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 analyzed 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 titer, 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.

中文翻译：

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CoronaVac 诱导的抗体促进 Fc 介导的中性粒细胞吞噬作用，可跟踪 COVID-19 疾病的消退。


尽管严重急性呼吸系统综合症冠状病毒 2 （SARS-CoV-2） 变体引发了人们对疫苗效力降低的担忧，但疫苗继续为人类提供强有力的保护，这意味着中和以外的免疫力有助于提高疫苗效力。除了中和作用外，抗体还可以介导各种 Fc 依赖性效应子功能，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 介导的效应子功能在促进人类 COVID-19 疾病减弱中的具体作用仍不清楚。为了完全定义 Fc 介导的效应子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 介导的效应子功能。在 CoronaVac 疫苗接种者队列中，与突破性感染者相比，没有突破性感染的个体表现出更高水平的 ADCP 和 ADNP 活性，并且交叉反应性程度更高。建立了一个包含 ADNP 活性和 IgG 滴度的预测模型，实现了 0.837 的曲线下面积 （AUC）。在 COVID-19 患者队列中，与较轻的结果相比，致命结局的 COVID-19 患者的 BA.5 特异性 ADCP 和 ADNP 反应显着降低。结合 WT 、 BA.5 和 XBB.1.5 刺突特异性 ADNP 的预后模型表现出有效的预测能力，AUC 为 0.890。同时，对感染急性期 COVID-19 患者的外周血单核细胞 （PBMC） 的转录组学分析突出了中性粒细胞活性和吞噬功能的显着上调，进一步加强了 ADNP 的重要作用。 总的来说，我们的研究结果强调了 Fc 介导的效应子活性，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。