Abstract
Post-kala-azar dermal leishmaniasis (PKDL) is a chronic, stigmatizing skin condition occurring frequently after apparent clinical cure from visceral leishmaniasis. Given an urgent need for new treatments, we conducted a phase IIa safety and immunogenicity trial of ChAd63-KH vaccine in Sudanese patients with persistent PKDL. LEISH2a (ClinicalTrials.gov: NCT02894008) was an open-label three-phase clinical trial involving sixteen adult and eight adolescent patients with persistent PKDL (median duration, 30 months; range, 6–180 months). Patients received a single intramuscular vaccination of 1 × 1010 viral particles (v.p.; adults only) or 7.5 × 1010 v.p. (adults and adolescents), with primary (safety) and secondary (clinical response and immunogenicity) endpoints evaluated over 42–120 days follow-up. AmBisome was provided to patients with significant remaining disease at their last visit. ChAd63-KH vaccine showed minimal adverse reactions in PKDL patients and induced potent innate and cell-mediated immune responses measured by whole-blood transcriptomics and ELISpot. 7/23 patients (30.4%) monitored to study completion showed >90% clinical improvement, and 5/23 (21.7%) showed partial improvement. A logistic regression model applied to blood transcriptomic data identified immune modules predictive of patients with >90% clinical improvement. A randomized controlled trial to determine whether these clinical responses were vaccine-related and whether ChAd63-KH vaccine has clinical utility is underway.
Highlights
The World Health Organization recognizes the leishmaniases as some of the most significant global neglected diseases associated with poverty, with over one billion people at risk of infection, with one million new cases and over 20,000 deaths reported each year.[1,2] These diseases are caused by infection with one of several species of the protozoan parasite Leishmania and are transmitted by the bite of female phlebotomine sand flies
In EnrichR, we identified enriched Gene Ontology (GO) and Reactome pathways related mainly to interferon type I and II signaling, antiviral response, myeloid cells, phago-lysosomal functions, and class I major histocompatibility complex (MHC)-mediated antigen processing and presentation (Table S4), in keeping with the results of the modular analysis described above
Previous studies in Sudan pioneered the use of immunotherapy with first-generation vaccines in combination with sodium stibogluconate,[16,32] but use of a vaccine as monotherapy in PKDL patients has not been previously reported
Summary
The World Health Organization recognizes the leishmaniases as some of the most significant global neglected diseases associated with poverty, with over one billion people at risk of infection, with one million new cases and over 20,000 deaths reported each year.[1,2] These diseases are caused by infection with one of several species of the protozoan parasite Leishmania and are transmitted by the bite of female phlebotomine sand flies. 2366 Molecular Therapy Vol 29 No 7 July 2021 a 2021 The Author(s) Leishmania as an intracellular pathogen may be targeted for immune destruction by effector mechanisms of CD8+ T cells (including IFNg production and granzyme/granulysin release21), and CD8+ T cell responses have been associated with vaccine-induced protection in animal models.[22,23,24,25] Vaccines designed to generate CD8+ T cell responses require a capacity for antigen delivery into the endogenous processing pathway This is achieved either by facilitating cross-presentation (e.g., using liposomal delivery) or through endogenous protein synthesis (e.g., naked DNA or viral vectors; so called “third-generation” vaccines)
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