Safety and Reproducibility of a Clinical Trial System Using Induced Blood Stage Plasmodium vivax Infection and Its Potential as a Model to Evaluate Malaria Transmission.
Safety and Reproducibility of a Clinical Trial System Using Induced Blood Stage Plasmodium vivax Infection and Its Potential as a Model to Evaluate Malaria Transmission.
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DOI：
10.1371/journal.pntd.0005139
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发表时间：
2016-12
影响因子：
3.8
通讯作者：
McCarthy J
中科院分区：
文献类型：
--
作者：
Griffin P;Pasay C;Elliott S;Sekuloski S;Sikulu M;Hugo L;Khoury D;Cromer D;Davenport M;Sattabongkot J;Ivinson K;Ockenhouse C;McCarthy J
阻断疟疾从人到蚊子传播的干预措施是协助消除疟疾的一种有吸引力的方法。一个局限性是缺乏系统来测试这种干预措施的功效，然后再进行实地功效试验。我们以前已经证明了用间日疟原虫诱导血液期疟疾（IBSM）感染的可行性。在这项研究中，我们报告了进一步验证的IBSM模型，并评估其传播的间日疟原虫斯氏按蚊的评估。6名健康受试者（3个队列，n = 2/队列）通过接种寄生红细胞感染间日疟原虫。通过定量PCR监测寄生虫生长，并通过mRNA pvs 25的定量逆转录酶PCR（qRT-PCR）监测配子体血症。用线性回归法计算寄生虫增殖率（PMR）和接种量。在开始抗疟治疗前3天内通过直接和膜摄食测定进行了蚊子传播研究，7-9天后解剖了吸血蚊子的中肠并检查了卵囊的存在。各队列的临床病程和寄生虫血症一致，所有受试者均出现轻度至中度疟疾症状。未报告严重不良事件。在6例受试者中的4例中检测到无症状的肝功能检查结果升高;这些症状在未经治疗的情况下消退。直接喂食蚊子的耐受性良好。估计的PMR为9.9倍/周期。从直接（4.5%; n = 20/411）和膜（0.9%; n = 12/1360）饲料中观察到蚊子感染的低流行率（1.8%; n = 32/1801）。间日疟原虫IBSM模型被证明是安全可靠的。临床过程和PMR是可重现的，与以前的研究使用该模型。本报告中提出的IBSM模型显示了作为测试传输阻塞干预措施的系统的前景。需要进一步开展工作，以验证传播情况并提高其流行率。Anzctr.org.au ACTRN 12613001008718阻断疟疾从受感染个体到蚊子的传播是消除疟疾的一种有吸引力的方法。然而，目前还没有可靠的实验模型来测试传播阻断干预措施的有效性。在这项研究中，我们评估了我们的临床试验模型的安全性和可重复性，在该模型中，我们将感染疟疾寄生虫的血细胞注射到健康志愿者体内。此外，我们测试了我们的临床试验模型是否可以用作评估疟疾传播的工具。我们用间日疟原虫寄生虫感染健康志愿者，并通过分子方法监测寄生虫的生长。当我们检测到对蚊子具有感染性的寄生虫阶段（性阶段）时，将受感染志愿者的血液喂给蚊子。然后，我们调查了蚊子中肠中寄生虫的存在。这项研究的结果表明，我们的临床试验模型是安全的和可重复的。此外，我们观察到疟疾寄生虫从受感染的志愿者到蚊子的传播水平很低。我们需要证实这一发现，并加以优化，以提高疟疾传播率。总而言之，我们的临床试验模式似乎是一个可靠的系统，可以评估阻断疟疾传播的干预措施，这具有巨大的公共卫生意义。
Interventions to interrupt transmission of malaria from humans to mosquitoes represent an appealing approach to assist malaria elimination. A limitation has been the lack of systems to test the efficacy of such interventions before proceeding to efficacy trials in the field. We have previously demonstrated the feasibility of induced blood stage malaria (IBSM) infection with Plasmodium vivax. In this study, we report further validation of the IBSM model, and its evaluation for assessment of transmission of P. vivax to Anopheles stephensi mosquitoes. Six healthy subjects (three cohorts, n = 2 per cohort) were infected with P. vivax by inoculation with parasitized erythrocytes. Parasite growth was monitored by quantitative PCR, and gametocytemia by quantitative reverse transcriptase PCR (qRT-PCR) for the mRNA pvs25. Parasite multiplication rate (PMR) and size of inoculum were calculated by linear regression. Mosquito transmission studies were undertaken by direct and membrane feeding assays over 3 days prior to commencement of antimalarial treatment, and midguts of blood fed mosquitoes dissected and checked for presence of oocysts after 7–9 days. The clinical course and parasitemia were consistent across cohorts, with all subjects developing mild to moderate symptoms of malaria. No serious adverse events were reported. Asymptomatic elevated liver function tests were detected in four of six subjects; these resolved without treatment. Direct feeding of mosquitoes was well tolerated. The estimated PMR was 9.9 fold per cycle. Low prevalence of mosquito infection was observed (1.8%; n = 32/1801) from both direct (4.5%; n = 20/411) and membrane (0.9%; n = 12/1360) feeds. The P. vivax IBSM model proved safe and reliable. The clinical course and PMR were reproducible when compared with the previous study using this model. The IBSM model presented in this report shows promise as a system to test transmission-blocking interventions. Further work is required to validate transmission and increase its prevalence. Anzctr.org.au ACTRN12613001008718 Blocking the transmission of malaria from infected individuals to mosquitoes is an appealing approach to malaria elimination. However, at present there is no reliable experimental model to test the efficacy of transmission blocking interventions. In this study, we assessed the safety and reproducibility of our clinical trial model, in which we inject blood cells infected with malaria parasites into healthy volunteers. Furthermore, we tested if our clinical trial model could be used as a tool to evaluate malaria transmission. We infected healthy volunteers with Plasmodium vivax parasites and monitored parasite growth by molecular methods. When we detected the parasite stage that is infective to mosquitoes (the sexual stage), blood from infected volunteers was fed to mosquitoes. Then, we investigated the presence of parasites in the midgut of mosquitoes. The results from this study show that our clinical trial model is safe and reproducible. Moreover, we observed low levels of transmission of the malaria parasite from infected volunteers to mosquitoes. We need to validate this finding and to optimize it to increase the rate of malaria transmission. Altogether, our clinical trial model seems to be a reliable system to assess interventions to block malaria transmission, which has enormous public health significance.
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DOI：
10.1016/0035-9203(80)90189-3
发表时间：
1980-01-01
影响因子：
2.2
作者：
GRAVES, PM
通讯作者：
GRAVES, PM
影响因子：
1.3
作者：
Adak, T;Singh, OP;Nanda, N
通讯作者：
Nanda, N
影响因子：
3.3
作者：
Chansamut, N.;Buates, S.;Sattabongkot, J.
通讯作者：
Sattabongkot, J.
影响因子：
3
作者：
Diallo, Mouctar;Toure, Abdoulaye M.;Doumbo, Ogobara K.
通讯作者：
Doumbo, Ogobara K.
DOI：
10.4269/ajtmh.1986.35.66
发表时间：
1986-01-01
影响因子：
3.3
作者：
CHULAY, JD;SCHNEIDER, I;HOCKMEYER, WT
通讯作者：
HOCKMEYER, WT