A human antibody epitope map of Pfs230D1 derived from analysis of individuals vaccinated with a malaria transmission-blocking vaccine.
A human antibody epitope map of Pfs230D1 derived from analysis of individuals vaccinated with a malaria transmission-blocking vaccine.
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DOI：
10.1016/j.immuni.2023.01.012
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发表时间：
2023-02
期刊：
影响因子：
32.4
通讯作者：
W. Tang;C. Coelho;K. Miura;Bergeline C. Nguemwo Tentokam;N. Salinas;D. Narum;S. Healy;I. Sagara;C. Long;P. Duffy;N. Tolia
中科院分区：
文献类型：
--
作者：
W. Tang;C. Coelho;K. Miura;Bergeline C. Nguemwo Tentokam;N. Salinas;D. Narum;S. Healy;I. Sagara;C. Long;P. Duffy;N. Tolia
Pfs230结构域1（Pfs230D1）是一种晚期疟疾传播阻断疫苗抗原，在临床试验中表现出高功能活性。然而，结构和功能相关的传输阻塞活动没有定义。在这里，我们的特点是一组人单克隆抗体（hmAbs）引起的疫苗免疫与Pfs230D1。这些hmAbs表现出不同的传输减少活性，但都结合到Pfs230D1与纳摩尔亲和力。我们汇编了17种hmAbs的表位分组数据和9种hmAbs复合物的结构，以构建高分辨率表位图谱，并揭示了有效的减少传输的hmAbs结合到Pfs230D1的一面，而非有效的hmAbs结合到相反的一面。Pfs230D1D2的结构揭示了第二结构域封闭了非有效的减少传播的表位。hmAb表位图描绘了二元hmAb组合，其协同作用具有极高的效力，减少传播的活性。这项工作为增强型免疫原的基于结构的设计提供了高分辨率的指导，并为测量减少传播反应的诊断提供了信息。
Pfs230 domain 1 (Pfs230D1) is an advanced malaria transmission-blocking vaccine antigen demonstrating high functional activity in clinical trials. However, the structural and functional correlates of transmission-blocking activity are not defined. Here, we characterized a panel of human monoclonal antibodies (hmAbs) elicited in vaccinees immunized with Pfs230D1. These hmAbs exhibited diverse transmission-reducing activity, yet all bound to Pfs230D1 with nanomolar affinity. We compiled epitope-binning data for seventeen hmAbs and structures of nine hmAbs complexes to construct a high-resolution epitope map and revealed that potent transmission-reducing hmAbs bound to one face of Pfs230D1, while non-potent hmAbs bound to the opposing side. The structure of Pfs230D1D2 revealed that non-potent transmission-reducing epitopes were occluded by the second domain. The hmAb epitope map delineated binary hmAb combinations that synergized for extremely high-potency, transmission-reducing activity. This work provides a high-resolution guide for structure-based design of enhanced immunogens and informs diagnostics that measure the transmission-reducing response.