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

Abstract

Background: Leishmaniasis is a globally important yet neglected parasitic disease transmitted by phlebotomine sand flies. With new candidate vaccines in or near the clinic, a controlled human challenge model (CHIM) using natural sand fly challenge would provide a method for early evaluation of prophylactic efficacy. Methods: We evaluated the biting frequency and adverse effects resulting from exposure of human volunteers to bites of either Phlebotomus papatasi or P. duboscqi, two natural vectors of Leishmania major. 12 healthy participants were recruited (mean age 40.2 ± 11.8 years) with no history of significant travel to regions where L. major-transmitting sand flies are prevalent. Participants were assigned to either vector by 1:1 allocation and exposed to five female sand flies for 30 minutes in a custom biting chamber. Bite frequency was recorded to confirm a bloodmeal was taken. Participant responses and safety outcomes were monitored using a visual analogue scale (VAS), clinical examination, and blood biochemistry. Focus groups were subsequently conducted to explore participant acceptability. Results: All participants had at least one successful sand fly bite with none reporting any serious adverse events, with median VAS scores of 0-1/10 out to day 21 post-sand fly bite. Corresponding assessment of sand flies confirmed that for each participant at least 1/5 sand flies had successfully taken a bloodmeal (overall mean 3.67±1.03 bites per participant). There was no significant difference between P. papatasi and P. duboscqi in the number of bites resulting from 5 sand flies applied to human participants (3.3±0.81 vs 3.00±1.27 bites per participant; p=0.56). In the two focus groups (n=5 per group), themes relating to positive participant-reported experiences of being bitten and the overall study, were identified. Conclusions: These results validate a protocol for achieving successful sand fly bites in humans that is safe, well-tolerated and acceptable for participants. Clinicaltrials.gov registration: NCT03999970 (27/06/2019)

Safety, effectiveness, and skin immune response in a controlled human infection model of sand fly transmitted cutaneous leishmaniasis

“…We previously reported on prior enabling studies, including development of a cGMP challenge strain of L. major (MHOM/IL/2019/MRC-02) 28 , development of a sand fly biting protocol 29 and focus group assessments of public perceptions of the project 30 . For this first study involving human challenge (LEISH_Challenge; ClinicalTrials.gov Identifier: NCT04512742 ), we enrolled 14 healthy Leishmania -naïve volunteers aged 18-50 at the University of York Translational Research Facility ( Fig.…”

“…Lymphadenopathy of the epitrochlear and axillary lymph nodes was absent in all volunteers. As previously used in our FLYBITE study 29 , additional safety outcomes were collated using an electronic participant-submitted visual analogue score diary card that recorded on a 1-10 scale participants subjective perceptions of the level of itch, pain, erythema, swelling, malaise, myalgia, fever and nausea ( Fig. 3o and Extended Data 6 ).…”

Overcoming roadblocks in the development of vaccines for leishmaniasis

“…Our own experience has been that ~$2 M was sufficient to develop a new candidate vaccine from conception through to completion of a first-in-human trial. If combined with human infection models [ 77 , 78 , 79 ] (and Parkash et al, this volume), we estimate that efficacy data on similar new vaccines could be achieved for a total development cost of under $4 M. Relative to the investment in vaccine antigen selection and other aspects of discovery research, this appears a rather modest sum. The leishmaniasis vaccine research development community should raise the bar and set an ambition for at least one new candidate vaccine to enter clinical development every other year.…”

Leishmaniasis Vaccines: Applications of RNA Technology and Targeted Clinical Trial Designs

“…Beyond establishing the rational and required tools, several practical and safety concerns with any proposed Leishmania CHIM then present themselves. A study involving non-infected sand fly biting was used to establish parameters for challenge and importantly to gauge and incorporate public perceptions of this type of study into a challenge protocol ( [75,76] and clinicaltrials.gov: NCT03999970). A clinical study to evaluate the reproducibility of a CHIM for sand fly transmitted cutaneous leishmaniasis has similarly gained ethical and institutional approval and is ongoing (clinicaltrials.gov: NCT04512742).…”