Characterization of a new Leishmania major strain for use in a controlled human infection model

Abstract

Leishmaniasis is widely regarded as a vaccine-preventable disease, but the costs required to reach pivotal Phase 3 studies and uncertainty about which candidate vaccines should be progressed into human studies significantly limits progress in vaccine development for this neglected tropical disease. Controlled human infection models (CHIMs) provide a pathway for accelerating vaccine development and to more fully understand disease pathogenesis and correlates of protection. Here, we describe the isolation, characterization and GMP manufacture of a new clinical strain of Leishmania major. Two fresh strains of L. major from Israel were initially compared by genome sequencing, in vivo infectivity and drug sensitivity in mice, and development and transmission competence in sand flies, allowing one to be selected for GMP production. This study addresses a major roadblock in the development of vaccines for leishmaniasis, providing a key resource for CHIM studies of sand fly transmitted cutaneous leishmaniasis.

A clinical study to optimise a sand fly biting protocol for use in a controlled human infection model of cutaneous leishmaniasis (the FLYBITE study)

“…In conclusion, the successful completion of this study complements further research aimed at developing a CHIM model for leishmaniasis. As reported elsewhere 84 , using a new fully characterised strain of Leishmania major, we have manufactured a clinical parasite bank under GMP conditions and confirmed that this isolate is fully transmissible to rodents via the bite of either P. papatasi and P. dubosqi. How well these preclinical and clinical studies translate into an effective CHIM will be addressed in a subsequent clinical study (LEISH_Challenge; ClinicalTrials.gov ID NCT04512742).…”

“…First, it is known that sand fly behaviour is altered following infection with Leishmania parasites, although usually this is associated with increased bite rate 96 . Though previous studies on mice revealed that L. major-infected females of both species readily take a bloodmeal on mice 84 , and P. duboscqi infected with L. major can cause cutaneous leishmaniasis in mice 97 and non-human primates 98 , we cannot be certain that the biting characteristics on human subjects will be faithfully reproduced using infected sand flies in a CHIM study. The second issue relates to uniformity between participants, which may impact on outcomes from a future CHIM.…”

“…A single individual was exposed to the bite of L. arabica-infected P. papatasi as part of a study on cross-protection, though no lesion developed 83 . We have described elsewhere a new Leishmania major strain suitable for use in a CHIM, with production of a clinical bank at Good Manufacturing Practices (GMP) and validation of its ability to infect P. papatasi and P. duboscqi sand flies and be transmitted to rodents through sand fly bite 84 .…”

Revival of Leishmanization and Leishmanin

“…One approach may be to consider a controlled human infection model (CHIM) that could provide a pathway for accelerated vaccine development and to identify correlates of protection. Recently, L. major strains have been developed under GMP conditions and characterized for potential use in CHIM studies that can be used in CL vaccine trials (Ashwin et al, 2021). CHIM trials would not however be possible for VL due to the risk from challenge infections with a visceral disease causing Leishmania species such as L. donovani.…”

Human leishmaniasis vaccines: Use cases, target population and potential global demand

“…Currently, only one therapeutic clinical trial is ongoing (Clinicaltrials.gov NCT03969134), and a clinical-grade genetically attenuated live L. major vaccine is due to be manufactured in 2021 [20] to support future trials. Recent progress towards the development of a controlled human challenge model for CL [21,22] may also provide a stimulus for the clinical development of other candidate vaccines. However, the absence of a consensus on the size of the target populations, the paucity of data to support an indication for use in each disease state and the lack of realistic demand scenarios are likely determinants of the scarce interest from the pharmaceutical industry and philanthropic donors.…”