New antigens for a multicomponent blood-stage malaria vaccine.
New antigens for a multicomponent blood-stage malaria vaccine.
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DOI：
10.1126/scitranslmed.3008705
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发表时间：
2014-07-30
影响因子：
17.1
通讯作者：
Marsh K
中科院分区：
文献类型：
--
作者：
Osier FH;Mackinnon MJ;Crosnier C;Fegan G;Kamuyu G;Wanaguru M;Ogada E;McDade B;Rayner JC;Wright GJ;Marsh K
针对恶性疟原虫的有效血液阶段疫苗仍然是研究的优先事项，但已转化为临床试验中测试的候选抗原的数量仍然有限。在寄生虫蛋白质组中发现的大量潜在靶点的研究受到无法产生用于免疫学研究的天然折叠重组抗原的限制。我们克服了这些限制，产生了一个大的图书馆，证明具有生物化学活性的裂殖子表面和分泌全长胞外域蛋白。然后，我们系统地检查了这些蛋白质的抗体反应性在一个队列的肯尼亚儿童（n=286）谁是在疟疾传播季节开始采样，并在随后的六个月内的疟疾临床发作进行前瞻性监测。我们发现，针对以前未经测试或很少研究的蛋白质的抗体具有上级或等同于当前少数领先的疟疾候选疫苗的潜在保护功效。此外，对包含10种排名最高的抗原中的5种（包括PF3D7_1136200、MSP 2、RhopH3、P41、MSP 11、MSP 3、PF3D7_0606800、AMA1、Pf113和MSRP 1）的组合的累积应答与针对疟疾临床发作的100%保护相关。这些数据表明，不仅有更多的潜在疫苗候选疫苗开发管道，而且可以通过结合这些抗原的选择，如在自然界中观察到的，实现高效的疫苗接种。
An effective blood stage vaccine against Plasmodium falciparum remains a research priority but the number of antigens that have been translated to candidates for testing in clinical trials remains limited. Investigations of the large number of potential targets found in the parasite proteome have been constrained by an inability to produce natively folded recombinant antigens for immunological studies. We overcame these constraints by generating a large library of demonstrably biochemically active merozoite surface and secreted full-length ectodomain proteins. We then systematically examined the antibody reactivity against these proteins in a cohort of Kenyan children (n=286) who were sampled at the start of a malaria transmission season and prospectively monitored for clinical episodes of malaria over the ensuing six months. We found that antibodies to previously untested or little-studied proteins had superior or equivalent potential protective efficacy to the handful of current leading malaria vaccine candidates. Moreover, cumulative responses to combinations comprising five of the ten top ranked antigens, including PF3D7_1136200, MSP2, RhopH3, P41, MSP11, MSP3, PF3D7_0606800, AMA1, Pf113 and MSRP1 were associated with 100% protection against clinical episodes of malaria. These data suggest that not only are there many more potential vaccine candidates for the vaccine development pipeline, but also that highly effective vaccination may be achieved through combining a selection of these antigens as observed in nature.