生发中心
抗体
亲和力成熟
B细胞
病毒学
生物
信使核糖核酸
免疫学
细胞生物学
基因
遗传学
作者
Xuesong Wang,Christopher A. Cottrell,Xiaozhen Hu,Rashmi Ray,Maria Bottermann,Paula Maldonado Villavicencio,Yu Yan,Zhenfei Xie,John E. Warner,Jordan Renae Ellis-Pugh,Oleksandr Kalyuzhniy,Alessia Liguori,Jordan R. Willis,Sergey Menis,Sebastian Rämisch,Saman Eskandarzadeh,Michael Kubitz,Ryan Tingle,Nicole Phelps,Bettina Gröschel
出处
期刊:Science immunology
[American Association for the Advancement of Science]
日期:2024-05-10
卷期号:9 (95)
被引量:7
标识
DOI:10.1126/sciimmunol.adn0622
摘要
Germline-targeting (GT) protein immunogens to induce VRC01-class broadly neutralizing antibodies (bnAbs) to the CD4-binding site of the HIV envelope (Env) have shown promise in clinical trials. Here, we preclinically validated a lipid nanoparticle-encapsulated nucleoside mRNA (mRNA-LNP) encoding eOD-GT8 60mer as a soluble self-assembling nanoparticle in mouse models. In a model with three humanized B cell lineages bearing distinct VRC01-precursor B cell receptors (BCRs) with similar affinities for eOD-GT8, all lineages could be simultaneously primed and undergo diversification and affinity maturation without exclusionary competition. Boosts drove precursor B cell participation in germinal centers; the accumulation of somatic hypermutations, including in key VRC01-class positions; and affinity maturation to boost and native-like antigens in two of the three precursor lineages. We have preclinically validated a prime-boost regimen of soluble self-assembling nanoparticles encoded by mRNA-LNP, demonstrating that multiple lineages can be primed, boosted, and diversified along the bnAb pathway.
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