Martín Pérez Carla, Ruiz-Rius Sílvia, Ramírez-Morros Anna, Vidal Marta, Opi D Herbert, Santamaria Pere, Blanco Julià, Vidal-Alaball Josep, Beeson James G, Molinos-Albert Luis M, Aguilar Ruth, Ruiz-Comellas Anna, Moncunill Gemma, Dobaño Carlota
ISGlobal, Barcelona, Catalonia, Spain; Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain.
Unitat de Suport a la Recerca de la Catalunya Central, Fundació Institut Universitari per a la Recerca a l'Atenció Primària de Salut Jordi Gol i Gurina, Manresa, Spain.
J Infect. 2025 Apr;90(4):106473. doi: 10.1016/j.jinf.2025.106473. Epub 2025 Mar 18.
Repeated COVID-19 mRNA vaccinations increase SARS-CoV-2 IgG4 antibodies, indicating extensive IgG class switching following the first booster dose. This shift in IgG subclasses raises concerns due to the limited ability of IgG4 to mediate Fc-dependent effector functions.
To assess the impact of IgG4 induction on protective immunity, we analyzed longitudinal SARS-CoV-2 IgG subclasses, C1q and FcγR responses, and neutralizing activity in a well-characterized cohort of healthcare workers in Spain.
Elevated IgG4 levels and higher ratios of non-cytophilic to cytophilic antibodies after booster vaccination were significantly associated with an increased risk of breakthrough infections (IgG4 HR[10-fold increase]=1.8, 95% CI=1.2-2.7; non-cytophilic to cytophilic ratio HR[10-fold increase]=1.5, 95% CI=1.1-1.9). Moreover, an increased non-cytophilic to cytophilic antibody ratio correlated with reduced functionality, including neutralization.
These findings suggest a potential association between IgG4 induction by mRNA vaccination and a higher risk of breakthrough infection, warranting further investigation into vaccination strategies to ensure sustained protection.
重复接种新冠病毒mRNA疫苗会增加严重急性呼吸综合征冠状病毒2（SARS-CoV-2）IgG4抗体，这表明在首次加强剂量后发生了广泛的IgG类别转换。由于IgG4介导Fc依赖性效应功能的能力有限，IgG亚类的这种转变引发了人们的担忧。
为了评估诱导产生IgG4对保护性免疫的影响，我们分析了西班牙一组特征明确的医护人员队列中SARS-CoV-2 IgG亚类、C1q和FcγR反应的纵向变化以及中和活性。
加强疫苗接种后，IgG4水平升高以及非嗜细胞性抗体与嗜细胞性抗体的比例更高，这与突破性感染风险增加显著相关（IgG4风险比[增加10倍]=1.8，95%置信区间=1.2 - 2.7；非嗜细胞性与嗜细胞性比例风险比[增加10倍]=1.5，95%置信区间=1.1 - 1.9）。此外，非嗜细胞性与嗜细胞性抗体比例增加与包括中和作用在内的功能降低相关。
这些发现表明，mRNA疫苗接种诱导产生IgG4与更高的突破性感染风险之间可能存在关联，有必要进一步研究疫苗接种策略以确保持续的保护作用。
