Introduction and Background of the Project

Introduction

Leprosy is an infectious disease caused by the bacillus Mycobacterium leprae, with involvement of the peripheral nervous system. Infection is dependent on the innate and adaptive immune response, genetic background, and environmental factors of the host. This devastating disease disproportionately affects poor and marginalized populations.

Despite the reduction of global leprosy incidence from 5.2 million people in 1985 to 140,594 people in 2021 (although numbers are likely underrepresented, due to operational limitations during the Covid pandemic), leprosy disease remains an important public health concern primarily in endemic regions of India, Brazil, and Indonesia, which make up 74.5% of new leprosy cases (1). Multidrug therapy (MDT) is mostly responsible for the dramatic decrease in new leprosy cases; however, even with the effectiveness of this chemotherapy, leprosy reactions, permanent disability, and occasional relapse and reinfection are frequently observed. Leprosy may be considered a rare disease worldwide and of low priority for national health programs, yet of new cases diagnosed in 2021 (128,405), 8,492 have grade 2 disabilities, and 9,052 are children (aged < 15 years). Therefore, elimination of leprosy remains a primary focus of the World Health Organization (WHO) (2), and transmission of infection is a main barrier.

Project objective

LepVax clinical research is advancing the mission of interrupting transmission and eliminating   leprosy disease. This project is a pivotal phase 1/2 safety study in a leprosy-endemic region of Brazil to demonstrate safety and immunogenicity of a defined subunit vaccine, LepVax, in healthy individuals and leprosy patients. A pioneering component of these clinical trials is the engagement of people affected by leprosy. We will work closely with the members of the organization of people affected by leprosy in Brazil, called MORHAN (Movement to Reintegrate Persons Affected by Hansen’s Disease), to bring their perspectives and insight in the investigation, with the goal of realizing quality leprosy services and uptake of interventions in Brazil. Together, we can increase leprosy awareness and clinical opportunities leading to elimination of leprosy.  This trial serves as a critical stage-gate for further development of LepVax for therapeutic and prophylactic indications.

Project design

American Leprosy Missions (ALM) partnered with the Access to Advanced Health Institute (AAHI) 15+ years ago to develop the word’s first leprosy-specific vaccine—LepVax—consisting of LEP-F1 antigen and GLA-SE adjuvant. LEP-F1 is a recombinant fusion protein consisting of four M. leprae antigens chosen to induce a T-cell mediated immune response in leprosy patients. 

Non-clinical studies in mice, armadillos, and rabbits have demonstrated safety and immunogenicity with LepVax (3). The vaccine was found to be safe and well tolerated in healthy adults in the US in 2019 at both doses tested.

Phase 1b and 2a trials are double-blind, randomized, placebo-controlled clinical trials designed to evaluate the safety, tolerability, and immunogenicity of LEP-F1 + GLA-SE study in healthy adult participants and leprosy patient adult participants, respectively.  The phase 1b trial will evaluate a low dose of LEP-F1 antigen (2 µg) or high dose of LEP-F1 (10 µg) combined with GLA-SE adjuvant (5 µg) compared to saline placebo.  There will be 18 participants per group.  A dose selection of LEP-F1 is proposed for testing in leprosy patients, paucibacillary (PB) and multibacillary (MB) leprosy patients.  Outcome measures of the phase 1b trial are local and systemic reactions of each study injection and number of participants spontaneously reporting adverse events. LEP-F1 IgG antibody and specific T cell responses based on cytokine secretion will be evaluated as a secondary outcome. Biomarker immune modulation are exploratory outcomes. Outcome measures of the phase 2a trial will also include measurements of inactive lesions, bacillary load, frequency and intensity of leprosy reactions, and neurological function for potential reactogenicity effect of the vaccine.

Sasakawa Health Foundation will leverage its global leadership in engaging people affected by leprosy who have the skills and lived experience to be involved in the research process. They will play a pivotal role in ensuring ethical credibility and practical efficiency, as well as disseminating the relevant information and the results of research to the concerned communities and stakeholders.

