Antibody response to a new member of the DBL family (EBP2) after a brief Plasmodium vivax exposure.
Antibody response to a new member of the DBL family (EBP2) after a brief Plasmodium vivax exposure.
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DOI：
10.1371/journal.pntd.0010493
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发表时间：
2022-06
影响因子：
3.8
通讯作者：
中科院分区：
文献类型：
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间日疟原虫血液阶段侵入网织红细胞对于寄生虫的发育至关重要。因此，新型寄生虫入侵配体的验证对于疟疾疫苗的开发至关重要。最近，我们证明 EBP2 是一种 Duffy 结合蛋白 (DBP) 旁系同源物，在抗原上与 DBP 不同，并且不能被抗 DBP 抗体进行功能性抑制。在这里，我们利用位于巴西非疟疾地区的间日疟原虫小规模爆发，首次调查了首次短暂接触间日疟原虫的个体（16 例病例和 22 例非病例）中针对 EBP2 和 DEKnull-2（一种工程 DBPII 疫苗）的 IgM/IgG 抗体。我们的实验方法包括 4 次横断面调查，间隔 3 个月（12 个月随访）。结果表明，虽然短暂的初始间日疟原虫感染不能有效诱导针对 EBP2 或 DEKnull-2 的 IgM/IgG 抗体，但针对 DEKnull-2（但不是 EBP2）的 IgG 抗体因治疗后反复发生的血液阶段感染而增强。有趣的是，在大多数复发性间日疟原虫感染中（6 名患者中的 4 名），DEKnull-2 IgG 抗体持续 6 至 12 个月。 ebp2 基因的多态性似乎不能解释 EBP2 的低免疫原性，因为与间日疟原虫爆发相关的 ebp2 等位基因与用作重组蛋白的原始 EBP2 分离株表现出高度同一性。尽管在初次感染间日疟原虫后几乎检测不到 EBP2 抗体，但长期暴露于疟疾的亚马逊人的血清 IgG 高度识别了 EBP2（根据之前的疟疾发作情况，范围为 35% 至 92%）。总而言之，结果表明，单次短暂接触间日疟原虫感染的个体产生的抗 EBP2 抗体非常低，而在长期接触疟疾后，这种抗体往往会增加。最后，研究结果强调了 DEKnull-2 作为候选疫苗的潜力，因为在非免疫个体中，即使在短暂接触间日疟原虫血液阶段后，抗 DEKnull-2 IgG 抗体也会增强。疫苗可能是当前控制和消除疟疾工作的重要组成部分，许多与间日疟原虫疫苗相关的研究都集中在达菲结合蛋白 (DBPII) 的 II 区，该蛋白是人类血液阶段感染的配体。最近，新描述的红细胞结合蛋白 2 (EBP2) 是一种间日疟原虫 DBP 旁系同源物，其抗原性与 DBP 不同，被确定为潜在的疫苗靶标。迄今为止，关于 EBP2 自然获得性免疫力的数据很少。在位于非疟疾地区的一次小规模间日疟原虫爆发中，我们研究了首次接触间日疟原虫是否会诱导针对 EBP2 的抗体，而这种抗体可能因间日疟原虫反复感染而增强。与此同时，我们纳入了一种工程化 DBPII 疫苗（名为 DEKnull-2），其抗体反应先前与广泛中和间日疟原虫抗体相关。这项研究表明，与 DEKnull-2 相比，EBP2 在首次经历血液阶段间日疟原虫感染的个体中免疫原性较差。然而，EBP2 在长期接触疟疾的个体中具有高度免疫原性，增强了其作为间日疟原虫血液阶段候选疫苗的潜力。最后，我们的结果强调，应该以多种血液阶段抗原为目标来开发针对间日疟原虫的有效疫苗。
Plasmodium vivax blood-stage invasion into reticulocyte is critical for parasite development. Thus, validation of novel parasite invasion ligands is essential for malaria vaccine development. Recently, we demonstrated that EBP2, a Duffy binding protein (DBP) paralog, is antigenically distinct from DBP and could not be functionally inhibited by anti-DBP antibodies. Here, we took advantage of a small outbreak of P.vivax malaria, located in a non-malarious area of Brazil, to investigate for the first time IgM/IgG antibodies against EBP2 and DEKnull-2 (an engineering DBPII vaccine) among individuals who had their first and brief exposure to P.vivax (16 cases and 22 non-cases). Our experimental approach included 4 cross sectional surveys at 3-month interval (12-month follow-up). The results demonstrated that while a brief initial P.vivax infection was not efficient to induce IgM/ IgG antibodies to either EBP2 or DEKnull-2, IgG antibodies against DEKnull-2 (but not EBP2) were boosted by recurrent blood-stage infections following treatment. Of interest, in most recurrent P. vivax infections (4 out of 6 patients) DEKnull-2 IgG antibodies were sustained for 6 to 12 months. Polymorphisms in the ebp2 gene does not seem to explain EBP2 low immunogenicity as the ebp2 allele associated with the P.vivax outbreak presented high identity to the original EBP2 isolate used as recombinant protein. Although EBP2 antibodies were barely detectable after a primary episode of P.vivax infection, EBP2 was highly recognized by serum IgG from long-term malaria-exposed Amazonians (range from 35 to 92% according to previous malaria episodes). Taken together, the results showed that individuals with a single and brief exposure to P.vivax infection develop very low anti-EBP2 antibodies, which tend to increase after long-term malaria exposure. Finally, the findings highlighted the potential of DEKnull-2 as a vaccine candidate, as in non-immune individuals anti-DEKnull-2 IgG antibodies were boosted even after a brief exposure to P.vivax blood stages. Vaccines might be a crucial component of the current efforts to malaria control and elimination, and much of the vaccine-related research on P. vivax has been focused on region II of the Duffy binding protein (DBPII), a ligand for human blood-stage infection. Recently, the newly described Erythrocyte binding protein 2 (EBP2), a P.vivax DBP paralog that it is antigenically distinct from DBP, was identified as potential vaccine targets. To date, scarce data are available about the naturally acquired immunity to EBP2. In a small outbreak of P.vivax malaria, located in a non-malarious area, we investigated whether a first P.vivax exposure induces antibodies against EBP2 that could be boosted by P.vivax recurrent infections. In parallel, we included an engineered DBPII vaccine (named DEKnull-2) whose antibody response were previously associated with broadly neutralizing P.vivax antibodies. This study shows EBP2, compared with DEKnull-2, was poorly immunogenic among individuals who experienced their first blood-stage P. vivax malaria infection. However, EBP2 was highly immunogenic in long-term malaria exposed individuals, reinforcing its potential as a P. vivax blood-stage vaccine candidate. Finally, our results reinforce that multiple blood-stage antigens should be targeted for the development of efficient vaccines against P. vivax.
影响因子：
15.8
作者：
Beeson JG;Crabb BS
通讯作者：
Crabb BS