Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford OX1 3QU, UK; The Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK.
Centre for Medicines Discovery, University of Oxford, Oxford OX3 7FZ, UK.
Cell. 2024 Sep 5;187(18):4964-4980.e21. doi: 10.1016/j.cell.2024.06.015. Epub 2024 Jul 25.
The highly conserved and essential Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) has emerged as the leading target for vaccines against the disease-causing blood stage of malaria. However, the features of the human vaccine-induced antibody response that confer highly potent inhibition of malaria parasite invasion into red blood cells are not well defined. Here, we characterize 236 human IgG monoclonal antibodies, derived from 15 donors, induced by the most advanced PfRH5 vaccine. We define the antigenic landscape of this molecule and establish that epitope specificity, antibody association rate, and intra-PfRH5 antibody interactions are key determinants of functional anti-parasitic potency. In addition, we identify a germline IgG gene combination that results in an exceptionally potent class of antibody and demonstrate its prophylactic potential to protect against P. falciparum parasite challenge in vivo. This comprehensive dataset provides a framework to guide rational design of next-generation vaccines and prophylactic antibodies to protect against blood-stage malaria.
高度保守且必需的恶性疟原虫血影蛋白同源物 5（PfRH5）已成为针对疟疾致病血期的疫苗的主要靶标。然而，赋予疟疾寄生虫入侵红细胞的高效抑制作用的人类疫苗诱导的抗体反应的特征尚未很好地定义。在这里，我们描述了由 15 位供体诱导的来自 PfRH5 疫苗的最先进的 236 个人类 IgG 单克隆抗体。我们定义了该分子的抗原景观，并确定了表位特异性、抗体结合率和 PfRH5 内抗体相互作用是功能抗寄生虫效力的关键决定因素。此外，我们确定了一种导致异常强效抗体类别的免疫球蛋白基因组合，并证明了其在预防体内疟原虫寄生虫挑战方面的潜力。这个全面的数据集为指导下一代疫苗和预防性抗体的合理设计提供了一个框架，以预防血期疟疾。
