IL-32 producing CD8<sup>+</sup>memory T cells and Tregs define the IDO1 / PD-L1 niche in human cutaneous leishmaniasis skin lesions

Dey, Nidhi S.; Dey, Shoumit; Brown, Naj; Senarathne, Sujai; Reis, Luiza Campos; Sengupta, Ritika; Lindoso, Jose Angelo L.; James, Sally; Gilbert, Lesley; Chatterjee, Mitali; Goto, Hiro; Ranasinghe, Shalindra; Kaye, Paul M.

doi:10.1101/2024.01.02.23300281

Cited by 3 publications

References 99 publications

(137 reference statements)

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Safety and reactogenicity of a controlled human infection model of sand fly-transmitted cutaneous leishmaniasis

Parkash,

Ashwin,

Dey

et al. 2024

Nat Med

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The leishmaniases are globally important parasitic diseases for which no human vaccines are currently available. To facilitate vaccine development, we conducted an open-label observational study to establish a controlled human infection model (CHIM) of sand fly-transmitted cutaneous leishmaniasis (CL) caused by Leishmania major. Between 24 January and 12 August 2022, we exposed 14 participants to L. major-infected Phlebotomus duboscqi. The primary objective was to demonstrate effectiveness of lesion development (take rate) and safety (absence of CL lesion at 12 months). Secondary and exploratory objectives included rate of lesion development, parasite load and analysis of local immune responses by immunohistology and spatial transcriptomics. Lesion development was terminated by therapeutic biopsy (between days 14 and 42 after bite) in ten participants with clinically compatible lesions, one of which was not confirmed by parasite detection. We estimated an overall take rate for CL development of 64% (9/14). Two of ten participants had one and one of ten participants had two lesion recurrences 4–8 months after biopsy that were treated successfully with cryotherapy. No severe or serious adverse events were recorded, but as expected, scarring due to a combination of CL and the biopsy procedure was evident. All participants were lesion free at >12-month follow-up. We provide the first comprehensive map of immune cell distribution and cytokine/chemokine expression in human CL lesions, revealing discrete immune niches. This CHIM offers opportunities for vaccine candidate selection based on human efficacy data and for a greater understanding of immune-mediated pathology. ClinicalTrials.gov identifier: NCT04512742.

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Safety and reactogenicity of a controlled human infection model of sand fly-transmitted cutaneous leishmaniasis

Parkash,

Ashwin,

Dey

et al. 2024

Nat Med

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A randomized double-blind Phase IIb trial to evaluate the efficacy of ChAd63-KH for the treatment of post kala-azar dermal leishmaniasis

Younis,

Wiggins,

Khalil

et al. 2024

Preprint

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Background. In a recent Phase IIa clinical trial, the candidate leishmaniasis vaccine ChAd63-KH was shown to be safe and immunogenic in Sudanese patients with post kala- azar dermal leishmaniasis (PKDL). However, its value as a stand-alone therapeutic was unknown. Methods. To assess the therapeutic efficacy of ChAd63-KH, we conducted a window of opportunity randomized, double-blind, placebo-controlled trial (Clinicaltrials.gov registration:NCT03969134). We aimed to enrol 100 participants (male and female aged 12-50 years) with uncomplicated PKDL of ≥ six months duration. ChAd63-KH (7.5x1010 viral particles) or saline placebo was administered once intramuscularly. Primary outcomes were safety and efficacy. Safety was determined by adverse event monitoring. Efficacy was the proportion of participants at 90 days post-vaccination with ≥ 90% improvement in clinical disease. Participants failing to reach this clinical endpoint were offered a standard of care (AmBisome). Secondary outcomes included changes in PKDL severity grade and measurements of vaccine-induced immune response. Findings. Between 4th April 2020 and 17th June 2022, 86 participants (66 adolescents, 20 adults; 47% female, 53% male) were enrolled and randomised to receive ChAd63-KH or placebo. 75 participants (87%) completed the trial as per protocol. No severe or serious adverse events were observed. At day 90 post vaccination, 6/40 (15%) and 4/35 (11%) participants in the vaccine and placebo groups respectively showed ≥ 90% clinical improvement (RR 1.31 [95% CI, 0.40 to 4.28], p=0.742). There were also no significant differences in PKDL grade between study arms. Whole blood transcriptomic analysis identified transcriptional modules associated with interferon responses and monocyte and dendritic cell activation, confirming vaccine reactogenicity. Interpretation. Single dose administration of ChAd63-KH vaccine had no therapeutic efficacy in this subset of Sudanese PKDL patients. Further studies are needed to evaluate whether this vaccine would have therapeutic benefit using alternate dosing regimens or in combination with standard chemotherapy or immune modulation, and whether it has efficacy as a prophylactic vaccine for cutaneous or visceral leishmaniasis.

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

Parkash,

Ashwin,

Dey

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

The leishmaniases are globally important parasitic diseases for which no human vaccines are currently available. To facilitate vaccine development, we conducted an open label observational study to establish a controlled human infection model of sand fly-transmitted cutaneous leishmaniasis caused by L. major. Between 24th January and 12th August 2022, we exposed 14 (8F, 6M) participants to infected Phlebotomus duboscqi. The primary objective was to demonstrate effectiveness (take rate) and safety (absence of CL lesion at 12 months), whereas secondary and exploratory objectives included rate of lesion development, parasite load and analysis of local immune responses by immunohistology and spatial transcriptomics. We estimated an overall take rate for CL development of 64% (9/14), or 82% (9/11) if calculated using only participants having confirmed bites following exposure. Lesion development was terminated by therapeutic biopsy in 10 participants with confirmed bites. 2/10 had one and 1/10 had two lesion recurrences 4-8 months after biopsy that were treated successfully with cryotherapy. No severe or serious adverse events were recorded, but scarring was evident as expected. All participants were lesion-free at >12 month follow up. We provide the first comprehensive map of immune cell distribution and cytokine/chemokine expression in human CL lesions, revealing discrete immune niches. This controlled human infection model offers opportunities for rapid vaccine candidate selection and a greater understanding of immune-mediated protection and pathology. The study was registered at ClinicalTrials.gov Identifier:NCT04512742

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IL-32 producing CD8⁺memory T cells and Tregs define the IDO1 / PD-L1 niche in human cutaneous leishmaniasis skin lesions

Cited by 3 publications

References 99 publications

Safety and reactogenicity of a controlled human infection model of sand fly-transmitted cutaneous leishmaniasis

Safety and reactogenicity of a controlled human infection model of sand fly-transmitted cutaneous leishmaniasis

A randomized double-blind Phase IIb trial to evaluate the efficacy of ChAd63-KH for the treatment of post kala-azar dermal leishmaniasis

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

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IL-32 producing CD8+memory T cells and Tregs define the IDO1 / PD-L1 niche in human cutaneous leishmaniasis skin lesions

Cited by 3 publications

References 99 publications

Safety and reactogenicity of a controlled human infection model of sand fly-transmitted cutaneous leishmaniasis

Safety and reactogenicity of a controlled human infection model of sand fly-transmitted cutaneous leishmaniasis

A randomized double-blind Phase IIb trial to evaluate the efficacy of ChAd63-KH for the treatment of post kala-azar dermal leishmaniasis

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

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IL-32 producing CD8⁺memory T cells and Tregs define the IDO1 / PD-L1 niche in human cutaneous leishmaniasis skin lesions