Generation of a Peptide Vaccine Candidate against Falciparum Placental Malaria Based on a Discontinuous Epitope.
Generation of a Peptide Vaccine Candidate against Falciparum Placental Malaria Based on a Discontinuous Epitope.
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DOI：
10.3390/vaccines8030392
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发表时间：
2020-07-18
期刊：
影响因子：
7.8
通讯作者：
Yanow SK
中科院分区：
文献类型：
--
作者：
Mitran CJ;Higa LM;Good MF;Yanow SK
在孕妇中，恶性疟原虫感染的红细胞通过寄生虫蛋白VAR 2CSA粘附在胎盘上。两种基于VAR 2CSA的候选疫苗目前正在临床试验中;然而，这些候选疫苗未能引起超越菌株的抗体应答。我们先前表明，针对间日疟原虫抗原PvDBP产生的交叉反应性单克隆抗体（3D 10）靶向VAR 2CSA中的表位。我们现在的目标是基于产生3D 10的表位设计针对VAR 2CSA的肽疫苗。我们将表位定位到PvDBP的亚结构域1（SD 1），并鉴定了包含最小序列的肽。然而，该肽在小鼠中不引发交叉反应性VAR 2CSA抗体。当针对跨越SD 1的更宽的重叠肽阵列进行测试时，3D 10实际上识别由SD 1的三个区段组成的不连续表位。这些发现提出了将这种较大的结构表位生成为合成肽的挑战，因为它通过两对二硫键稳定。我们使用合成支架克服了这一点，以构象约束SD 1肽，并将其偶联到钥孔血蓝蛋白（KLH）。SD 1-KLH缀合物在小鼠中引发与VAR 2CSA交叉反应的抗体。该策略成功地用合成肽重现了不连续表位，并代表了针对VAR 2CSA的第一个异源疫苗候选物。
In pregnant women, Plasmodium falciparum-infected red blood cells adhere to the placenta via the parasite protein VAR2CSA. Two vaccine candidates based on VAR2CSA are currently in clinical trials; however, these candidates failed to elicit strain-transcending antibody responses. We previously showed that a cross-reactive monoclonal antibody (3D10) raised against the P. vivax antigen PvDBP targets epitopes in VAR2CSA. We now aim to design a peptide vaccine against VAR2CSA based on the epitope that generated 3D10. We mapped the epitope to subdomain 1 (SD1) of PvDBP and identified a peptide that contained the minimal sequence. However, this peptide did not elicit cross-reactive VAR2CSA antibodies in mice. When tested against a broader, overlapping peptide array spanning SD1, 3D10 in fact recognized a discontinuous epitope consisting of three segments of SD1. These findings presented the challenge to generate this larger structural epitope as a synthetic peptide since it is stabilized by two pairs of disulfide bonds. We overcame this using a synthetic scaffold to conformationally constrain the SD1 peptide and coupled it to keyhole limpet hemocyanin (KLH). The SD1-KLH conjugate elicited antibodies in mice that cross-reacted with VAR2CSA. This strategy successfully recapitulated a discontinuous epitope with a synthetic peptide and represents the first heterologous vaccine candidate against VAR2CSA.
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影响因子：
2.1
作者：
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通讯作者：
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影响因子：
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2.2
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64.5
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通讯作者：
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