美国斯克里普斯研究所William R. Schief，Shane Crotty，Ian A. Wilson和美国哈佛大学Facundo D. Batista合作取得重要工作进展。他们研究提出，疫苗接种可诱导广泛中和的HIV gp41抗体前体。相关研究成果2024年5月30日在线发表于《自然—免疫学》杂志上。

据介绍，开发诱导针对人类免疫缺陷病毒（HIV）和其他高抗原多样性病毒的广泛中和抗体（bnAb）的疫苗的一个关键障碍是，设计诱导罕见bnAb前体B细胞的启动免疫原。HIV bnAb 10E8的高中和广度使得10E8类bnAb的激发是可取的，然而，gp41内凹陷的表位使包膜三聚体成为较差的起始免疫原，并要求10E8类bnAb具有长的重链互补决定区3（HCDR3）和特定的结合基团。

研究人员开发了对10E8类前体具有亲和力的种系靶向表位支架和用于多价展示的工程纳米颗粒。支架在离体筛选中表现出表位结构模拟并结合bnAb前体的人类幼稚B细胞，蛋白质纳米颗粒在严格的小鼠模型和恒河猴中诱导bnAb前体反应，mRNA编码的纳米颗粒在小鼠中引发类似反应。因此，种系靶向表位支架纳米颗粒可以诱导，具有预定义结合特异性和HCDR3特征的罕见bnAb前体B细胞。

附：英文原文

Title: Vaccination induces broadly neutralizing antibody precursors to HIV gp41

Author: Schiffner, Torben, Phung, Ivy, Ray, Rashmi, Irimia, Adriana, Tian, Ming, Swanson, Olivia, Lee, Jeong Hyun, Lee, Chang-Chun D., Marina-Zrate, Ester, Cho, So Yeon, Huang, Jiachen, Ozorowski, Gabriel, Skog, Patrick D., Serra, Andreia M., Rantalainen, Kimmo, Allen, Joel D., Baboo, Sabyasachi, Rodriguez, Oscar L., Himansu, Sunny, Zhou, Jianfu, Hurtado, Jonathan, Flynn, Claudia T., McKenney, Katherine, Havenar-Daughton, Colin, Saha, Swati, Shields, Kaitlyn, Schulze, Steven, Smith, Melissa L., Liang, Chi-Hui, Toy, Laura, Pecetta, Simone, Lin, Ying-Cing, Willis, Jordan R., Sesterhenn, Fabian, Kulp, Daniel W., Hu, Xiaozhen, Cottrell, Christopher A., Zhou, Xiaoya, Ruiz, Jennifer, Wang, Xuesong, Nair, Usha, Kirsch, Kathrin H., Cheng, Hwei-Ling, Davis, Jillian, Kalyuzhniy, Oleksandr, Liguori, Alessia, Diedrich, Jolene K.

Issue&Volume: 2024-05-30

Abstract: A key barrier to the development of vaccines that induce broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV) and other viruses of high antigenic diversity is the design of priming immunogens that induce rare bnAb-precursor B cells. The high neutralization breadth of the HIV bnAb 10E8 makes elicitation of 10E8-class bnAbs desirable; however, the recessed epitope within gp41 makes envelope trimers poor priming immunogens and requires that 10E8-class bnAbs possess a long heavy chain complementarity determining region 3 (HCDR3) with a specific binding motif. We developed germline-targeting epitope scaffolds with affinity for 10E8-class precursors and engineered nanoparticles for multivalent display. Scaffolds exhibited epitope structural mimicry and bound bnAb-precursor human naive B cells in ex vivo screens, protein nanoparticles induced bnAb-precursor responses in stringent mouse models and rhesus macaques, and mRNA-encoded nanoparticles triggered similar responses in mice. Thus, germline-targeting epitope scaffold nanoparticles can elicit rare bnAb-precursor B cells with predefined binding specificities and HCDR3 features.

DOI: 10.1038/s41590-024-01833-w

Source: https://www.nature.com/articles/s41590-024-01833-w