人类免疫球蛋白基因等位基因变异影响靶向生殖系的疫苗启动。

Human immunoglobulin gene allelic variation impacts germline-targeting vaccine priming.

作者信息

deCamp Allan C, Corcoran Martin M, Fulp William J, Willis Jordan R, Cottrell Christopher A, Bader Daniel L V, Kalyuzhniy Oleksandr, Leggat David J, Cohen Kristen W, Hyrien Ollivier, Menis Sergey, Finak Greg, Ballweber-Fleming Lamar, Srikanth Abhinaya, Plyler Jason R, Rahaman Farhad, Lombardo Angela, Philiponis Vincent, Whaley Rachael E, Seese Aaron, Brand Joshua, Ruppel Alexis M, Hoyland Wesley, Mahoney Celia R, Cagigi Alberto, Taylor Alison, Brown David M, Ambrozak David R, Sincomb Troy, Mullen Tina-Marie, Maenza Janine, Kolokythas Orpheus, Khati Nadia, Bethony Jeffrey, Roederer Mario, Diemert David, Koup Richard A, Laufer Dagna S, McElrath Juliana M, McDermott Adrian B, Hedestam Gunilla B Karlsson, Schief William R

出版信息

medRxiv. 2023 Mar 15:2023.03.10.23287126. doi: 10.1101/2023.03.10.23287126.

DOI:10.1101/2023.03.10.23287126

PMID:36993183

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10055468/

Abstract

UNLABELLED

Vaccine priming immunogens that activate germline precursors for broadly neutralizing antibodies (bnAbs) have promise for development of precision vaccines against major human pathogens. In a clinical trial of the eOD-GT8 60mer germline-targeting immunogen, higher frequencies of vaccine-induced VRC01-class bnAb-precursor B cells were observed in the high dose compared to the low dose group. Through immunoglobulin heavy chain variable (IGHV) genotyping, statistical modeling, quantification of IGHV1-2 allele usage and B cell frequencies in the naive repertoire for each trial participant, and antibody affinity analyses, we found that the difference between dose groups in VRC01-class response frequency was best explained by IGHV1-2 genotype rather than dose and was most likely due to differences in IGHV1-2 B cell frequencies for different genotypes. The results demonstrate the need to define population-level immunoglobulin allelic variations when designing germline-targeting immunogens and evaluating them in clinical trials.

ONE-SENTENCE SUMMARY: Human genetic variation can modulate the strength of vaccine-induced broadly neutralizing antibody precursor B cell responses.

摘要

未标记

激活种系前体以产生广泛中和抗体（bnAbs）的疫苗启动免疫原有望用于开发针对主要人类病原体的精准疫苗。在一项针对eOD-GT8 60聚体种系靶向免疫原的临床试验中，与低剂量组相比，高剂量组中疫苗诱导的VRC01类bnAb前体B细胞频率更高。通过免疫球蛋白重链可变区（IGHV）基因分型、统计建模、对每个试验参与者的天然库中IGHV1-2等位基因使用情况和B细胞频率进行量化以及抗体亲和力分析，我们发现VRC01类反应频率在剂量组之间的差异最好由IGHV1-2基因型而非剂量来解释，并且很可能是由于不同基因型的IGHV1-2 B细胞频率存在差异。结果表明，在设计种系靶向免疫原并在临床试验中对其进行评估时，需要定义群体水平的免疫球蛋白等位基因变异。