Leishmaniasis is a serious disease caused by parasites spread through the bite of infected sandflies. It can cause skin sores that may leave scars (cutaneous leishmaniasis) or, in more severe cases, affect internal organs and become life-threatening (visceral leishmaniasis or kala-azar). Every year, more than one million people around the world are affected, but there is currently no approved vaccine to prevent the disease. Controlling sandflies, the insects that spread leishmaniasis, is very difficult, so developing a vaccine is considered the best long-term solution. Scientists know that people who recover from leishmaniasis often become naturally protected against future infections, which makes vaccine development promising. Using modern gene-editing technology (CRISPR), researchers

created a weakened version of the parasite called Leishmania major LmCen-/-. This weakened parasite cannot cause disease but may help the body build protection. The SANDFLY study is the first human trial of this vaccine. It will test its safety and whether it triggers an immune response in healthy adults between 18 and 50 years old in two countries where leishmaniasis is common: Kenya and Brazil. A total of 72 volunteers will participate, with half in each country. Volunteers will receive either the vaccine or a harmless placebo injection, and neither the participants nor the study staff will know which was given until the study ends (double-blind

design). Participants will be monitored closely for about a year to check for side effects and to measure how their immune system responds. The study will last about two years in total. Independent safety experts and research monitors will oversee the trial to ensure participants’ safety.

Leishmaniasis, a parasitic disease transmitted by infected sandflies, presents in forms ranging from mild cutaneous lesions to life-threatening visceral disease. Despite more than 1 million new cases annually, there are currently no licensed human vaccines available. As vector control is difficult, control measures have focused on vaccination as a means to prevent infection. It is known that infection with Leishmania, either cutaneous or visceral, confers long-term immunity against any form of subsequent infection. Based on these findings, a live attenuated L. major vaccine strain, LmCen-/-, was developed using CRISPR gene editing. Preclinical studies show its effectiveness against both cutaneous and visceral leishmaniasis. This Phase 1, multi-site, double-blind, placebocontrolled

clinical trial (SANDFLY) aims to evaluate the safety and immunogenicity of a live attenuated Leishmania major vaccine strain (LmCen-/-), developed through CRISPR gene editing, in healthy adults aged 18 to 50 years in leishmaniasis-endemic regions of Kenya and Brazil. Leishmaniasis, a parasitic disease transmitted by infected sandflies, ranges from self-healing cutaneous lesions to life-threatening visceral leishmaniasis (VL). Despite over one million new cases

annually, there is currently no licensed human vaccine, and control efforts are increasingly challenged by political instability, migration, and the expanding range of sandfly vectors due to climate change. Preclinical studies of the LmCen-/- vaccine have demonstrated protective efficacy against both cutaneous and visceral disease. The trial will enroll 72 participants, with 36 each at Kericho, Kenya, and São Paulo, Brazil, randomized in a 2:1 ratio to receive either the vaccine or

placebo at two ascending dose levels (105 and 106 promastigotes). Primary objectives are to assess vaccine safety and monitor adverse events, while secondary objectives include evaluating parasite persistence, immune responses, and biomarkers of immunogenicity. Exploratory analyses will investigate cytokine and chemokine responses, humoral immunity, and local immune activation at the vaccination site. Each participant will be followed for approximately 12 months, and the trial is expected to span 24 months in total. Oversight will be provided by a Safety Monitoring Committee, research monitors, and site investigators, ensuring participant safety and scientific rigor.