Severe acute respiratory syndrome coronavirus 2 mRNA vaccination has reduced effectiveness in certain immunocompromised individuals. However, the cellular mechanisms underlying these defects, as well as the contribution of disease-induced cellular abnormalities, remain largely unexplored. In this study, we conducted a comprehensive serological and cellular analysis of patients with autoimmune systemic lupus erythematosus (SLE) who received the Wuhan-Hu-1 monovalent mRNA coronavirus disease 2019 vaccine. Our findings revealed that patients with SLE exhibited reduced avidity of anti-receptor-binding domain antibodies, leading to decreased neutralization potency and breadth. We also observed a sustained anti-spike response in IgD⁻CD27⁻ ‘double-negative (DN)’ DN2/DN3 B cell populations persisting during memory responses and with greater representation in the SLE cohort. Additionally, patients with SLE displayed compromised anti-spike T cell immunity. Notably, low vaccine efficacy strongly correlated with higher values of a newly developed extrafollicular B and T cell score, supporting the importance of distinct B cell endotypes. Finally, we found that anti-BAFF blockade through belimumab treatment was associated with poor vaccine immunogenicity due to inhibition of naive B cell priming and an unexpected impact on circulating T follicular helper cells.

严重急性呼吸系统综合症冠状病毒 2 mRNA 疫苗接种对某些免疫功能低下个体的有效性降低。然而，这些缺陷背后的细胞机制以及疾病诱导的细胞异常的贡献在很大程度上仍未得到探索。在这项研究中，我们对接受 Wuhan-胡-1 单价 mRNA 冠状病毒病 2019 疫苗的自身免疫性系统性红斑狼疮 （SLE） 患者进行了全面的血清学和细胞分析。我们的研究结果显示，SLE 患者表现出抗受体结合域抗体的亲和力降低，导致中和效力和广度降低。我们还观察到 IgD-CD27^-“双阴性 （DN）”DN2/DN3 B 细胞群在记忆反应期间持续存在，并且在 SLE 队列中具有更大的代表性。此外，SLE 患者的抗刺突 T 细胞免疫力受损。值得注意的是，低疫苗效力与新开发的滤泡外 B 细胞和 T 细胞评分的较高值密切相关，支持不同 B 细胞内型的重要性。最后，我们发现通过贝利尤单抗治疗阻断抗 BAFF 与疫苗免疫原性差有关，这是由于抑制初始 B 细胞启动和对循环滤泡辅助细胞的意外影响。