Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
Science. 2024 May 17;384(6697):eadj8321. doi: 10.1126/science.adj8321.
Germline-targeting immunogens hold promise for initiating the induction of broadly neutralizing antibodies (bnAbs) to HIV and other pathogens. However, antibody-antigen recognition is typically dominated by heavy chain complementarity determining region 3 (HCDR3) interactions, and vaccine priming of HCDR3-dominant bnAbs by germline-targeting immunogens has not been demonstrated in humans or outbred animals. In this work, immunization with N332-GT5, an HIV envelope trimer designed to target precursors of the HCDR3-dominant bnAb BG18, primed bnAb-precursor B cells in eight of eight rhesus macaques to substantial frequencies and with diverse lineages in germinal center and memory B cells. We confirmed bnAb-mimicking, HCDR3-dominant, trimer-binding interactions with cryo-electron microscopy. Our results demonstrate proof of principle for HCDR3-dominant bnAb-precursor priming in outbred animals and suggest that N332-GT5 holds promise for the induction of similar responses in humans.
种系靶向免疫原有望引发针对 HIV 和其他病原体的广泛中和抗体 (bnAb)。然而，抗体-抗原识别通常由重链互补决定区 3 (HCDR3)相互作用主导，种系靶向免疫原对 HCDR3 主导型 bnAb 的疫苗引发在人类或杂交动物中尚未得到证实。在这项工作中，用 N332-GT5 免疫接种，一种设计用于靶向 HCDR3 主导型 bnAb BG18 前体的 HIV 包膜三聚体，在 8 只恒河猴中的 8 只中引发了大量具有不同谱系的 bnAb 前体 B 细胞在生发中心和记忆 B 细胞中。我们通过冷冻电镜确认了 bnAb 模拟、HCDR3 主导、三聚体结合相互作用。我们的结果证明了在杂交动物中 HCDR3 主导型 bnAb 前体引发的原理，并表明 N332-GT5 有望在人类中诱导类似的反应。
