Toward the Rational Design of a Malaria Vaccine Construct Using the MSP3 Family as an Example: Contribution of Immunogenicity Studies in Models
Toward the Rational Design of a Malaria Vaccine Construct Using the MSP3 Family as an Example: Contribution of Immunogenicity Studies in Models
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DOI：
10.1128/iai.00941-08
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发表时间：
2010-01-01
影响因子：
3.1
通讯作者：
Druilhe, Pierre
中科院分区：
文献类型：
--
作者：
Daher, Lena-Juliette;Demanga, Corine G.;Druilhe, Pierre
恶性疟原虫裂殖子表面蛋白3（MSP 3）是与血液单核细胞合作介导寄生虫杀伤并与暴露人群中的保护相关的抗体的靶标，是正在开发的候选疫苗。它属于一个由六个结构相关基因组成的家族。为了优化免疫原性，我们试图改善其设计的基础上的知识，从保守的C末端的六个蛋白质和分析的免疫原性的“定制”的构建体的各个区域的抗原性。免疫原性研究在BALB/c和C57 BL/6 J小鼠中进行，使用MSP 3（此处称为MSP 3 -1）作为模型。设计了四种构建体，以评估先前显示为生物活性抗体靶标的MSP 3 -1的69个氨基酸区域侧翼序列的作用。结果表明去除（i）69个氨基酸序列下游的亚区的主要有益效果，因为抗体滴度增加了2个数量级，和（ii）上游亚区，尽管其限定了T辅助细胞表位，但不是抗体的靶标。该构建体，不包括两个侧翼序列，能够诱导Th 1样反应，具有嗜细胞抗体的优势。这导致基于这些结果设计多基因构建体，组合MSP 3家族的六个成员。这种新的结构在小鼠中具有免疫原性，诱导识别寄生虫天然蛋白的抗体，并在功能性抗体依赖性细胞抑制试验中抑制寄生虫生长，从而满足有价值的候选疫苗的临床前标准。
Plasmodium falciparum merozoite surface protein 3 (MSP3), the target of antibodies that mediate parasite killing in cooperation with blood monocytes and are associated with protection in exposed populations, is a vaccine candidate under development. It belongs to a family of six structurally related genes. To optimize immunogenicity, we attempted to improve its design based on knowledge of antigenicity of various regions from the conserved C terminus of the six proteins and an analysis of the immunogenicity of "tailored" constructs. The immunogenicity studies were conducted in BALB/c and C57BL/6J mice, using MSP3 (referred to here as MSP3-1) as a model. Four constructs were designed in order to assess the effect of sequences flanking the 69-amino-acid region of MSP3-1 previously shown to be the target of biologically active antibodies. The results indicate major beneficial effects of removing (i) the subregion downstream from the 69-amino-acid sequence, since antibody titers increased by 2 orders of magnitude, and (ii) the upstream subregion which, although it defines a T-helper cell epitope, is not the target of antibodies. The construct, excluding both flanking sequences, was able to induce Th1-like responses, with a dominance of cytophilic antibodies. This led to design a multigenic construct based on these results, combining the six members of the MSP3 family. This new construction was immunogenic in mice, induced antibodies that recognized the parasite native proteins, and inhibited parasite growth in the functional antibody-dependent cellular inhibition assay, thus satisfying the preclinical criteria for a valuable vaccine candidate.