de Jong Roos M, Meerstein-Kessel Lisette, Da Dari F, Nsango Sandrine, Challenger Joseph D, van de Vegte-Bolmer Marga, van Gemert Geert-Jan, Duarte Elias, Teyssier Noam, Sauerwein Robert W, Churcher Thomas S, Dabire Roch K, Morlais Isabelle, Locke Emily, Huynen Martijn A, Bousema Teun, Jore Matthijs M
Department of Medical Microbiology and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.
Center for Molecular and Biomolecular Informatics, Radboud University Medical Center, Nijmegen, The Netherlands.
NPJ Vaccines. 2021 Aug 12;6(1):101. doi: 10.1038/s41541-021-00366-9.
Malaria parasite transmission to mosquitoes relies on the uptake of sexual stage parasites during a blood meal and subsequent formation of oocysts on the mosquito midgut wall. Transmission-blocking vaccines (TBVs) and monoclonal antibodies (mAbs) target sexual stage antigens to interrupt human-to-mosquito transmission and may form important tools for malaria elimination. Although most epitopes of these antigens are considered highly conserved, little is known about the impact of natural genetic diversity on the functional activity of transmission-blocking antibodies. Here we measured the efficacy of three mAbs against leading TBV candidates (Pfs48/45, Pfs25 and Pfs230) in transmission assays with parasites from naturally infected donors compared to their efficacy against the strain they were raised against (NF54). Transmission-reducing activity (TRA) was measured as reduction in mean oocyst intensity. mAb 45.1 (α-Pfs48/45) and mAb 4B7 (α-Pfs25) reduced transmission of field parasites from almost all donors with IC values similar to NF54. Sequencing of oocysts that survived high mAb concentrations did not suggest enrichment of escape genotypes. mAb 2A2 (α-Pfs230) only reduced transmission of parasites from a minority of the donors, suggesting that it targets a non-conserved epitope. Using six laboratory-adapted strains, we revealed that mutations in one Pfs230 domain correlate with mAb gamete surface binding and functional TRA. Our findings demonstrate that, despite the conserved nature of sexual stage antigens, minor sequence variation can significantly impact the efficacy of transmission-blocking mAbs. Since mAb 45.1 shows high potency against genetically diverse strains, our findings support its further clinical development and may inform Pfs48/45 vaccine design.
疟原虫向蚊子的传播依赖于在吸食血液期间摄取有性阶段的寄生虫，以及随后在蚊子中肠壁上形成卵囊。传播阻断疫苗（TBV）和单克隆抗体（mAb）靶向有性阶段抗原以中断人到蚊子的传播，可能成为消除疟疾的重要工具。尽管这些抗原的大多数表位被认为高度保守，但关于自然遗传多样性对传播阻断抗体功能活性的影响却知之甚少。在这里，我们在传播试验中测量了三种单克隆抗体针对主要的传播阻断疫苗候选物（Pfs48/45、Pfs25和Pfs230）对来自自然感染供体的寄生虫的效力，并将其与针对其产生的菌株（NF54）的效力进行比较。传播减少活性（TRA）以平均卵囊强度的降低来衡量。单克隆抗体45.1（α-Pfs48/45）和单克隆抗体4B7（α-Pfs25）降低了几乎所有供体的野外寄生虫传播，其IC值与NF54相似。对在高浓度单克隆抗体中存活的卵囊进行测序并未表明逃逸基因型的富集。单克隆抗体2A2（α-Pfs230）仅降低了少数供体的寄生虫传播，表明它靶向一个非保守表位。使用六个实验室适应菌株，我们发现一个Pfs230结构域中的突变与单克隆抗体配子表面结合和功能性TRA相关。我们的研究结果表明，尽管有性阶段抗原具有保守性质，但微小的序列变异可显著影响传播阻断单克隆抗体的效力。由于单克隆抗体45.1对基因多样化菌株显示出高效力，我们的研究结果支持其进一步的临床开发，并可能为Pfs48/45疫苗设计提供信息。
