Defining the antigenic diversity of Plasmodium falciparum apical membrane antigen 1 and the requirements for a multi-allele vaccine against malaria.
Defining the antigenic diversity of Plasmodium falciparum apical membrane antigen 1 and the requirements for a multi-allele vaccine against malaria.
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DOI：
10.1371/journal.pone.0051023
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Beeson JG
中科院分区：
文献类型：
--
作者：
Drew DR;Hodder AN;Wilson DW;Foley M;Mueller I;Siba PM;Dent AE;Cowman AF;Beeson JG
顶膜抗原 1 (AMA1) 是一种领先的疟疾候选疫苗，也是人类自然获得免疫力的目标。恶性疟原虫 AMA1 具有多态性，在疫苗试验中它可诱导菌株特异性保护。这种抗原多样性是 AMA1 作为疟疾疫苗开发的主要障碍，了解如何克服它至关重要。为了评估 AMA1 抗原多样性如何限制交叉菌株生长抑制，我们组装了一组 18 个不同的恶性疟原虫分离株，它们广泛代表了全球 AMA1 序列多样性。针对 4 个经过充分研究的 AMA1 等位基因（W2Mef、3D7、HB3 和 FVO）产生的抗体在生长抑制测定 (GIA) 中测试了 18 种不同恶性疟原虫分离株的生长抑制情况。所有抗体均表现出针对不同分离株的显着交叉抑制活性，并且四种不同 AMA1 抗体的混合物抑制所有 18 个测试分离株，表明 AMA1 等位基因之间存在显着的抗原重叠，而 AMA1 的抗原多样性有限。抗体的交叉菌株抑制仅与 AMA1 等位基因之间的序列多样性水平存在中度且不一致的相关性，这表明序列差异并不是抗原差异或抗等位基因抗体的交叉抑制活性的强有力的预测因子。通过生成用于 GIA 测试的新型转基因恶性疟原虫株系，评估了高度多态性 C1-L 区域对于抑制性抗体和潜在疫苗逃逸的重要性。虽然多态性 C1-L 表位被确定为一些生长抑制性抗体的重要靶标，但这些抗体仅占总抑制性抗体库的一小部分，表明抑制性表位的抗原多样性是有限的。我们的研究结果支持这样的概念，即多等位基因 AMA1 疫苗将广泛覆盖 AMA1 等位基因的多样性，并建立新工具来定义对疫苗逃逸重要的多态性。
Apical Membrane Antigen 1 (AMA1) is a leading malaria vaccine candidate and a target of naturally-acquired human immunity. Plasmodium falciparum AMA1 is polymorphic and in vaccine trials it induces strain-specific protection. This antigenic diversity is a major roadblock to development of AMA1 as a malaria vaccine and understanding how to overcome it is essential. To assess how AMA1 antigenic diversity limits cross-strain growth inhibition, we assembled a panel of 18 different P. falciparum isolates which are broadly representative of global AMA1 sequence diversity. Antibodies raised against four well studied AMA1 alleles (W2Mef, 3D7, HB3 and FVO) were tested for growth inhibition of the 18 different P. falciparum isolates in growth inhibition assays (GIA). All antibodies demonstrated substantial cross-inhibitory activity against different isolates and a mixture of the four different AMA1 antibodies inhibited all 18 isolates tested, suggesting significant antigenic overlap between AMA1 alleles and limited antigenic diversity of AMA1. Cross-strain inhibition by antibodies was only moderately and inconsistently correlated with the level of sequence diversity between AMA1 alleles, suggesting that sequence differences are not a strong predictor of antigenic differences or the cross-inhibitory activity of anti-allele antibodies. The importance of the highly polymorphic C1-L region for inhibitory antibodies and potential vaccine escape was assessed by generating novel transgenic P. falciparum lines for testing in GIA. While the polymorphic C1-L epitope was identified as a significant target of some growth-inhibitory antibodies, these antibodies only constituted a minor proportion of the total inhibitory antibody repertoire, suggesting that the antigenic diversity of inhibitory epitopes is limited. Our findings support the concept that a multi-allele AMA1 vaccine would give broad coverage against the diversity of AMA1 alleles and establish new tools to define polymorphisms important for vaccine escape.
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影响因子：
3.7
作者：
Kusi KA;Faber BW;Riasat V;Thomas AW;Kocken CH;Remarque EJ
通讯作者：
Remarque EJ
DOI：
10.1073/pnas.0701464104
发表时间：
2007-07-24
影响因子：
11.1
作者：
Dutta, Sheetij;Lee, Seung Yeon;Lanar, David E.
通讯作者：
Lanar, David E.
影响因子：
1.5
作者：
Fowler, EV;Peters, JM;Cheng, Q
通讯作者：
Cheng, Q
影响因子：
64.5
作者：
Maier AG;Rug M;O'Neill MT;Brown M;Chakravorty S;Szestak T;Chesson J;Wu Y;Hughes K;Coppel RL;Newbold C;Beeson JG;Craig A;Crabb BS;Cowman AF
通讯作者：
Cowman AF
DOI：
10.1056/nejmp1108322
发表时间：
2011-09-22
期刊：
The New England journal of medicine
影响因子：
--
作者：
Dondorp AM;Fairhurst RM;Slutsker L;Macarthur JR;Breman JG;Guerin PJ;Wellems TE;Ringwald P;Newman RD;Plowe CV
通讯作者：
Plowe CV