Background

The RTS,S/AS01_E malaria vaccine showed lower antibody response and protective efficacy in infants aged 6–12 weeks compared with children aged 5–17 months (for whom this vaccine is recommended). We aimed to study the effect of previous Plasmodium falciparum exposure on the antibody responses to RTS,S/AS01_E vaccination in infants and children, and the mediating effect of baseline (including maternal) anti-circumsporozoite protein (CSP) antibodies.

Methods

In this observational study, we included children and infants from six African countries (Burkina Faso, Gabon, Ghana, Kenya, Mozambique, and Tanzania) enrolled in the MAL067 immunology ancillary study of the RTS,S/AS01_E phase 3 clinical trial from March 27, 2009, to Jan 21, 2011. We used comparator-vaccinated infants and children to identify antibody-based signatures of previous P falciparum exposure, which were later applied to RTS,S/AS01_E-vaccinated infants and children. In these participants, we explored the relationship between vaccine antibody immunoglobulin G (IgG) responses measured by ELISA and pre-vaccination serological markers of malaria exposure by assessing the IgG levels against 1000 P falciparum antigens using partial proteome microarrays.

Findings

We included 718 comparator-vaccinated infants (348 [48%]) and children (370 [52%]) and 606 RTS,S/AS01_E-vaccinated infants (329 [54%]) and children (277 [46%]). Anti-CSP IgG responses to primary vaccination did not correlate with a baseline signature of previous exposure in children, suggesting that prior P falciparum exposure does not significantly affect antibody immunogenicity in children (Pearson's r=–0·02 [95% CI –0·13 to 0·10]). By contrast, high P falciparum exposure signature levels at the time of vaccination in infants, presumably driven by maternally transferred antibodies and declining within the initial 6–12 months of life, correlated with reduced RTS,S/AS01_E responses (r=–0·17 [–0·27 to –0·06]). This negative correlation was stronger for anti-CSP IgG than for the exposure signature or any other more immunogenic blood stage P falciparum antigens (r=–0·42 [–0·50 to –0·33]), persisted after adjustment by baseline levels of the exposure signature (semi-partial correlation r=–0·44 [–0·55 to –0·33]), and involved antibodies to the central NANP region (r=–0·39 [–0·49 to –0·28]) but not the C-terminal region (r=0·02 [–0·10 to 0·15]) of CSP. The negative effect of maternal anti-CSP IgG in infants did not appear to be confounded by other malaria transmission-dependent variables.

Interpretation

Interference between passive immunity and vaccine response is clinically significant and might affect the implementation of next-generation CSP-based vaccines for young infants and mothers as well as passive immunisation with human monoclonal antibodies.

Funding

US National Institutes of Health, National Institute of Allergy and Infectious Diseases; PATH–Malaria Vaccine Initiative; Spanish Ministerio de Economía y Competitividad (Instituto de Salud Carlos III), European Regional Development Fund and European Social Fund; Fundación Ramón Areces; Spanish Ministry of Science and Innovation; and Generalitat de Catalunya (CERCA Program).

中文翻译：

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恶性疟原虫暴露和母体抗环子孢子蛋白抗体对婴儿和儿童对 RTS、S/AS01E 疫苗接种反应的影响：3 期随机临床试验的辅助观察性免疫学研究

 背景

与 5-17 个月大的儿童（推荐接种这种疫苗）相比，RTS，S/AS01_E 疟疾疫苗对 6-12 周龄婴儿的抗体反应和保护效力较低。我们旨在研究既往恶性疟原虫暴露对婴儿和儿童对 RTS、S/AS01_E 疫苗接种抗体反应的影响，以及基线 （包括母体） 抗环子孢子蛋白 （CSP） 抗体的介导作用。

 方法

在这项观察性研究中，我们纳入了来自 6 个非洲国家（布基纳法索、加蓬、加纳、肯尼亚、莫桑比克和坦桑尼亚）的儿童和婴儿，这些儿童和婴儿参加了 2009 年 3 月 27 日至 2011 年 1 月 21 日期间参加 RTS、S/AS01_E 3 期临床试验的 MAL067 免疫学辅助研究。我们使用接种了对照疫苗的婴儿和儿童来识别既往恶性疟原虫暴露的基于抗体的特征，这些特征后来应用于 RTS，S/AS01_E 疫苗接种的婴儿和儿童。在这些参与者中，我们通过使用部分蛋白质组微阵列评估针对 1000 个恶性疟原虫抗原的 IgG 水平，探讨了通过 ELISA 测量的疫苗抗体免疫球蛋白 G （IgG） 反应与疫苗接种前疟疾暴露血清学标志物之间的关系。

 发现

我们纳入了 718 名接种了对照疫苗的婴儿 （348 [48%]） 和儿童 （370 [52%]） 和 606 名 RTS，S/AS01_电子疫苗接种婴儿 （329 [54%]） 和儿童 （277 [46%]）。抗 CSP IgG 对初次疫苗接种的反应与儿童既往暴露的基线特征无关，表明既往恶性疟原虫暴露不会显著影响儿童的抗体免疫原性（Pearson 的 r=–0·02 [95% CI –0·13 至 0·10]）。相比之下，婴儿接种疫苗时恶性疟原虫暴露特征水平高，可能是由母体转移的抗体驱动的，并且在出生后的最初 6-12 个月内下降，与 RTS，S/AS01_E 反应减少相关（r=–0·17 [–0·27 至 –0·06]）。抗CSP IgG的这种负相关性强于暴露特征或任何其他更具免疫原性的血期恶性P抗原（r=–0·42 [–0·50至–0·33]），在通过暴露特征的基线水平调整后持续存在（半偏相关 r=–0·44 [–0·55 至 –0·33]），并涉及针对中央 NANP 区域的抗体（r=–0·39 [–0·49 至 –0·28]），但不涉及 C 端区域的抗体 （r=0·02 [–0·10 至 0·15]） 的 CSP。母体抗 CSP IgG 对婴儿的负面影响似乎没有被其他疟疾传播相关变量混淆。

 解释

被动免疫和疫苗反应之间的干扰具有临床意义，可能会影响针对幼儿婴儿和母亲的下一代基于 CSP 的疫苗的实施，以及使用人类单克隆抗体的被动免疫。

 资金

美国国立卫生研究院，国家过敏和传染病研究所;PATH——疟疾疫苗倡议;西班牙卡洛斯三世健康研究所 （Instituto de Salud Carlos III）、欧洲区域发展基金和欧洲社会基金;Fundación Ramón Areces;西班牙科学与创新部;和 Generalitat de Catalunya（CERCA 计划）。