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Visceral leishmaniasis

About: Visceral leishmaniasis is a research topic. Over the lifetime, 7486 publications have been published within this topic receiving 184865 citations. The topic is also known as: Kala-Azar & viscus leishmaniasis.


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Journal ArticleDOI
TL;DR: The first clinical trial of a third-generation leishmaniasis vaccine, developed intentionally to induce Leishmania-specific CD8+ T cells, and results support the further development of ChAd63-KH as a novel third generation vaccine for VL and PKDL are reported.
Abstract: Background 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. Methods 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. Findings 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. Conclusion The results of this study support the further development of ChAd63-KH as a novel third generation vaccine for VL and PKDL. Trial registration This clinical trial (LEISH1) was registered at EudraCT (2012-005596-14) and ISRCTN (07766359).

104 citations

Journal ArticleDOI
TL;DR: A generic, reverse transcriptase-loop-mediated isothermal amplification (RT-LAMP) assay, for the identification of Leishmania species from clinical samples, and the potential to use LAMP as a diagnostic tool for leishmaniasis is discussed.
Abstract: Here we describe a generic, reverse transcriptase-loop-mediated isothermal amplification (RT-LAMP) assay, for the identification of Leishmania species from clinical samples. LAMP is an isothermal reaction recently developed as a point-of-care diagnostic tool. Primers were designed in the conserved region of the 18S ribosomal RNA (rRNA) gene; amplification was visualized by the pre-amplification addition of fluorescent detection reagent (FDR) and a simple UV lamp. By using a reverse-transcriptase step, the system detected infections between 10 and 100 parasites per mL. The assay was tested on a range of nucleic acid extracts from Leishmania species, visceral leishmaniasis (VL) patients from Sudan, and cutaneous leishmaniasis (CL) patients from Suriname. The sensitivity of RT-LAMP from the blood of VL patients was 83% (N = 30) compared with microscopy of bone-marrow and lymph-node aspirates; for CL patients the observed sensitivity was 98% (N = 43). The potential to use LAMP as a diagnostic tool for leishmaniasis is discussed.

104 citations

Journal ArticleDOI
TL;DR: The comparatively low prevalence of Leishmania (Viannia) in the blood of symptomatic dogs indicates that PCR with blood cannot be the “gold standard” for the (mass) screening of samples in epidemiological studies.
Abstract: A PCR-based protocol for the detection of Leishmania ( Viannia ) parasites in canine blood, buffy coat, and bone marrow was developed and was then tested with field samples taken from a random sample of 545 dogs from villages in Peru where Leishmania ( Viannia ) braziliensis and Leishmania ( Viannia ) peruviana are endemic. Comparative tests with cultured parasites mixed with dog blood showed that the PCR assay9s sensitivity was significantly dependent on the DNA extraction protocol and the PCR primers used. Mass screening of field samples by the preferred PCR protocol detected American cutaneous leishmaniasis (ACL) in 44 of 545 (8.1%) dogs; 31 of 402 (7.7%), 20 of 223 (9.0%), and 8 of 46 (17.4%) were PCR positive when whole blood, buffy coat, and bone marrow aspirates, respectively, were tested. The high prevalence of Leishmania in both asymptomatic (7.6%) and symptomatic (18.0%) dogs provides further circumstantial evidence for their suspected role as reservoir hosts of ACL and indicates that hematogenous dissemination of parasites may be a more common pathological phenomenon than has previously been acknowledged. However, unlike for zoonotic visceral leishmaniasis, the comparatively low prevalence of Leishmania ( Viannia ) in the blood of symptomatic dogs indicates that PCR with blood cannot be the “gold standard” for the (mass) screening of samples in epidemiological studies.

104 citations

Journal ArticleDOI
TL;DR: Cutaneous and visceral leishmaniasis in the Middle East has been known since the early 1900s, whereas zoonotic foci of Leishmania major in the Jericho area and Negev desert present a threat to increasing populations.

103 citations

Journal ArticleDOI
25 Jul 2018-Nature
TL;DR: Development of an anti-leishmanial drug-like chemical series based on a pyrazolopyrimidine scaffold is described, and cdc2-related kinase 12 (CRK12) is identified as the probable primary drug target for visceral leishmaniasis.
Abstract: Visceral leishmaniasis causes considerable mortality and morbidity in many parts of the world. There is an urgent need for the development of new, effective treatments for this disease. Here we describe the development of an anti-leishmanial drug-like chemical series based on a pyrazolopyrimidine scaffold. The leading compound from this series (7, DDD853651/GSK3186899) is efficacious in a mouse model of visceral leishmaniasis, has suitable physicochemical, pharmacokinetic and toxicological properties for further development, and has been declared a preclinical candidate. Detailed mode-of-action studies indicate that compounds from this series act principally by inhibiting the parasite cdc-2-related kinase 12 (CRK12), thus defining a druggable target for visceral leishmaniasis.

103 citations


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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
2023192
2022442
2021269
2020285
2019286
2018253