Human Gene Set: OSMAN_BLOOD_CHAD63_KH_AGE_18_50YO_HIGH_DOSE_SUBJECTS_24HR_DN


Standard name OSMAN_BLOOD_CHAD63_KH_AGE_18_50YO_HIGH_DOSE_SUBJECTS_24HR_DN
Systematic name M40937
Brief description Genes down-regulated in blood 24hr vs 0hr in adults (18-50) (high dose subjects) after exposure to ChAd63-KH , time point 24H , administered Intramuscular injection. Comment: DE gene list for high dose subjects.
Full description or 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 IFN-gamma 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: This clinical trial (LEISH1) was registered at EudraCT (2012-005596-14) and ISRCTN (07766359).
Collection C7: Immunologic Signature
      VAX: HIPC Vaccine Response
Source publication Pubmed 28498840   Authors: Osman M,Mistry A,Keding A,Gabe R,Cook E,Forrester S,Wiggins R,Di Marco S,Colloca S,Siani L,Cortese R,Smith DF,Aebischer T,Kaye PM,Lacey CJ
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External links https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5443534/bin/pntd.0005527.s002.xls
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Source species Homo sapiens
Contributed by HIPC SIGNATURES (NIAID/HIPC SIGNATURES)
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identifier namespace		 HUMAN_GENE_SYMBOL
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