Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
Sci Transl Med. 2018 Jul 4;10(448). doi: 10.1126/scitranslmed.aat0381.
Traditional vaccine development to prevent some of the worst current pandemic diseases has been unsuccessful so far. Germline-targeting immunogens have potential to prime protective antibodies (Abs) via more targeted immune responses. Success of germline-targeting vaccines in humans will depend on the composition of the human naive B cell repertoire, including the frequencies and affinities of epitope-specific B cells. However, the human naive B cell repertoire remains largely undefined. Assessment of antigen-specific human naive B cells among hundreds of millions of B cells from multiple donors may be used as pre-phase 1 ex vivo human testing to potentially forecast B cell and Ab responses to new vaccine designs. VRC01 is an HIV broadly neutralizing Ab (bnAb) against the envelope CD4-binding site (CD4bs). We characterized naive human B cells recognizing eOD-GT8, a germline-targeting HIV-1 vaccine candidate immunogen designed to prime VRC01-class Abs. Several distinct subclasses of VRC01-class naive B cells were identified, sharing sequence characteristics with inferred precursors of known bnAbs VRC01, VRC23, PCIN63, and N6. Multiple naive B cell clones exactly matched mature VRC01-class bnAb L-CDR3 sequences. Non-VRC01-class B cells were also characterized, revealing recurrent public light chain sequences. Unexpectedly, we also identified naive B cells related to the IOMA-class CD4bs bnAb. These different subclasses within the human repertoire had strong initial affinities () to the immunogen, up to 13 nM, and represent encouraging indications that multiple independent pathways may exist for vaccine-elicited VRC01-class bnAb development in most individuals. The frequencies of these distinct eOD-GT8 B cell specificities give insights into antigen-specific compositional features of the human naive B cell repertoire and provide actionable information for vaccine design and advancement.
传统的疫苗开发旨在预防一些目前最严重的大流行病,但迄今为止一直未能成功。种系靶向免疫原有可能通过更靶向的免疫反应来引发保护性抗体 (Ab)。种系靶向疫苗在人类中的成功将取决于人类原始 B 细胞库的组成,包括表位特异性 B 细胞的频率和亲和力。然而,人类原始 B 细胞库在很大程度上仍未得到定义。从多个供体的数亿个 B 细胞中评估抗原特异性人类原始 B 细胞,可作为前 1 期体外人体测试,潜在预测新疫苗设计的 B 细胞和 Ab 反应。VRC01 是一种针对包膜 CD4 结合位点 (CD4bs) 的 HIV 广泛中和抗体 (bnAb)。我们鉴定了能够识别 eOD-GT8 的原始人类 B 细胞,eOD-GT8 是一种种系靶向 HIV-1 疫苗候选免疫原,旨在引发 VRC01 类 Ab。确定了几种不同的 VRC01 类原始 B 细胞亚类,它们与已知 bnAbs VRC01、VRC23、PCIN63 和 N6 的推断前体具有序列特征。多个原始 B 细胞克隆与成熟的 VRC01 类 bnAb L-CDR3 序列完全匹配。还对非 VRC01 类 B 细胞进行了鉴定,揭示了反复出现的公共轻链序列。出乎意料的是,我们还鉴定了与 IOMA 类 CD4bs bnAb 相关的原始 B 细胞。人类库中这些不同的亚类对免疫原具有强烈的初始亲和力 (),最高可达 13 nM,这表明在大多数个体中,疫苗引发 VRC01 类 bnAb 发展可能存在多种独立途径,这是令人鼓舞的迹象。这些不同的 eOD-GT8 B 细胞特异性的频率提供了人类原始 B 细胞库的抗原特异性组成特征的深入了解,并为疫苗设计和推进提供了可行的信息。
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