/- vaccine produced by Gennova Biopharmaceuticals under cGMP conditions using preclinical animal models,

2) Produce a GMP master cell bank (MCB) and a GMP working cell bank (WCB) of LmCen-/- parasites,

3) Establish cGMP manufacturing of the LmCen-/- vaccine,

4) Complete preclinical toxicology studies in accordance with regulatory guidelines using a GLP LmCen-/- vaccine produced from an engineering run of the cGMP cell bank, and

5) Finalize the IND package for the LmCen-/- product for submission to regulatory authorities.

In the current project, the project team propose to evaluate the safety of the LmCen-/- vaccine in healthy volunteers living in leishmaniasis-endemic countries, Brazil and Kenya, where other factors such as subclinical nutritional deficiencies and co-infections, such as diarrhea, malaria, Chagas disease (in Brazil) and helminth infections, are common and have been documented to impact vaccine safety and immunogenicity.

How can your partnership (project) address global health challenges?

A prophylactic vaccine against visceral and cutaneous leishmaniasis has the potential to enable the global elimination of this disease.

What sort of innovation are you bringing in your project?

No vaccine is currently approved for human use against leishmaniasis. This project will test the safety and immunogenicity of a novel live-attenuated LmCen-/- vaccine developed using CRISPR-Cas9 genome-editing technology.

Role and Responsibility of Each Partner

The Ohio State University: Project management and coordination, procurement of materials and supplies for clinical trials, and oversight of Phase I trials in both Kenya and Brazil.

Gennova Biopharmaceuticals: Supply the cGMP-grade LmCen-/- vaccine for clinical testing in Kenya and Brazil.

Institute of Tropical Medicine (NEKKEN), Nagasaki University: Establish protocols for PBMC collection, isolation and antigen stimulation assays; analyze cytokine responses in PBMC assays in Kenya; and coordinate with Terumo Corporation (Tokyo, Japan) to procure injection devices, including the Immucise Intradermal Injection System, for clinical studies.

Universidade Federal de Minas Gerais (UFMG):  Obtain regulatory/IRB approvals and conduct Phase I clinical trials in healthy volunteers in Brazil to evaluate the safety and efficacy of the cGMP-grade LmCen-/- vaccine supplied by Gennova.

HJF Medical Research International (HJFMRI): Obtain regulatory/IRB approvals and conduct Phase I clinical trials in healthy volunteers in Kenya to evaluate the safety and efficacy of the cGMP-grade LmCen-/- vaccine supplied by Gennova.

Johns Hopkins University: Support the development of clinical protocols and the establishment of the REDCap study database.