Centre for Geographic Medicine Research (Coast), Kenya Medical Research Institute, Wellcome Trust Research Programme, Kilifi, Kenya.
Centre for translational Medicine & Parasitology, Department of Immunology and Microbiology, University of Copenhagen and Department of Infectious Diseases, Righospitalet, Copenhagen, Denmark.
J Infect. 2024 Oct;89(4):106252. doi: 10.1016/j.jinf.2024.106252. Epub 2024 Aug 23.
Acquisition of antibodies to Plasmodium falciparum variant surface antigens (VSA) expressed on infected red blood cells (iRBCs) is associated with naturally acquired immunity to malaria. We have previously shown that antibodies to VSA on iRBCs are associated with protection against parasite growth in the context of controlled human malaria infection (CHMI). This study explored whether antibodies to recombinant antigens derived from PfEMP1 domains were independently associated with protection during CHMI in semi-immune Kenyan adults.
We used a multiplex bead assay to measure levels of IgG antibody against a panel of 27 recombinant PfEMP1 antigens derived from the PfEMP1 repertoire of the 3D7 parasite clone. We measured IgG levels in plasma samples collected from the CHMI participants before inoculation with Sanaria® PfSPZ Challenge, on the day of diagnosis, and 35 days post-inoculation. Univariable and multivariable Cox regression analysis was used to evaluate the relationship between the levels of antibodies to the antigens and CHMI outcome. We also adjusted for previous data including antibodies to VSA on iRBCs, and we assessed the kinetics of antibody acquisition to the different PfEMP1 recombinant antigens over time.
All study participants had detectable antibodies to multiple PfEMP1 proteins before inoculation. All PfEMP1 antigens were associated with protection against parasite growth to the threshold criteria for treatment in CHMI, albeit with substantial collinearity. However, individual PfEMP1 antigens were not independently associated with protection following adjustment for breadth of reactivity to VSA on iRBCs and schizont extract. In addition, antibodies to PfEMP1 antigens derived from group B PfEMP1 were induced and sustained in the participants who could not control parasite growth.
This study shows that the breadth of antibody response to VSA on iRBCs, and not to specific PfEMP1 antigens, is predictive of protection against malaria in CHMI.
感染红细胞（iRBC）上表达的恶性疟原虫变异表面抗原（VSA）的抗体的获得与疟疾的自然获得性免疫有关。我们之前已经表明，iRBC 上的 VSA 抗体与控制人体疟疾感染（CHMI）背景下寄生虫生长的保护有关。本研究探讨了在半免疫肯尼亚成年人的 CHMI 中，源自 PfEMP1 结构域的重组抗原的抗体是否与保护作用独立相关。
我们使用多指标珠状分析来测量针对 3D7 寄生虫克隆 PfEMP1 库中 27 种重组 PfEMP1 抗原的 IgG 抗体的水平。我们在接种 Sanaria® PfSPZ 挑战之前、诊断日和接种后 35 天，从 CHMI 参与者的血浆样本中测量 IgG 水平。单变量和多变量 Cox 回归分析用于评估针对抗原的抗体水平与 CHMI 结果之间的关系。我们还调整了以前的数据，包括 iRBC 上的 VSA 抗体，并评估了随着时间的推移对不同 PfEMP1 重组抗原的抗体获得的动力学。
所有研究参与者在接种前均能检测到针对多种 PfEMP1 蛋白的抗体。所有 PfEMP1 抗原均与 CHMI 中治疗阈值标准的寄生虫生长保护有关，尽管存在大量的共线性。然而，在调整针对 iRBC 上 VSA 和裂殖体提取物的反应广度后，单个 PfEMP1 抗原与保护作用无关。此外，无法控制寄生虫生长的参与者中诱导并维持了源自 B 组 PfEMP1 的 PfEMP1 抗原的抗体。
本研究表明，iRBC 上 VSA 抗体的反应广度，而不是特定 PfEMP1 抗原，是预测 CHMI 中疟疾保护的指标。
