Direct venous inoculation of Plasmodium falciparum sporozoites for controlled human malaria infection: a dose-finding trial in two centres
Direct venous inoculation of Plasmodium falciparum sporozoites for controlled human malaria infection: a dose-finding trial in two centres
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DOI：
10.1186/s12936-015-0628-0
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发表时间：
2015-03-18
期刊：
影响因子：
3
通讯作者：
Kremsner, Peter G.
中科院分区：
文献类型：
--
作者：
Mordmueller, Benjamin;Supan, Christian;Kremsner, Peter G.
背景：控制人疟疾感染（CHMI）加速了抗疟疾干预措施的发展。到目前为止，CHMI是通过让志愿者接触5只携带恶性疟原虫孢子虫（PfSPZ）的蚊子叮咬来完成的，这种技术在全世界只有少数几个中心可用。蚊子介导的CHMI物流复杂，PfSPZ的精确剂量是不可能的，以活蚊为基础的干预措施不适合进一步的临床发展。方法：在18-45岁、健康、未患疟疾的志愿者中进行了一项开放标记、随机、剂量发现研究，以评估静脉注射50至3200份无菌、纯化、冷冻保存的PfSPZ是否安全，并达到与蚊子介导的CHMI相当的感染动力学。一个独立的研究地点证实了使用直接静脉接种PfSPZ的完全感染剂量。采用厚血涂片镜检和实时荧光定量PCR检测寄生虫动力学。结果：接种50、200、800、3200 PfSPZ分别导致1/3、1/3、7/9、9/9志愿者出现寄生虫血症。在3,200 PfSPZ IV组中，几何平均专利前期（GMPPP）为11.2天（范围10.5-12.5）。随后，6名志愿者在一个独立的研究地点接受了3200 PfSPZ的直接静脉接种。所有6例均出现寄生虫病（GMPPP: 11.4天，范围：10.4-12.3）。接种PfSPZ是安全的。感染率和专利前时间与剂量有关，注射3200只PfSPZ导致5只PfSPZ感染蚊子的GMPPP与CHMI相似。PfSPZ的感染剂量预测了成功接种辐射减毒PfSPZ所需的剂量。结论：PfSPZ静脉接种安全、耐受性好、重复性高。通过CHMI的标准化和便利化，进一步加快抗疟疾干预措施的发展。除此之外，基于pfspz的全免疫的合理剂量选择和复杂的研究设计现在是可能的。
Background: Controlled human malaria infection (CHMI) accelerates development of anti-malarial interventions. So far, CHMI is done by exposure of volunteers to bites of five mosquitoes carrying Plasmodium falciparum sporozoites (PfSPZ), a technique available in only a few centres worldwide. Mosquito-mediated CHMI is logistically complex, exact PfSPZ dosage is impossible and live mosquito-based interventions are not suitable for further clinical development.Methods: An open-labelled, randomized, dose-finding study in 18-45 year old, healthy, malaria-naive volunteers was performed to assess if intravenous (IV) injection of 50 to 3,200 aseptic, purified, cryopreserved PfSPZ is safe and achieves infection kinetics comparable to published data of mosquito-mediated CHMI. An independent study site verified the fully infectious dose using direct venous inoculation of PfSPZ. Parasite kinetics were assessed by thick blood smear microscopy and quantitative real time PCR.Results: IV inoculation with 50, 200, 800, or 3,200 PfSPZ led to parasitaemia in 1/3, 1/3, 7/9, and 9/9 volunteers, respectively. The geometric mean pre-patent period (GMPPP) was 11.2 days (range 10.5-12.5) in the 3,200 PfSPZ IV group. Subsequently, six volunteers received 3,200 PfSPZ by direct venous inoculation at an independent investigational site. All six developed parasitaemia (GMPPP: 11.4 days, range: 10.4-12.3). Inoculation of PfSPZ was safe. Infection rate and pre-patent period depended on dose, and injection of 3,200 PfSPZ led to a GMPPP similar to CHMI with five PfSPZ-infected mosquitoes. The infectious dose of PfSPZ predicted dosage of radiation-attenuated PfSPZ required for successful vaccination.Conclusions: IV inoculation of PfSPZ is safe, well tolerated and highly reproducible. It shall further accelerate development of anti-malarial interventions through standardization and facilitation of CHMI. Beyond this, rational dose selection for whole PfSPZ-based immunization and complex study designs are now possible.