School of Public Health & School of Basic Medicine Sciences, Hengyang Medical School & Ministry of Education Key Laboratory of Rare Pediatric Diseases, University of South China, Hengyang, China.
Translational Medicine Institute, The First People's Hospital of Chenzhou, Hengyang Medical School, University of South China, Chenzhou, China.
Front Immunol. 2024 Feb 14;15:1355949. doi: 10.3389/fimmu.2024.1355949. eCollection 2024.
Since December 2019, the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) has presented considerable public health challenges. Multiple vaccines have been used to induce neutralizing antibodies (nAbs) and memory B-cell responses against the viral spike (S) glycoprotein, and many essential epitopes have been defined. Previous reports have identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike-reactive naïve B cells and preexisting memory B cells in unexposed individuals. However, the role of these spike-reactive B cells in vaccine-induced immunity remains unknown.
To elucidate the characteristics of preexisting SARS-CoV-2 S-reactive B cells as well as their maturation after antigen encounter, we assessed the relationship of spike-reactive B cells before and after vaccination in unexposed human individuals. We further characterized the sequence identity, targeting domain, broad-spectrum binding activity and neutralizing activity of these SARS-CoV-2 S-reactive B cells by isolating monoclonal antibodies (mAbs) from these B cells.
The frequencies of both spike-reactive naïve B cells and preexisting memory B cells before vaccination correlated with the frequencies of spike-reactive memory B cells after vaccination. Isolated mAbs from spike-reactive naïve B cells before vaccination had fewer somatic hypermutations (SHMs) than mAbs isolated from spike-reactive memory B cells before and after vaccination, but bound SARS-CoV-2 spike . Intriguingly, these germline-like mAbs possessed broad binding profiles for SARS-CoV-2 and its variants, although with low or no neutralizing capacity. According to tracking of the evolution of IGHV4-4/IGKV3-20 lineage antibodies from a single donor, the lineage underwent SHMs and developed increased binding activity after vaccination.
Our findings suggest that spike-reactive naïve B cells can be expanded and matured by vaccination and cocontribute to vaccine-elicited antibody responses with preexisting memory B cells. Selectively and precisely targeting spike-reactive B cells by rational antigen design may provide a novel strategy for next-generation SARS-CoV-2 vaccine development.
自 2019 年 12 月以来，严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）的出现导致了 2019 年冠状病毒病（COVID-19），这给公共卫生带来了巨大挑战。已经使用多种疫苗来诱导针对病毒刺突（S）糖蛋白的中和抗体（nAbs）和记忆 B 细胞反应，并且已经定义了许多重要的表位。先前的报告已经确定了在未暴露个体中存在严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）刺突反应性幼稚 B 细胞和预先存在的记忆 B 细胞。然而，这些刺突反应性 B 细胞在疫苗诱导的免疫中的作用尚不清楚。
为了阐明预先存在的 SARS-CoV-2 S 反应性 B 细胞的特征以及它们在抗原接触后的成熟情况，我们评估了未暴露个体中疫苗接种前后刺突反应性 B 细胞之间的关系。我们通过从这些 B 细胞中分离单克隆抗体（mAbs），进一步表征了这些 SARS-CoV-2 S 反应性 B 细胞的序列同一性、靶向域、广谱结合活性和中和活性。
疫苗接种前刺突反应性幼稚 B 细胞和预先存在的记忆 B 细胞的频率与疫苗接种后刺突反应性记忆 B 细胞的频率相关。疫苗接种前从刺突反应性幼稚 B 细胞中分离出的 mAbs 的体细胞超突变（SHMs）少于疫苗接种前和接种后的刺突反应性记忆 B 细胞中分离出的 mAbs，但与 SARS-CoV-2 刺突结合。有趣的是，这些类似原始的 mAbs 具有针对 SARS-CoV-2 及其变体的广泛结合谱，尽管结合能力低或没有中和能力。根据对来自单个供体的 IGHV4-4/IGKV3-20 谱系抗体的进化跟踪，该谱系在接种疫苗后经历了 SHMs 并发展出了更高的结合活性。
我们的研究结果表明，刺突反应性幼稚 B 细胞可以通过疫苗接种而被扩增和成熟，并与预先存在的记忆 B 细胞共同促进疫苗诱导的抗体反应。通过合理的抗原设计选择性和精确地靶向刺突反应性 B 细胞可能为下一代 SARS-CoV-2 疫苗的开发提供一种新策略。
