Strategies for designing and monitoring malaria vaccines targeting diverse antigens.
Strategies for designing and monitoring malaria vaccines targeting diverse antigens.
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设计和监测针对多种抗原的疟疾疫苗的策略。
DOI：
10.3389/fimmu.2014.00359
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发表时间：
2014
影响因子：
7.3
通讯作者：
Arnott A
中科院分区：
文献类型：
--
作者：
Barry AE;Arnott A
经过50多年的密集研发，只有一种疟疾候选疫苗“RTS，S”进入了3期临床试验。尽管这种候选疫苗只有部分功效，但现在预计它将成为首个获得许可的疟疾疫苗。因此，迫切需要能够显著减少传播的更有效的第二代疟疾疫苗。这篇综述将集中讨论阻碍开发有效疟疾疫苗的一个主要障碍：寄生虫抗原多样性。尽管主要候选抗原具有广泛的遗传多样性，但疫苗一直并将继续使用仅代表一种或两种菌株的重组抗原来配制。这些疫苗株仅代表天然寄生虫种群中传播的多样性的一小部分，导致非疫苗株的逃逸，并对研究人员在疫苗试验中测量菌株特异性效力的能力提出了挑战。为了疫苗开发的成功，需要新的策略来克服抗原多样性。许多研究现已对全球主要恶性疟原虫和间日疟原虫疫苗抗原的多样性进行了编目。在这篇综述中，我们描述了群体遗传学方法如何应用于这一丰富的数据源，以预测最能代表抗原多样性的等位基因，促进它的多态性，并确定与抗原逃逸相关的关键多态性。我们还提出了一种方法来总结已知的给定抗原的全球多样性，以预测抗原多样性，如何选择最能代表自然寄生虫种群中传播的菌株的变体，以及如何调查疫苗试验的菌株特异性功效。在疫苗试验的设计和监测中使用这些战略不仅将阐明遗传多样性对疟疾抗原多样性的贡献，而且还将最大限度地发挥未来疟疾候选疫苗的潜力。
After more than 50 years of intensive research and development, only one malaria vaccine candidate, “RTS,S,” has progressed to Phase 3 clinical trials. Despite only partial efficacy, this candidate is now forecast to become the first licensed malaria vaccine. Hence, more efficacious second-generation malaria vaccines that can significantly reduce transmission are urgently needed. This review will focus on a major obstacle hindering development of effective malaria vaccines: parasite antigenic diversity. Despite extensive genetic diversity in leading candidate antigens, vaccines have been and continue to be formulated using recombinant antigens representing only one or two strains. These vaccine strains represent only a small fraction of the diversity circulating in natural parasite populations, leading to escape of non-vaccine strains and challenging investigators’ abilities to measure strain-specific efficacy in vaccine trials. Novel strategies are needed to overcome antigenic diversity in order for vaccine development to succeed. Many studies have now cataloged the global diversity of leading Plasmodium falciparum and Plasmodium vivax vaccine antigens. In this review, we describe how population genetic approaches can be applied to this rich data source to predict the alleles that best represent antigenic diversity, polymorphisms that contribute to it, and to identify key polymorphisms associated with antigenic escape. We also suggest an approach to summarize the known global diversity of a given antigen to predict antigenic diversity, how to select variants that best represent the strains circulating in natural parasite populations and how to investigate the strain-specific efficacy of vaccine trials. Use of these strategies in the design and monitoring of vaccine trials will not only shed light on the contribution of genetic diversity to the antigenic diversity of malaria, but will also maximize the potential of future malaria vaccine candidates.