在马里儿童中用恶性疟原虫顶膜蛋白 1 候选疫苗 FMP2.1/AS02 免疫后的免疫球蛋白 G 亚类和抗体亲合力反应。
Immunoglobulin G subclass and antibody avidity responses in Malian children immunized with Plasmodium falciparum apical membrane antigen 1 vaccine candidate FMP2.1/AS02.
机构信息
Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA.
Warren Alpert Medical School, Brown University, Providence, RI, USA.
出版信息
Malar J. 2019 Jan 18;18(1):13. doi: 10.1186/s12936-019-2637-x.
BACKGROUND
A malaria vaccine based on Plasmodium falciparum apical membrane antigen 1 (AMA1) elicited strain specific efficacy in Malian children that waned in the second season after vaccination despite sustained AMA1 antibody titers. With the goal of identifying a humoral correlate of vaccine-induced protection, pre- and post-vaccination sera from children vaccinated with the AMA1 vaccine and from a control group that received a rabies vaccine were tested for AMA1-specific immunoglobulin G (IgG) subclasses (IgG1, IgG2, IgG3, and IgG4) and for antibody avidity.
METHODS
Samples from a previously completed Phase 2 AMA1 vaccine trial in children residing in Mali, West Africa were used to determine AMA1-specific IgG subclass antibody titers and avidity by ELISA. Cox proportional hazards models were used to assess correlation between IgG subclass antibody titers and risk of time to first or only clinical malaria episode and risk of multiple episodes. Asexual P. falciparum parasite density measured for each child as area under the curve were used to assess correlation between IgG subclass antibody titers and parasite burden.
RESULTS
AMA1 vaccination did not elicit a change in antibody avidity; however, AMA1 vaccinees had a robust IgG subclass response that persisted over the malaria transmission season. AMA1-specific IgG subclass responses were not associated with decreased risk of subsequent clinical malaria. For the AMA1 vaccine group, IgG3 levels at study day 90 correlated with high parasite burden during days 90-240. In the control group, AMA1-specific IgG subclass rise and persistence over the malaria season was modest and correlated with age. In the control group, titers of several IgG subclasses at days 90 and 240 correlated with parasite burden over the first 90 study days, and IgG3 at day 240 correlated with parasite burden during days 90-240.
CONCLUSIONS
Neither IgG subclass nor avidity was associated with the modest, strain-specific efficacy elicited by this blood stage malaria vaccine. Although a correlate of protection was not identified, correlations between subclass titers and age, and correlations between IgG subclass titers and parasite burden, defined by area under the curve parasitaemia levels, were observed, which expand knowledge about IgG subclass responses. IgG3, known to have the shortest half-life of the IgG subclasses, might be the most temporally relevant indicator of ongoing malaria exposure when examining antibody responses to AMA1.
背景
基于恶性疟原虫顶膜蛋白 1（AMA1）的疟疾疫苗在马里儿童中产生了针对菌株的效力，但在接种后第二个季节逐渐减弱，尽管 AMA1 抗体滴度持续存在。为了确定疫苗诱导保护的体液相关性，用 AMA1 疫苗接种的儿童和接受狂犬病疫苗的对照组的接种前和接种后的血清检测 AMA1 特异性免疫球蛋白 G（IgG）亚类（IgG1、IgG2、IgG3 和 IgG4）和抗体亲和力。
方法
使用来自以前在西非马里进行的 2 期 AMA1 疫苗试验的样本，通过 ELISA 确定 AMA1 特异性 IgG 亚类抗体滴度和亲和力。Cox 比例风险模型用于评估 IgG 亚类抗体滴度与首次或仅发生临床疟疾发作风险以及多次发作风险之间的相关性。每个儿童的恶性疟原虫寄生虫密度曲线下面积用于评估 IgG 亚类抗体滴度与寄生虫负荷之间的相关性。
结果
AMA1 疫苗接种并未改变抗体亲和力；然而，AMA1 疫苗接种者产生了持续整个疟疾传播季节的强大 IgG 亚类反应。AMA1 特异性 IgG 亚类反应与随后发生临床疟疾的风险无关。对于 AMA1 疫苗组，在研究第 90 天的 AMA1 特异性 IgG3 水平与第 90-240 天期间的高寄生虫负荷相关。在对照组中，AMA1 特异性 IgG 亚类在疟疾季节的升高和持续存在是适度的，与年龄相关。在对照组中，第 90 天和第 240 天的几种 IgG 亚类的滴度与前 90 天研究期间的寄生虫负荷相关，第 240 天的 IgG3 与第 90-240 天期间的寄生虫负荷相关。
结论
无论是 IgG 亚类还是亲和力都与这种血液阶段疟疾疫苗产生的适度、针对菌株的效力无关。尽管未确定保护相关性，但观察到 IgG 亚类滴度与年龄之间以及 IgG 亚类滴度与寄生虫负荷之间的相关性（通过曲线下寄生虫血症水平定义），这扩展了对 IgG 亚类反应的认识。IgG3 是 IgG 亚类中半衰期最短的，当检查针对 AMA1 的抗体反应时，它可能是正在进行的疟疾暴露的最相关的时间指标。
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