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

The need for a vaccine is globally recognized; LepVax is aligned with the WHO 2030 Global Leprosy Strategy Strategic Pillar 2, cited as: “Trials of other existing and potential new vaccines, including LepVax…may result in an important new tool for leprosy prevention during this strategy period.” Should LepVax prove effective, we could see over 800,000 cases of disability due to leprosy averted, representing over 200,000 disability-adjusted life years (DALYs) by 2040.

Additionally, both the Leprosy Research Initiative and The Global Partnership for Zero Leprosy highlight the need for both prophylactic and therapeutic interventions, which LepVax addresses with:

– Improved preventive approaches including chemoprophylaxis regimen and vaccines

– Optimized and new treatment options for reactions and nerve function impairment

Likewise, WHO published “Guidelines for strengthening participation of persons affected by leprosy in leprosy services” in 2011 to highlight the importance of involving people affected by leprosy as an essential aspect of the shift from a provider-centered approach to an individual-centered one to realize quality services (4).

Hence, the latest WHO Global Leprosy Strategy 2021-2030 “Toward Zero Leprosy” also highly recommends the people’s involvement in particular activities of all four strategic pillars. Specifically, ‘Research’ is one of the areas that was raised in the Guidelines to strengthen the involvement of those affected in operational aspects. However, this practice in research is scant to date not only for leprosy but also for other NTDs. This project will be a leading initiative and can be the model of equitable participation by affected people.

What sort of innovation are you bringing in your project?

LepVax is a T-cell directed subunit vaccine. It differs from previously tested vaccines in that it is the first leprosy vaccine candidate evaluated for a therapeutic indication, the first leprosy subunit vaccine, and the first immunotherapeutic to be evaluated for reducing immune related neuropathy in leprosy patients. Likewise, community engagement of leprosy patients in vaccine clinical trials is novel in Brazil. 

The involvement of affected people in the trial will ensure they are not only informed but play a role in research and resulting programs that will have an impact on their own lives. The resulting human rights impact is creating a norm of equity, justice, and fairness in ensuring every person's right to health and wellbeing.

Role and Responsibility of Each Partner

American Leprosy Missions (ALM) is the Trial Director, leading the vision for a leprosy vaccine over the last 20 years, and will oversee the phase 1b and phase 2a clinical trials. ALM’s responsibilities include assembling the LepVax Vaccine Advisory Board, a global consortium to advise, guide, and direct vaccine efforts.

Oswaldo Cruz Institute (IOC), Fiocruz, in Rio de Janeiro, Brazil, is the study sponsor of these clinical studies and will be responsible for trial management, sample collection and testing, reporting, and publication. The clinical site for both trials is the Leprosy Laboratory (LAHAN) / Souza Araújo Outpatient Clinic (ASA), located on the Oswaldo Cruz campus. 

Sasakawa Health Foundation (SHF) is the longtime partner and supporter to organizations of people affected by leprosy in leprosy-endemic countries, and will be responsible for bridging and the coordination between the project and the organization/individuals of people affected by leprosy in Brazil. SHF will also provide relevant scientific expertise.

Others (including references if necessary)

(1) WHO, Weekly Epidemiological Record. Global leprosy (Hansen disease) update, 2021: moving towards interruption of transmission, (2022).

(2) WHO, Towards zero leprosy. Global leprosy (Hansen’s Disease) strategy 2021– 2030. World Health Organization. License: CC BY-NC-SA 3.0 IGO, (2021).

(3) Duthie MS, Pena MT, Ebenezer GJ, Gillis TP, Sharma R, Cunningham K, Polydefkis M, Maeda Y, Makino M, Truman RW, and Reed SG. LepVax, a defined subunit vaccine that provides effective pre-exposure and post-exposure prophylaxis of M. leprae infection. npj Vaccines (2018) 3:12; doi:10.1038/s41541-018-0050-z

(4) WHO, Guidelines for strengthening participation of persons affected by leprosy in leprosy services, World Health Organization, 2011, License: CC BY-NC-SA 3.0 IGO.