Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Sci Transl Med. 2021 Nov 24;13(621):eabk1533. doi: 10.1126/scitranslmed.abk1533.
Broadly neutralizing antibodies (bNAbs) against HIV-1 develop after prolonged virus and antibody coevolution. Previous studies showed that sequential immunization with a V3-glycan patch germline-targeting HIV-1 envelope trimer (Env) followed by variant Envs can reproduce this process in mice carrying V3-glycan bNAb precursor B cells. However, eliciting bNAbs in animals with polyclonal antibody repertoires is more difficult. We used a V3-glycan immunogen multimerized on virus-like particles (VLPs), followed by boosting with increasingly native-like Env-VLPs, to elicit heterologous neutralizing antibodies in nonhuman primates (NHPs). Structures of antibody/Env complexes after prime and boost vaccinations demonstrated target epitope recognition with apparent maturation to accommodate glycans. However, we also observed increasing off-target antibodies with boosting. Eight vaccinated NHPs were subsequently challenged with simian-human immunodeficiency virus (SHIV), and seven of eight animals became infected. The single NHP that remained uninfected after viral challenge exhibited one of the lowest neutralization titers against the challenge virus. These results demonstrate that more potent heterologous neutralization resulting from sequential immunization is necessary for protection in this animal model. Thus, improved prime-boost regimens to increase bNAb potency and stimulate other immune protection mechanisms are essential for developing anti–HIV-1 vaccines.
广谱中和抗体（bnAbs）在 HIV-1 病毒和抗体长时间共同进化后产生。先前的研究表明，在携带 V3 糖基 bnAb 前体 B 细胞的小鼠中，通过 V3 糖基 HIV-1 包膜三聚体（Env）的连续免疫接种和变体 Env 可重现这一过程。然而，在具有多克隆抗体库的动物中引发 bnAbs 更为困难。我们使用 V3 糖基免疫原多聚体化在病毒样颗粒（VLPs）上，然后用越来越接近天然的 Env-VLPs 加强，以在非人类灵长类动物（NHP）中引发异源中和抗体。初次和加强免疫接种后抗体/Env 复合物的结构表明，靶表位识别具有明显的成熟度，以适应糖基。然而，我们在加强时也观察到了越来越多的脱靶抗体。随后，8 只接种疫苗的 NHP 受到猴免疫缺陷病毒（SHIV）的挑战，其中 7 只动物感染。在病毒挑战后仍未感染的唯一一只 NHP 对挑战病毒的中和效价最低。这些结果表明，在这种动物模型中，通过连续免疫接种产生更有效的异源中和作用对于保护是必要的。因此，为提高 bnAb 效力并刺激其他免疫保护机制，改进初始-加强免疫方案对于开发抗 HIV-1 疫苗至关重要。
