Protective Efficacy of Plasmodium vivax Radiation-Attenuated Sporozoites in Colombian Volunteers: A Randomized Controlled Trial.
Protective Efficacy of Plasmodium vivax Radiation-Attenuated Sporozoites in Colombian Volunteers: A Randomized Controlled Trial.
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DOI：
10.1371/journal.pntd.0005070
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发表时间：
2016-10
影响因子：
3.8
通讯作者：
Herrera S
中科院分区：
文献类型：
--
作者：
Arévalo-Herrera M;Vásquez-Jiménez JM;Lopez-Perez M;Vallejo AF;Amado-Garavito AB;Céspedes N;Castellanos A;Molina K;Trejos J;Oñate J;Epstein JE;Richie TL;Herrera S
通过辐射减弱的恶性疟原虫子孢子（RAS）对被蚊子叮咬的人类志愿者进行免疫，可以实现高水平的感染保护。只有两名志愿者接受了类似的间日疟原虫 (Pv) RAS 免疫，并且两人都受到了保护。进行了一项 2 期对照临床试验来评估 PvRAS 免疫的安全性和保护功效。进行了一项随机、单盲试验。达菲阳性（Fy+；Pv 易感）个体被纳入：14 例被经辐射（150 ± 10 cGy）Pv 感染的按蚊 (RAS) 叮咬，7 例被未经辐射的未感染蚊子 (Ctl) 叮咬。另外一组由 7 名 Fy（Pv 难治性）志愿者组成，他们通过未受辐射的 Pv 感染蚊子的叮咬进行了免疫接种。平均间隔九周总共进行七次免疫接种。最后一次免疫后八周，用未受辐射的 Pv 感染的蚊子进行受控人类疟疾感染 (CHMI)。 19 名志愿者完成了 7 次免疫接种（12 名 RAS、2 名 Ctl 和 5 名 Fy-）并接受了 CHMI。与 0/2 Ctl 相比，12 名 RAS 志愿者中有 5 名 (42%) 受到保护（中位数为 434 次感染性叮咬）。在第七次免疫接种或 CHMI 后，没有一位 Fy-志愿者出现感染。所有未受保护的志愿者均在 CHMI 后 8-13 天出现症状，平均潜伏期为 12.8 天。没有观察到与免疫接种相关的严重不良事件。特异性 IgG1 抗 PvCS 反应与保护相关。 PvRAS 免疫是安全的、具有免疫原性的，并且在 42% 的 Fy+ 志愿者中诱导了无菌免疫。此外，Fy-志愿者对Pv疟疾具有抵抗力。标识符：NCT01082341。尽管恶性疟原虫（Pf）疫苗的开发取得了进展，但间日疟原虫（Pv）疫苗的开发进展却远远落后。通过蚊子叮咬用 Pf 辐射衰减子孢子 (RAS) 进行免疫一直是针对疟疾感染诱导无菌保护的金标准模型，并允许研究复杂的免疫机制。首次使用 PfRAS 的试验于 20 世纪 60 年代末进行，此后极大地促进了 Pf 疫苗的开发。然而，自 1974 年以来，人类 PvRAS 免疫仅在两名志愿者中进行。据我们所知，这是首次使用大量志愿者进行 PvRAS 免疫的临床试验。我们的研究结果证实，PvRAS 免疫是安全的、具有免疫原性，并且可以在 42% 的志愿者中诱导无菌免疫。它表明，与 PfRAS 一样，PvRAS 可以诱导无菌保护，并证实针对 PvCS 蛋白（IgG1 水平）的免疫力与保护相关。这项研究中产生的研究结果和试剂预计将深入了解针对 Pv 的无菌保护的关键免疫决定因素，这可能会指导开发针对这种寄生虫物种的具有成本效益的疫苗。
Immunizing human volunteers by mosquito bite with radiation-attenuated Plasmodium falciparum sporozoites (RAS) results in high-level protection against infection. Only two volunteers have been similarly immunized with P. vivax (Pv) RAS, and both were protected. A phase 2 controlled clinical trial was conducted to assess the safety and protective efficacy of PvRAS immunization. A randomized, single-blinded trial was conducted. Duffy positive (Fy+; Pv susceptible) individuals were enrolled: 14 received bites from irradiated (150 ± 10 cGy) Pv-infected Anopheles mosquitoes (RAS) and 7 from non-irradiated non-infected mosquitoes (Ctl). An additional group of seven Fy- (Pv refractory) volunteers was immunized with bites from non-irradiated Pv-infected mosquitoes. A total of seven immunizations were carried out at mean intervals of nine weeks. Eight weeks after last immunization, a controlled human malaria infection (CHMI) with non-irradiated Pv-infected mosquitoes was performed. Nineteen volunteers completed seven immunizations (12 RAS, 2 Ctl, and 5 Fy-) and received a CHMI. Five of 12 (42%) RAS volunteers were protected (receiving a median of 434 infective bites) compared with 0/2 Ctl. None of the Fy- volunteers developed infection by the seventh immunization or after CHMI. All non-protected volunteers developed symptoms 8–13 days after CHMI with a mean pre-patent period of 12.8 days. No serious adverse events related to the immunizations were observed. Specific IgG1 anti-PvCS response was associated with protection. Immunization with PvRAS was safe, immunogenic, and induced sterile immunity in 42% of the Fy+ volunteers. Moreover, Fy- volunteers were refractory to Pv malaria. Identifier: NCT01082341. Despite the advances in Plasmodium falciparum (Pf) vaccine development, progress in developing P. vivax (Pv) vaccines lags far behind. Immunization via mosquito bites with Pf radiation-attenuated sporozoites (RAS) has been the gold standard model for induction of sterile protection against malaria infection and has allowed the study of the complex mechanisms of immunity. The first trials using PfRAS were performed in the late 1960’s, and thereafter greatly contributed to the development of vaccines against Pf. However, PvRAS immunization in humans has only been carried out in two volunteers since 1974. To our knowledge, this is the first clinical trial using significant numbers of volunteers for PvRAS immunization. Our findings confirm that immunization with PvRAS is safe, immunogenic and induces sterile immunity in 42% of the volunteers. It demonstrates that it is possible to induce sterile protection with PvRAS as seen with PfRAS and confirms that immunity against the PvCS protein (IgG1 levels) correlates with protection. Research findings and reagents generated in this study are expected to yield insights on key immune determinants of sterile protection against Pv, which may guide the development of a cost-effective vaccine against this parasite species.
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影响因子：
3.7
作者：
Arévalo-Herrera M;Forero-Peña DA;Rubiano K;Gómez-Hincapie J;Martínez NL;Lopez-Perez M;Castellanos A;Céspedes N;Palacios R;Oñate JM;Herrera S
通讯作者：
Herrera S
白按蚊间日疟原虫感染膜喂养测定的优化。
影响因子：
3.8
作者：
Vallejo AF;Rubiano K;Amado A;Krystosik AR;Herrera S;Arévalo-Herrera M
通讯作者：
Arévalo-Herrera M
影响因子：
9.3
作者：
Cutts JC;Powell R;Agius PA;Beeson JG;Simpson JA;Fowkes FJ
通讯作者：
Fowkes FJ
影响因子：
7.8
作者：
Giefing-Kröll C;Berger P;Lepperdinger G;Grubeck-Loebenstein B
通讯作者：
Grubeck-Loebenstein B
DOI：
10.4269/ajtmh.1975.24.397
发表时间：
1975-01-01
影响因子：
3.3
作者：
CLYDE, DF;MCCARTHY, VC;WOODWARD, WE
通讯作者：
WOODWARD, WE