Global diversity and balancing selection of 23 leading Plasmodium falciparum candidate vaccine antigens.
Global diversity and balancing selection of 23 leading Plasmodium falciparum candidate vaccine antigens.
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DOI：
10.1371/journal.pcbi.1009801
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发表时间：
2022-03
影响因子：
4.3
通讯作者：
Barry AE
中科院分区：
文献类型：
--
作者：
Naung MT;Martin E;Munro J;Mehra S;Guy AJ;Laman M;Harrison GLA;Tavul L;Hetzel M;Kwiatkowski D;Mueller I;Bahlo M;Barry AE
对疟原虫抗原多样性的研究有助于确定它们作为候选疫苗的优先次序和有效性，并确定最常见的变异体以纳入疫苗制剂。针对最致命的人类疟疾寄生虫-恶性疟原虫的候选疫苗的研究主要集中在少数几种众所周知的抗原上，而其他几种抗原从未被研究过。在这里，我们使用MalariaGEN Pf 3 K（5.1版）资源，包括来自15个疟疾流行国家的2600多个基因组，研究了恶性疟原虫主要疫苗候选抗原的全球多样性和种群结构。使用严格的变体调用管道从全局数据集中提取高质量的抗原基因“单倍型”，并使用名为VaxPack的新R-包来简化群体遗传分析。此外，一种新开发的算法，使空间平均的选择压力的3D蛋白质结构被应用到数据集。我们分析了编码23种主要和新型候选疟疾疫苗抗原的基因，包括csp、trap、eba 175、ama 1、rh 5和CelTOS。我们的分析表明，目前的疟疾疫苗配方是基于罕见的单倍型，因此可能对自然寄生虫种群的疗效有限。检测到大多数红细胞和红细胞前抗原具有平衡选择证据的高水平多样性。然后将自然选择的测量映射到3D蛋白质结构，以预测功能性抗体的靶点。对于一些抗原，这些信号在3D结构上的强度和分布的地理变化表明适应不同的人类宿主或蚊子媒介种群。本研究为恶性疟原虫抗原的多样性在下一代疟疾疫苗的设计中提供了一个必要的框架。高效疟疾疫苗对于可持续消除疟疾至关重要。然而，疟疾疫苗针对的寄生虫抗原的多样性在很大程度上被忽视了，大多数疫苗制剂仅基于单一抗原变体。如果不能适应这种多样性，可能会导致疫苗仅对疫苗样变体有效，从而导致保护效力有限。对编码寄生虫抗原的基因多样性的调查可以帮助优先考虑和验证它们作为疫苗候选物，以及确定最常见的变体以纳入下一代疟疾疫苗。在这里，我们测量23种疫苗抗原的恶性疟原虫的多样性，使用公共可用的MalariaGEN Pf 3 K（5.1版）资源，包括来自15个疟疾流行国家的2600多个基因组。我们发现，在目前的疫苗配方中发现的变异是罕见的，因此可能只针对一小部分循环疟疾寄生虫株。来自不同地理区域的寄生虫的免疫选择强度的变化表明适应不同的人类宿主或媒介种群。这项研究为设计下一代疟疾疫苗提供了一个基本框架，同时也为疟疾生物学提供了新的见解。
Investigation of the diversity of malaria parasite antigens can help prioritize and validate them as vaccine candidates and identify the most common variants for inclusion in vaccine formulations. Studies of vaccine candidates of the most virulent human malaria parasite, Plasmodium falciparum, have focused on a handful of well-known antigens, while several others have never been studied. Here we examine the global diversity and population structure of leading vaccine candidate antigens of P. falciparum using the MalariaGEN Pf3K (version 5.1) resource, comprising more than 2600 genomes from 15 malaria endemic countries. A stringent variant calling pipeline was used to extract high quality antigen gene ‘haplotypes’ from the global dataset and a new R-package named VaxPack was used to streamline population genetic analyses. In addition, a newly developed algorithm that enables spatial averaging of selection pressure on 3D protein structures was applied to the dataset. We analysed the genes encoding 23 leading and novel candidate malaria vaccine antigens including csp, trap, eba175, ama1, rh5, and CelTOS. Our analysis shows that current malaria vaccine formulations are based on rare haplotypes and thus may have limited efficacy against natural parasite populations. High levels of diversity with evidence of balancing selection was detected for most of the erythrocytic and pre-erythrocytic antigens. Measures of natural selection were then mapped to 3D protein structures to predict targets of functional antibodies. For some antigens, geographical variation in the intensity and distribution of these signals on the 3D structure suggests adaptation to different human host or mosquito vector populations. This study provides an essential framework for the diversity of P. falciparum antigens to be considered in the design of the next generation of malaria vaccines. Highly effective malaria vaccines are important for the sustainable elimination of malaria. However, the diversity of parasite antigens targeted by malaria vaccines has been largely overlooked, with most vaccine formulations based only on a single antigen variant. Failure to accommodate this diversity may result in vaccines only being effective against vaccine-like variants, resulting in limited protective efficacy. Investigation of the diversity of genes encoding parasite antigens can help prioritize and validate them as vaccine candidates as well as to identify the most common variants for inclusion in the next generation of malaria vaccines. Here we measure the diversity of 23 vaccine antigens of Plasmodium falciparum, using the publicly available MalariaGEN Pf3K (version 5.1) resource comprising more than 2600 genomes from 15 malaria endemic countries. We find that variants found in current vaccine formulations are rare and thus may target only a small proportion of circulating malaria parasite strains. Variation in intensity of immune selection in parasites from different geographic areas suggests adaptation to different human host or vector populations. This study provides an essential framework for the design of the next generation of malaria vaccines, in addition to providing novel insights into malaria biology.
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影响因子：
6.7
作者：
Chen E;Paing MM;Salinas N;Sim BK;Tolia NH
通讯作者：
Tolia NH
影响因子：
9.8
作者：
Akey JM;Eberle MA;Rieder MJ;Carlson CS;Shriver MD;Nickerson DA;Kruglyak L
通讯作者：
Kruglyak L
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
3.3
作者：
Bell GJ;Agnandji ST;Asante KP;Ghansah A;Kamthunzi P;Emch M;Bailey JA
通讯作者：
Bailey JA
影响因子：
1.2
作者：
Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.