RTS,S/AS01 疟疾疫苗在 3 期临床试验中诱导非洲儿童针对 CSP 和与疫苗无关的抗原产生 IgA 应答。

RTS,S/AS01 malaria vaccine induces IgA responses against CSP and vaccine-unrelated antigens in African children in the phase 3 trial.

机构信息

ISGlobal, Hospital Clínic, Universitat de Barcelona, Carrer Rosselló 153 CEK Building, E-08036 Barcelona, Catalonia, Spain.

ISGlobal, Hospital Clínic, Universitat de Barcelona, Carrer Rosselló 153 CEK Building, E-08036 Barcelona, Catalonia, Spain; Centro de Investigação em Saúde de Manhiça (CISM), Rua 12, Cambeve, Vila de Manhiça, CP 1929 Maputo, Mozambique.

出版信息

Vaccine. 2021 Jan 22;39(4):687-698. doi: 10.1016/j.vaccine.2020.12.038. Epub 2020 Dec 25.

DOI:10.1016/j.vaccine.2020.12.038

PMID:33358704

Abstract

BACKGROUND

The evaluation of immune responses to RTS,S/AS01 has traditionally focused on immunoglobulin (Ig) G antibodies that are only moderately associated with protection. The role of other antibody isotypes that could also contribute to vaccine efficacy remains unclear. Here we investigated whether RTS,S/AS01 elicits antigen-specific serum IgA antibodies to the vaccine and other malaria antigens, and we explored their association with protection.

METHODS

Ninety-five children (age 5-17 months old at first vaccination) from the RTS,S/AS01 phase 3 clinical trial who received 3 doses of RTS,S/AS01 or a comparator vaccine were selected for IgA quantification 1 month post primary immunization. Two sites with different malaria transmission intensities (MTI) and clinical malaria cases and controls, were included. Measurements of IgA against different constructs of the circumsporozoite protein (CSP) vaccine antigen and 16 vaccine-unrelated Plasmodium falciparum antigens were performed using a quantitative suspension array assay.

RESULTS

RTS,S vaccination induced a 1.2 to 2-fold increase in levels of serum/plasma IgA antibodies to all CSP constructs, which was not observed upon immunization with a comparator vaccine. The IgA response against 13 out of 16 vaccine-unrelated P. falciparum antigens also increased after vaccination, and levels were higher in recipients of RTS,S than in comparators. IgA levels to malaria antigens before vaccination were more elevated in the high MTI than the low MTI site. No statistically significant association of IgA with protection was found in exploratory analyses.

CONCLUSIONS

RTS,S/AS01 induces IgA responses in peripheral blood against CSP vaccine antigens and other P. falciparum vaccine-unrelated antigens, similar to what we previously showed for IgG responses. Collectively, data warrant further investigation of the potential contribution of vaccine-induced IgA responses to efficacy and any possible interplay, either synergistic or antagonistic, with protective IgG, as identifying mediators of protection by RTS,S/AS01 immunization is necessary for the design of improved second-generation vaccines.

CLINICAL TRIAL REGISTRATION

ClinicalTrials.gov: NCT008666191.

摘要

背景

传统上，评估 RTS,S/AS01 的免疫应答主要集中在与保护作用仅有中度相关性的免疫球蛋白 (Ig) G 抗体上。其他可能有助于疫苗效力的抗体同种型的作用尚不清楚。在这里，我们研究了 RTS,S/AS01 是否会引起针对疫苗和其他疟疾抗原的抗原特异性血清 IgA 抗体，并探讨了它们与保护作用的关联。

方法

从 RTS,S/AS01 三期临床试验中选择了 95 名年龄在 5-17 个月（第一次接种时）的儿童，在初次免疫接种后 1 个月进行 IgA 定量检测。包括两个疟疾传播强度 (MTI) 和临床疟疾病例和对照不同的地点。使用定量悬浮阵列测定法测量针对环子孢子蛋白 (CSP) 疫苗抗原的不同结构和 16 种与疫苗无关的恶性疟原虫抗原的 IgA。

结果

RTS,S 疫苗接种可使血清/血浆 IgA 抗体对所有 CSP 结构的水平增加 1.2 至 2 倍，而用对照疫苗免疫则不会发生这种情况。接种疫苗后，16 种与疫苗无关的恶性疟原虫抗原中的 13 种的 IgA 反应也增加，而 RTS,S 的接受者比对照者的水平更高。接种疫苗前，高 MTI 地点的疟疾抗原的 IgA 水平比低 MTI 地点的更高。在探索性分析中，未发现 IgA 与保护之间存在统计学显著关联。

结论

RTS,S/AS01 在周围血液中诱导针对 CSP 疫苗抗原和其他恶性疟原虫疫苗无关抗原的 IgA 反应，与我们之前对 IgG 反应的观察结果相似。数据表明，需要进一步研究疫苗诱导的 IgA 反应对疗效的潜在贡献，以及与保护性 IgG 的任何可能相互作用，无论是协同作用还是拮抗作用，因为鉴定 RTS,S/AS01 免疫接种的保护作用的介导物对于设计改进的第二代疫苗是必要的。