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.

中文翻译：

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mRNA-LNP 初免加强在临床前人源化小鼠模型中将前体进化为类似 VRC01 的广泛中和抗体


种系靶向 (GT) 蛋白免疫原可诱导 VRC01 类广泛中和抗体 (bnAb) 至 HIV 包膜 (Env) 的 CD4 结合位点，这在临床试验中已显示出前景。在这里，我们在小鼠模型中对编码 eOD-GT8 60mer 的脂质纳米颗粒封装的核苷 mRNA (mRNA-LNP) 作为可溶性自组装纳米颗粒进行了临床前验证。在具有对 eOD-GT8 具有相似亲和力的三个人源化 B 细胞谱系的模型中，所有谱系都可以同时启动并经历多样化和亲和力成熟，而无需排他性竞争。 Boosts 促进前体 B 细胞参与生发中心；体细胞超突变的积累，包括关键的 VRC01 级位置；以及在三个前体谱系中的两个中对增强抗原和天然样抗原的亲和力成熟。我们已经在临床前验证了由 mRNA-LNP 编码的可溶性自组装纳米颗粒的初免-加强方案，证明多个谱系可以沿着 bnAb 途径进行初免、加强和多样化。