An Antibody Screen of a Plasmodium vivax Antigen Library Identifies Novel Merozoite Proteins Associated with Clinical Protection.
An Antibody Screen of a Plasmodium vivax Antigen Library Identifies Novel Merozoite Proteins Associated with Clinical Protection.
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DOI：
10.1371/journal.pntd.0004639
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发表时间：
2016-05
影响因子：
3.8
通讯作者：
Mueller I
中科院分区：
文献类型：
--
作者：
França CT;Hostetler JB;Sharma S;White MT;Lin E;Kiniboro B;Waltmann A;Darcy AW;Li Wai Suen CS;Siba P;King CL;Rayner JC;Fairhurst RM;Mueller I
研制出有效的疫苗将大大促进消灭间日疟原虫疟疾。对暴露人群中间日疟原虫抗原的抗体进行全面、系统的鉴定有助于指导疫苗的合理设计。在这项研究中，我们调查了2个亚太地区人群中间日疟原虫整个外结构域merozoite蛋白的抗体，分析了抗体水平与当前和累积疟疾暴露标志物以及社会经济和临床指标的关系。确定了29个天然免疫抗原靶点。其中，12种高免疫原性蛋白与所罗门群岛居民的年龄和累积终身暴露密切相关（P< 0.001-0.027）。在免疫原性和表达水平的基础上选择了6种蛋白质的一个子集，用于检测巴布亚新几内亚年轻儿童群体血浆样本中的抗体水平，这些儿童在接触方面存在明显的个体差异。该分析确定了临床疾病风险降低与P12、P41抗体水平和一种新的假设蛋白PVX_081550 （IRR 0.46-0.74； P< 0.001-0.041）之间的强烈关联。这些数据强调了无偏筛选方法在鉴定新型疫苗候选抗原方面的益处。现在需要进行功能研究，以确定PVX_081550是自然获得性保护性免疫反应的关键组成部分，还是免疫状态的生物标志物，或者两者兼而有之。间日疟原虫现在是非洲以外主要的疟疾寄生虫。由于间日疟原虫可在肝脏中潜伏数月，因此在无症状个体中识别和治疗间日疟原虫是困难的。此外，目前广泛使用的病媒控制措施对传播间日疟原虫的蚊子效率较低。因此，有效的疫苗将极大地促进间日疟原虫的消灭。不幸的是，人们对间日疟原虫的生物学知之甚少，只有少数蛋白质被研究作为疫苗开发的靶点。为了解决这些知识空白，我们测量了来自2个疟疾流行的亚太国家的个体样本中34个被预测与间日疟原虫侵袭红细胞有关的整个外结构域蛋白的抗体水平。我们发现，暴露于疟疾的所罗门群岛居民的抗体对我们小组中的大多数蛋白质都有反应，其中12种蛋白质的抗体强烈反映了间日疟原虫的累积暴露。在巴布亚新几内亚儿童的样本中，我们发现了3种蛋白质的抗体与临床疟疾防护之间的关联。我们的研究结果表明，筛选针对大量间日疟原虫蛋白的抗体是鉴定新的免疫靶点的有用方法。现在需要进行功能研究，以确定这些蛋白质是个体免疫状态的生物标志物，还是值得进一步开发的潜在候选疫苗，或者两者兼而有之。
Elimination of Plasmodium vivax malaria would be greatly facilitated by the development of an effective vaccine. A comprehensive and systematic characterization of antibodies to P. vivax antigens in exposed populations is useful in guiding rational vaccine design. In this study, we investigated antibodies to a large library of P. vivax entire ectodomain merozoite proteins in 2 Asia-Pacific populations, analysing the relationship of antibody levels with markers of current and cumulative malaria exposure, and socioeconomic and clinical indicators. 29 antigenic targets of natural immunity were identified. Of these, 12 highly-immunogenic proteins were strongly associated with age and thus cumulative lifetime exposure in Solomon Islanders (P<0.001–0.027). A subset of 6 proteins, selected on the basis of immunogenicity and expression levels, were used to examine antibody levels in plasma samples from a population of young Papua New Guinean children with well-characterized individual differences in exposure. This analysis identified a strong association between reduced risk of clinical disease and antibody levels to P12, P41, and a novel hypothetical protein that has not previously been studied, PVX_081550 (IRR 0.46–0.74; P<0.001–0.041). These data emphasize the benefits of an unbiased screening approach in identifying novel vaccine candidate antigens. Functional studies are now required to establish whether PVX_081550 is a key component of the naturally-acquired protective immune response, a biomarker of immune status, or both. Plasmodium vivax is now the predominant malaria parasite outside Africa. Because P. vivax can remain dormant in the liver for months, identifying and treating P. vivax in asymptomatic individuals is difficult. Additionally, current widely-used vector control measures are less efficient against mosquitoes that transmit P. vivax. An effective vaccine would therefore immensely facilitate P. vivax elimination. Unfortunately, little is known about P. vivax biology and only a few proteins have been investigated as targets for vaccine development. To address these knowledge gaps, we measured antibody levels to 34 entire ectodomain proteins predicted to be involved in P. vivax invasion of erythrocytes, in samples from individuals living in 2 malaria-endemic Asia-Pacific countries. We found that antibodies in malaria-exposed Solomon Islanders were reactive to the majority of proteins in our panel, and that antibodies to 12 of these proteins strongly reflected cumulative life-time exposure to P. vivax. In samples from Papua New Guinea children, we identified an association between antibodies to 3 proteins and protection against clinical malaria. Our results demonstrate that screening antibodies to a large number of P. vivax proteins is a useful approach in identifying novel targets of immunity. Functional studies are now required to establish whether these proteins are biomarkers of an individual’s immune status, potential vaccine candidates that warrant further development, or both.