Germline-targeting (GT) HIV vaccine strategies are predicated on deriving broadly neutralizing antibodies (bnAbs) through multiple boost immunogens. However, as the recruitment of memory B cells (MBCs) to germinal centers (GCs) is inefficient and may be derailed by serum antibody–induced epitope masking, driving further B cell receptor (BCR) modification in GC-experienced B cells after boosting poses a challenge. Using humanized immunoglobulin knockin mice, we found that GT protein trimer immunogen N332-GT5 could prime inferred-germline precursors to the V3-glycan–targeted bnAb BG18 and that B cells primed by N332-GT5 were effectively boosted by either of two novel protein immunogens designed to have minimum cross-reactivity with the off-target V1-binding responses. The delivery of the prime and boost immunogens as messenger RNA lipid nanoparticles (mRNA-LNPs) generated long-lasting GCs, somatic hypermutation, and affinity maturation and may be an effective tool in HIV vaccine development.

中文翻译：

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mRNA-LNP HIV-1 三聚体增强剂引发广泛中和抗体的前体


种系靶向 (GT) HIV 疫苗策略的基础是通过多种加强免疫原产生广泛中和抗体 (bnAb)。然而，由于记忆 B 细胞 (MBC) 向生发中心 (GC) 的募集效率低下，并且可能会因血清抗体诱导的表位掩蔽而脱轨，因此在加强姿势后，会推动经历过 GC 的 B 细胞进一步发生 B 细胞受体 (BCR) 修饰一个挑战。使用人源化免疫球蛋白敲入小鼠，我们发现 GT 蛋白三聚体免疫原 N332-GT5 可以引发 V3-聚糖靶向 bnAb BG18 的推断种系前体，并且由 N332-GT5 引发的 B 细胞可以通过两种新型蛋白免疫原中的任何一种有效增强旨在与脱靶 V1 结合反应具有最小的交叉反应性。作为信使 RNA 脂质纳米粒子 (mRNA-LNP) 传递初免和加强免疫原可产生持久的 GC、体细胞超突变和亲和力成熟，可能是 HIV 疫苗开发的有效工具。