Antibody mechanisms of protection against malaria in RTS,S-vaccinated children: a post-hoc serological analysis of phase 2 trial

IF 20.9 1区生物学 Q1 INFECTIOUS DISEASES

Lancet Microbe Pub Date : 2024-10-01 DOI:10.1016/S2666-5247(24)00130-7

Liriye Kurtovic PhD , Gaoqian Feng PhD , Alessia Hysa MBSc , Ali Haghiri PhD , Katherine O’Flaherty PhD , Bruce D Wines PhD , Rebeca Santano PhD , Laura D’Andrea PhD , Prof Heidi E Drummer PhD , Prof P Mark Hogarth PhD , Prof Jahit Sacarlal PhD , Prof Freya J I Fowkes DPhil , Prof Julie A Simpson PhD , Prof Carlota Dobaño PhD , Prof James G Beeson PhD

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引用次数: 0

Abstract

Background

The RTS,S malaria vaccine is currently recommended for children aged 5–6 months in regions with moderate-to-high Plasmodium falciparum transmission. However, vaccination only confers 55% efficacy over 12 months and wanes within 18 months. The immunological mechanisms of RTS,S-mediated immunity are poorly understood; therefore, we aimed to identify antibody response types associated with protection against malaria in children vaccinated with RTS,S.

Methods

In this post-hoc analysis, we evaluated antibody responses in 737 children aged 1–4 years vaccinated with RTS,S in a phase 2b clinical trial conducted in Mozambique in 2003. We evaluated all available samples collected from children 30 days after the three-dose vaccination schedule at study month 3 (M3; n=737 available of 803 children allocated to receive RTS,S). For comparison, we tested a subset of samples collected before vaccination at study month 0 (M0; n=50) and from children in the control vaccine group (M0 n=25; M3 n=99). We quantified the induction of antibodies to different regions of the vaccine antigen that function by fixing serum complement proteins and binding to Fcγ receptors (FcγRs; FcγRI, FcγRIIa, and FcγRIII) expressed on immune cells as potential mechanisms of immunity.

Findings

Functional antibody responses to the C-terminal region of the vaccine antigen, circumsporozoite protein (CSP), were associated with a reduced risk of malaria (C1q p=0·0060, FcγRIIa p=0·014, and FcγRIII p=0·019). These associations remained significant in male participants when the analyses were stratified by sex (C1q p=0·012, FcγRI p=0·023, FcγRIIa p=0·0070, and FcγRIII p=0·0080). IgA to the central repeat (p=0·0010) and C-terminal (p=0·0040) regions of CSP were also associated with protection. We show that IgA can bind FcαRI and mediate opsonic phagocytosis using a serum pool and monoclonal antibodies. Multiparameter analysis using machine-learning methods suggest that IgA, complement fixation, and FcγRI binding were most predictive of protection against malaria (hazard ratio <1) and suggested that associations differed between male and female participants.

Interpretation

We provide evidence that functional antibody responses mediated by IgG and IgA are associated with protection against malaria in young children vaccinated with RTS,S, and suggest potential differences in the correlates of immunity between males and females. These findings reveal new avenues that could be used to achieve malaria vaccines with higher efficacy.

Funding

National Health and Medical Research Council, Australia, and Thrasher Research Fund.

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接种 RTS,S 疫苗的儿童对疟疾的抗体保护机制：第二阶段试验的事后血清学分析。

背景：目前，在恶性疟原虫中度至高度传播地区，建议为 5-6 个月大的儿童接种 RTS S 疟疾疫苗。然而，接种疫苗在 12 个月内仅有 55% 的效力，并在 18 个月内减弱。RTS,S介导免疫的免疫学机制尚不清楚；因此，我们的目的是确定与接种RTS,S疫苗的儿童的疟疾保护相关的抗体反应类型：在这项事后分析中，我们评估了 2003 年在莫桑比克进行的一项 2b 期临床试验中接种 RTS,S 的 737 名 1-4 岁儿童的抗体反应。我们评估了在研究第 3 个月（M3；803 名被分配接种 RTS,S 的儿童中约有 737 人）接种三剂疫苗 30 天后从儿童身上采集的所有可用样本。为了进行比较，我们检测了在研究第 0 个月接种疫苗前采集的样本子集（M0；n=50）和对照疫苗组儿童的样本子集（M0 n=25; M3 n=99）。我们对疫苗抗原不同区域的抗体诱导情况进行了量化，这些区域通过固定血清补体蛋白和与免疫细胞上表达的 Fcγ 受体（FcγRs；FcγRI、FcγRIIa 和 FcγRIII）结合发挥作用，是潜在的免疫机制：对疫苗抗原环孢子虫蛋白（CSP）C末端区域的功能性抗体反应与疟疾风险的降低有关（C1q p=0-0060，FcγRIIa p=0-014，FcγRIII p=0-019）。当按性别进行分层分析时，这些关联在男性参与者中仍然显著（C1q p=0-012，FcγRI p=0-023，FcγRIIa p=0-0070，FcγRIII p=0-0080）。CSP中央重复区（p=0-0010）和C末端区（p=0-0040）的IgA也与保护有关。我们利用血清池和单克隆抗体证明了 IgA 可与 FcαRI 结合并介导虹膜吞噬作用。使用机器学习方法进行的多参数分析表明，IgA、补体固定和 FcγRI 结合最能预测对疟疾的保护作用（危险比）：我们提供的证据表明，IgG 和 IgA 介导的功能性抗体反应与接种 RTS,S 疫苗的幼儿对疟疾的保护有关，并表明男性和女性在免疫相关性方面可能存在差异。这些发现揭示了可用于提高疟疾疫苗疗效的新途径：澳大利亚国家健康与医学研究委员会和 Thrasher 研究基金。

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来源期刊

Lancet Microbe Multiple-

CiteScore

27.20

自引率

0.80%

发文量

278

审稿时长

6 weeks

期刊介绍： The Lancet Microbe is a gold open access journal committed to publishing content relevant to clinical microbiologists worldwide, with a focus on studies that advance clinical understanding, challenge the status quo, and advocate change in health policy.