Li Chuang, Yu Jie, Issa Rahma, Wang Lili, Ning Mingzhe, Yin Shengxia, Li Jie, Wu Chao, Chen Yuxin
Department of Laboratory Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, People's Republic of China.
Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, People's Republic of China.
Emerg Microbes Infect. 2025 Dec;14(1):2434567. doi: 10.1080/22221751.2024.2434567. Epub 2025 Jan 13.
Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants raise concerns about decreased vaccine efficacy, vaccines continue to confer robust protection in humans, implying that immunity beyond neutralization contributes to vaccine efficacy. In addition to neutralization, antibodies can mediate various Fc-dependent effector functions, including antibody-dependent cellular phagocytosis (ADCP), antibody-dependent neutrophil phagocytosis (ADNP) and antibody-dependent cellular cytotoxicity (ADCC). However, the specific role of each Fc-mediated effector function in contributing to COVID-19 disease attenuation in human remains unclear. To fully define the potential immune correlates of Fc-mediated effector functions, we comprehensively analysed the above Fc-mediated effector functions in two study cohorts. In the CoronaVac vaccinee cohort, individuals without breakthrough infection exhibited higher levels of ADCP and ADNP activities with a greater degree of cross-reactivity compared to those who had breakthrough infection. A predictive model was established incorporating ADNP activity and IgG titre, achieving an area under the curve (AUC) of 0.837. In the COVID-19 patient cohort, BA.5-specific ADCP and ADNP responses were significantly reduced in COVID-19 patients with fatal outcomes compared to milder outcomes. The prognostic model incorporating WT, BA.5, and XBB.1.5 spike-specific ADNP demonstrated effective predictive ability, achieving an AUC of 0.890. Meanwhile, transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) from COVID-19 patients in the acute phases of infection highlighted remarkably upregulation of neutrophil activity and phagocytic function, further reinforcing the essential role of ADNP. Collectively, our findings underscored Fc-mediated effector activities, especially neutrophil phagocytosis, as significant antibody biomarkers for the risk of SARS-CoV-2 breakthrough infection and COVID-19 prognosis.
尽管严重急性呼吸综合征冠状病毒2（SARS-CoV-2）变种引发了对疫苗效力下降的担忧，但疫苗在人类中仍能提供强大的保护，这意味着中和作用之外的免疫力有助于疫苗效力。除中和作用外，抗体还可介导多种Fc依赖性效应功能，包括抗体依赖性细胞吞噬作用（ADCP）、抗体依赖性中性粒细胞吞噬作用（ADNP）和抗体依赖性细胞毒性（ADCC）。然而，每种Fc介导的效应功能在减轻人类COVID-19疾病方面的具体作用仍不清楚。为了全面定义Fc介导的效应功能的潜在免疫相关性，我们在两个研究队列中全面分析了上述Fc介导的效应功能。在科兴疫苗接种者队列中，与发生突破性感染的个体相比，未发生突破性感染的个体表现出更高水平的ADCP和ADNP活性，且交叉反应程度更高。建立了一个纳入ADNP活性和IgG滴度的预测模型，曲线下面积（AUC）为0.837。在COVID-19患者队列中，与症状较轻的患者相比，出现致命结果的COVID-19患者中BA.5特异性ADCP和ADNP反应显著降低。纳入野生型、BA.5和XBB.1.5刺突特异性ADNP的预后模型显示出有效的预测能力，AUC为0.890。同时，对感染急性期COVID-19患者外周血单个核细胞（PBMC）的转录组分析突出显示中性粒细胞活性和吞噬功能显著上调，进一步强化了ADNP的重要作用。总体而言，我们的研究结果强调了Fc介导的效应活性，尤其是中性粒细胞吞噬作用，是SARS-CoV-2突破性感染风险和COVID-19预后的重要抗体生物标志物。
