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

Vivak Parkash, Helen Ashwin, Jovana Sadlova, Barbora Vojtkova, Georgina Jones, Nina Martin, Elizabeth Greensted, Victoria Allgar, Shaden Kamhawi, Jesus G Valenzuela, Alison M Layton, Charles L Jaffe, Petr Volf, Paul M Kaye, Charles J N Lacey, Vivak Parkash, Helen Ashwin, Jovana Sadlova, Barbora Vojtkova, Georgina Jones, Nina Martin, Elizabeth Greensted, Victoria Allgar, Shaden Kamhawi, Jesus G Valenzuela, Alison M Layton, Charles L Jaffe, Petr Volf, Paul M Kaye, Charles J N Lacey

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).

Keywords: Controlled human infection models; leishmaniasis; focus groups; sand flies; public engagement; vaccines.

Conflict of interest statement

Competing interests: The authors declare no competing interests. PMK and CNJL are co-authors of a patent protecting the gene insert used in Leishmania candidate vaccine ChAd63-KH (Europe 10719953.1; India 315101).

Copyright: © 2021 Parkash V et al.

Figures

Figure 1.. Schedule of events.
Figure 1.. Schedule of events.
Figure illustrates schedule of events with day of visit given in relation to biting visit (Day 0). Window for visits is indicated in brackets.
Figure 2.. CONSORT (Consolidated Standards of Reporting…
Figure 2.. CONSORT (Consolidated Standards of Reporting Trials) flow diagram.
Figure 3.. Sand fly biting chamber and…
Figure 3.. Sand fly biting chamber and procedures.
Photographs to illustrate key steps in the sand fly biting procedure. (A &B) Using fine tweezers, 5 sand flies are placed inside the biting chamber on ice. The sand fly biting chamber is approximately 5cm in diameter. (C) A gauze covering is placed over the bottom of the biting chamber with sand flies positioned inside. (D) Filter paper is used to form an aperture of between 6-8mm to limit the area of sand fly biting. (E &F) An adjustable Velcro strap is used to customise the fit for each participant, and biting chamber placed 3–4cm distal to the antecubital fossa. (G) Sand flies within the biting chamber; biting aperture with gauze visible (arrow). (H) Participant skin demonstrating pressure mark from biting chamber and small visible bite marks (circled). (I) Microscope image of sand fly, following biting on participants, with red swollen abdomen demonstrating blood meal has been taken and (J) sand fly following biting on participants with absence of red swollen abdomen suggesting blood meal has not been taken.
Figure 4.. Summed adverse events reported by…
Figure 4.. Summed adverse events reported by type during FLYBITE.
Adverse events were recorded by each participant at each visit on a visual analogue scale of 0-10 (see Methods). Pooled data for all 12 participants are presented separately for each adverse event (as indicated in panels) at each time point. Data are shown as median (circles) and range (vertical bar).
Figure 5.. Summed adverse events reported by…
Figure 5.. Summed adverse events reported by individual participants during FLYBITE.
Ten adverse events were recorded by each participant at each visit on a visual analogue scale of 0–10 (see Methods). Data are presented as the sum of all scores (out of 100) for each participant (as indicated in panels) at each time point.

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