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• W2613163210 endingPage "e0005527" @default.
• W2613163210 startingPage "e0005527" @default.
• W2613163210 abstract "Visceral leishmaniasis (VL or kala azar) is the most serious form of human leishmaniasis, responsible for over 20,000 deaths annually, and post kala azar dermal leishmaniasis (PKDL) is a stigmatizing skin condition that often occurs in patients after successful treatment for VL. Lack of effective or appropriately targeted cell mediated immunity, including CD8+ T cell responses, underlies the progression of VL and progression to PKDL, and can limit the therapeutic efficacy of anti-leishmanial drugs. Hence, in addition to the need for prophylactic vaccines against leishmaniasis, the development of therapeutic vaccines for use alone or in combined immuno-chemotherapy has been identified as an unmet clinical need. Here, we report the first clinical trial of a third-generation leishmaniasis vaccine, developed intentionally to induce Leishmania-specific CD8+ T cells.We conducted a first-in-human dose escalation Phase I trial in 20 healthy volunteers to assess the safety, tolerability and immunogenicity of a prime-only adenoviral vaccine for human VL and PKDL. ChAd63-KH is a replication defective simian adenovirus expressing a novel synthetic gene (KH) encoding two Leishmania proteins KMP-11 and HASPB. Uniquely, the latter was engineered to reflect repeat domain polymorphisms and arrangements identified from clinical isolates. We monitored innate immune responses by whole blood RNA-Seq and antigen specific CD8+ T cell responses by IFNγ ELISPOT and intracellular flow cytometry.ChAd63-KH was safe at intramuscular doses of 1x1010 and 7.5x1010 vp. Whole blood transcriptomic profiling indicated that ChAd63-KH induced innate immune responses characterized by an interferon signature and the presence of activated dendritic cells. Broad and quantitatively robust CD8+ T cell responses were induced by vaccination in 100% (20/20) of vaccinated subjects.The results of this study support the further development of ChAd63-KH as a novel third generation vaccine for VL and PKDL.This clinical trial (LEISH1) was registered at EudraCT (2012-005596-14) and ISRCTN (07766359)." @default.
• W2613163210 created "2017-05-19" @default.
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• W2613163210 date "2017-05-12" @default.
• W2613163210 modified "2023-10-16" @default.
• W2613163210 title "A third generation vaccine for human visceral leishmaniasis and post kala azar dermal leishmaniasis: First-in-human trial of ChAd63-KH" @default.
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• W2613163210 doi "https://doi.org/10.1371/journal.pntd.0005527" @default.
• W2613163210 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/5443534" @default.
• W2613163210 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/28498840" @default.
• W2613163210 hasPublicationYear "2017" @default.
• W2613163210 type Work @default.

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