Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Cell Rep. 2020 Mar 17;30(11):3755-3765.e7. doi: 10.1016/j.celrep.2020.02.061.
Rational immunogen design aims to focus antibody responses to vulnerable sites on primary antigens. Given the size of these antigens, there is, however, potential for eliciting unwanted, off-target responses. Here, we use our electron microscopy polyclonal epitope mapping approach to describe the antibody specificities elicited by immunization of non-human primates with soluble HIV envelope trimers and subsequent repeated viral challenge. An increased diversity of epitopes recognized and the approach angle by which these antibodies bind constitute a hallmark of the humoral response in most protected animals. We also show that fusion peptide-specific antibodies are likely responsible for some neutralization breadth. Moreover, cryoelectron microscopy (cryo-EM) analysis of a fully protected animal reveals a high degree of clonality within a subset of putatively neutralizing antibodies, enabling a detailed molecular description of the antibody paratope. Our results provide important insights into the immune response against a vaccine candidate that entered into clinical trials in 2019.
理性免疫原设计旨在将抗体反应集中在主要抗原的脆弱部位。然而，由于这些抗原的体积较大，有可能引发不需要的、针对非目标的反应。在这里，我们使用电子显微镜多克隆表位作图方法来描述用可溶性 HIV 包膜三聚体免疫接种非人类灵长类动物并随后进行反复病毒挑战所引起的抗体特异性。识别的表位多样性增加以及这些抗体结合的角度构成了大多数受保护动物体液免疫反应的标志。我们还表明，融合肽特异性抗体可能负责一些中和广度。此外，对完全受保护动物的冷冻电镜 (cryo-EM) 分析揭示了一组假定具有中和作用的抗体中存在高度的克隆性，从而能够对抗体结合位进行详细的分子描述。我们的研究结果为 2019 年进入临床试验的候选疫苗的免疫反应提供了重要的见解。
