用于人类内脏利什曼病和黑热病后皮肤利什曼病的第三代疫苗：ChAd63-KH的首次人体试验。
A third generation vaccine for human visceral leishmaniasis and post kala azar dermal leishmaniasis: First-in-human trial of ChAd63-KH.
作者信息
Osman Mohamed, Mistry Anoop, Keding Ada, Gabe Rhian, Cook Elizabeth, Forrester Sarah, Wiggins Rebecca, Di Marco Stefania, Colloca Stefano, Siani Loredana, Cortese Riccardo, Smith Deborah F, Aebischer Toni, Kaye Paul M, Lacey Charles J
机构信息
Centre for Immunology and Infection, Dept. of Biology and Hull York Medical School, University of York, Heslington, York, United Kingdom.
Department of Health Sciences, University of York, Heslington, York, United Kingdom.
出版信息
PLoS Negl Trop Dis. 2017 May 12;11(5):e0005527. doi: 10.1371/journal.pntd.0005527. eCollection 2017 May.
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).
背景
内脏利什曼病（VL，即黑热病）是人类利什曼病最严重的形式，每年导致超过20000人死亡，而黑热病后皮肤利什曼病（PKDL）是一种常出现在VL患者成功治疗后的有损形象的皮肤疾病。缺乏有效的或靶向适当的细胞介导免疫，包括CD8+ T细胞反应，是VL进展以及进展为PKDL的基础，并且会限制抗利什曼药物的治疗效果。因此，除了需要针对利什曼病的预防性疫苗外，开发单独使用或用于联合免疫化疗的治疗性疫苗已被确定为一项未满足的临床需求。在此，我们报告了一种第三代利什曼病疫苗的首次临床试验，该疫苗旨在诱导利什曼原虫特异性CD8+ T细胞。
方法
我们在20名健康志愿者中进行了首次人体剂量递增的I期试验，以评估一种用于人类VL和PKDL的仅初免腺病毒疫苗的安全性、耐受性和免疫原性。ChAd63-KH是一种复制缺陷型猿猴腺病毒，表达一种新型合成基因（KH），该基因编码两种利什曼原虫蛋白KMP-11和HASPB。独特的是，后者经过工程改造以反映从临床分离株中鉴定出的重复结构域多态性和排列。我们通过全血RNA测序监测先天免疫反应，并通过IFNγ ELISPOT和细胞内流式细胞术监测抗原特异性CD8+ T细胞反应。
结果
ChAd63-KH在1×10¹⁰和7.5×10¹⁰ vp的肌肉注射剂量下是安全的。全血转录组分析表明，ChAd63-KH诱导了以干扰素特征和活化树突状细胞的存在为特征的先天免疫反应。100%（20/20）的接种受试者通过接种诱导了广泛且定量强大的CD8+ T细胞反应。
结论
本研究结果支持进一步开发ChAd63-KH作为一种用于VL和PKDL的新型第三代疫苗。
试验注册
该临床试验（LEISH1）已在欧洲临床试验数据库（EudraCT，编号2012-005596-14）和国际标准随机对照试验编号注册库（ISRCTN，编号07766359）注册。
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