Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Brigham and Women's Hospital, Boston, Massachusetts, USA.
mBio. 2022 Aug 30;13(4):e0157722. doi: 10.1128/mbio.01577-22. Epub 2022 Jun 28.
Persistent SARS-CoV-2 replication and systemic dissemination are linked to increased COVID-19 disease severity and mortality. However, the precise immune profiles that track with enhanced viral clearance, particularly from systemic RNAemia, remain incompletely defined. To define whether antibody characteristics, specificities, or functions that emerge during natural infection are linked to accelerated containment of viral replication, we examined the relationship of SARS-CoV-2-specific humoral immune evolution in the setting of SARS-CoV-2 plasma RNAemia, which is tightly associated with disease severity and death. On presentation to the emergency department, S-specific IgG3, IgA1, and Fc-γ-receptor (Fcγ R) binding antibodies were all inversely associated with higher baseline plasma RNAemia. Importantly, the rapid development of spike (S) and its subunit (S1/S2/receptor binding domain)-specific IgG, especially FcγR binding activity, were associated with clearance of RNAemia. These results point to a potentially critical and direct role for SARS-CoV-2-specific humoral immune clearance on viral dissemination, persistence, and disease outcome, providing novel insights for the development of more effective therapeutics to resolve COVID-19. We showed that persistent SARS-CoV-2 RNAemia is an independent predictor of severe COVID-19. We observed that SARS-CoV-2-targeted antibody maturation, specifically Fc-effector functions rather than neutralization, was strongly linked with the ability to rapidly clear viremia. This highlights the critical role of key humoral features in preventing viral dissemination or accelerating viremia clearance and provides insights for the design of next-generation monoclonal therapeutics. The main key points will be that (i) persistent SARS-CoV-2 plasma RNAemia independently predicts severe COVID-19 and (ii) specific humoral immune functions play a critical role in halting viral dissemination and controlling COVID-19 disease progression.
持续性 SARS-CoV-2 复制和系统性传播与 COVID-19 疾病严重程度和死亡率的增加有关。然而，确切的免疫特征与增强的病毒清除相关，特别是从系统性 RNAemia 中，仍然不完全明确。为了确定在自然感染过程中出现的抗体特征、特异性或功能是否与加速病毒复制的控制有关，我们研究了 SARS-CoV-2 特异性体液免疫进化与 SARS-CoV-2 血浆 RNAemia 的关系，SARS-CoV-2 血浆 RNAemia 与疾病严重程度和死亡密切相关。在急诊科就诊时，S 特异性 IgG3、IgA1 和 Fc-γ-受体 (FcγR) 结合抗体均与较高的基线血浆 RNAemia 呈负相关。重要的是，刺突 (S) 及其亚基 (S1/S2/受体结合域) 特异性 IgG 的快速发展，特别是 FcγR 结合活性，与 RNAemia 的清除有关。这些结果表明 SARS-CoV-2 特异性体液免疫清除在病毒传播、持续存在和疾病结局中具有潜在的关键和直接作用，为开发更有效的治疗方法以解决 COVID-19 提供了新的见解。我们表明，持续性 SARS-CoV-2 RNAemia 是严重 COVID-19 的独立预测因子。我们观察到，针对 SARS-CoV-2 的抗体成熟，特别是 Fc 效应功能而不是中和作用，与迅速清除病毒血症的能力密切相关。这突出了关键体液特征在阻止病毒传播或加速病毒血症清除中的关键作用，并为下一代单克隆治疗药物的设计提供了思路。主要要点将是：（i）持续性 SARS-CoV-2 血浆 RNAemia 独立预测严重 COVID-19，（ii）特定的体液免疫功能在阻止病毒传播和控制 COVID-19 疾病进展中起着关键作用。
