Baseline exposure, antibody subclass, and hepatitis B response differentially affect malaria protective immunity following RTS,S/AS01E vaccination in African children
Baseline exposure, antibody subclass, and hepatitis B response differentially affect malaria protective immunity following RTS,S/AS01E vaccination in African children
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DOI：
10.1186/s12916-018-1186-4
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发表时间：
2018-10-31
期刊：
影响因子：
9.3
通讯作者：
Dobano, Carlota
中科院分区：
文献类型：
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作者：
Ubillos, Itziar;Ayestaran, Aintzane;Dobano, Carlota
RTS，S/AS 01 E疫苗为非洲儿童提供了部分疟疾保护，但免疫应答仅得到部分表征，不能可靠地预测保护效力。我们的目的是全面评估疫苗在高峰应答时的免疫原性、影响因素以及与参与多中心3期试验以获得许可证的年轻非洲儿童中预防临床疟疾相关的抗体。针对恶性疟原虫环子孢子蛋白（CSP）和肝炎B表面抗原（HBsAg）的三种构建体的IgG（1-4）亚类抗体作为RTS，S疫苗的一部分。采用病例对照研究设计，分析了来自加纳（金坦波）和莫桑比克（Manhica）两个不同传播强度地点的195名婴儿和儿童的血浆和血清样本。我们应用回归模型和机器学习技术来分析免疫原性，保护的相关性，和影响他们的因素。ResultsRTS，S/AS 01 E诱导IgM和IgG，主要是IgG 1和IgG 3，但也IgG 2和IgG 4，亚类反应。年龄、部位、既往疟疾发作和基线特征（包括CSP抗体和反映疟疾暴露和母体IgG的其他抗原）、营养状况和血红蛋白浓度显著影响疫苗免疫原性。我们在RTS、S/AS 01 E中识别出疟疾保护和风险的独特特征，但在对照疫苗接种者中没有。免疫后对RTS、S抗原的IgG 2和IgG 4应答以及免疫前抗CSP和抗恶性疟原虫抗体水平与1年随访期内的疟疾风险相关。相比之下，对HBsAg（所有同种型、亚类和时间点）的抗体应答以及接种后对CSP C端和NANP的IgG 1和IgG 3与保护相关。年龄和网站影响的相对贡献的反应在correlates identified.ConclusionsCytophilic IgG反应的C-末端和NANP重复区域的CSP和抗-HBsAg抗体诱导RTS，S/AS 01 E疫苗接种与疟疾保护。相比之下，基线时较高的疟疾暴露和对CSP的非嗜细胞IgG应答与疾病风险相关。数据提供了非洲儿童疫苗成功和失败的新相关性，并揭示了可以指导开发更有效的下一代疫苗的行动模式的关键见解。
BackgroundThe RTS,S/AS01E vaccine provides partial protection against malaria in African children, but immune responses have only been partially characterized and do not reliably predict protective efficacy. We aimed to evaluate comprehensively the immunogenicity of the vaccine at peak response, the factors affecting it, and the antibodies associated with protection against clinical malaria in young African children participating in the multicenter phase 3 trial for licensure.MethodsWe measured total IgM, IgG, and IgG(1-4) subclass antibodies to three constructs of the Plasmodium falciparum circumsporozoite protein (CSP) and hepatitis B surface antigen (HBsAg) that are part of the RTS,S vaccine, by quantitative suspension array technology. Plasma and serum samples were analyzed in 195 infants and children from two sites in Ghana (Kintampo) and Mozambique (Manhica) with different transmission intensities using a case-control study design. We applied regression models and machine learning techniques to analyze immunogenicity, correlates of protection, and factors affecting them.ResultsRTS,S/AS01E induced IgM and IgG, predominantly IgG1 and IgG3, but also IgG2 and IgG4, subclass responses. Age, site, previous malaria episodes, and baseline characteristics including antibodies to CSP and other antigens reflecting malaria exposure and maternal IgGs, nutritional status, and hemoglobin concentration, significantly affected vaccine immunogenicity. We identified distinct signatures of malaria protection and risk in RTS,S/AS01E but not in comparator vaccinees. IgG2 and IgG4 responses to RTS,S antigens post-vaccination, and anti-CSP and anti-P. falciparum antibody levels pre-vaccination, were associated with malaria risk over 1-year follow-up. In contrast, antibody responses to HBsAg (all isotypes, subclasses, and timepoints) and post-vaccination IgG1 and IgG3 to CSP C-terminus and NANP were associated with protection. Age and site affected the relative contribution of responses in the correlates identified.ConclusionsCytophilic IgG responses to the C-terminal and NANP repeat regions of CSP and anti-HBsAg antibodies induced by RTS,S/AS01E vaccination were associated with malaria protection. In contrast, higher malaria exposure at baseline and non-cytophilic IgG responses to CSP were associated with disease risk. Data provide new correlates of vaccine success and failure in African children and reveal key insights into the mode of action that can guide development of more efficacious next-generation vaccines.