Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany.
Deutsches Rheumaforschungszentrum (DRFZ), Berlin, Germany.
Front Immunol. 2022 Aug 10;13:943476. doi: 10.3389/fimmu.2022.943476. eCollection 2022.
Durable vaccine-mediated immunity relies on the generation of long-lived plasma cells and memory B cells (MBCs), differentiating upon germinal center (GC) reactions. SARS-CoV-2 mRNA vaccination induces a strong GC response in healthy volunteers (HC), but limited data is available about response longevity upon rituximab treatment.
We evaluated humoral and cellular responses upon 3rd vaccination in seven patients with rheumatoid arthritis (RA) who initially mounted anti-spike SARS-CoV-2 IgG antibodies after primary 2x vaccination and got re-exposed to rituximab (RTX) 1-2 months after the second vaccination. Ten patients with RA on other therapies and ten HC represented the control groups. As control for known long-lived induced immunity, we analyzed humoral and cellular tetanus toxoid (TT) immune responses in steady-state.
After 3 vaccination, 5/7 seroconverted RTX patients revealed lower anti-SARS-CoV-2 IgG levels but similar neutralizing capacity compared with HC. Antibody levels after 3rd vaccination correlated with values after 2nd vaccination. Despite significant reduction of circulating total and antigen-specific B cells in RTX re-exposed patients, we observed the induction of IgG+ MBCs upon 3 vaccination. Notably, only RTX treated patients revealed a high amount of IgA+ MBCs before and IgA+ plasmablasts after 3 vaccination. IgA+ B cells were not part of the steady state TT+ B cell pool. TNF-secretion and generation of effector memory CD4 spike-specific T cells were significantly boosted upon 3 vaccination.
On the basis of pre-existing affinity matured MBCs within primary immunisation, RTX re-exposed patients revealed a persistent but atypical GC immune response accompanied by boosted spike-specific memory CD4 T cells upon SARS-CoV-2 recall vaccination.
持久的疫苗介导的免疫依赖于长寿命浆细胞和记忆 B 细胞（MBC）的产生，这些细胞在生发中心（GC）反应中分化。SARS-CoV-2 mRNA 疫苗在健康志愿者（HC）中诱导强烈的 GC 反应，但关于利妥昔单抗治疗后的反应持久性的数据有限。
我们评估了 7 例类风湿关节炎（RA）患者在第三次接种后的体液和细胞反应，这些患者在初次接种 2 剂后最初产生了针对刺突 SARS-CoV-2 的 IgG 抗体，并在第二次接种后 1-2 个月再次接触利妥昔单抗（RTX）。10 例接受其他治疗的 RA 患者和 10 例 HC 作为对照组。作为已知诱导的长期免疫的对照，我们在稳定状态下分析了破伤风类毒素（TT）的体液和细胞免疫反应。
在第三次接种后，5/7 例 RTX 患者血清转换，与 HC 相比，其 SARS-CoV-2 IgG 水平较低，但中和能力相似。第三次接种后的抗体水平与第二次接种后的水平相关。尽管 RTX 再暴露患者的循环总 B 细胞和抗原特异性 B 细胞显著减少，但我们观察到在第三次接种后诱导 IgG+MBC。值得注意的是，只有 RTX 治疗的患者在第三次接种前后显示出大量的 IgA+MBC 和 IgA+浆母细胞。IgA+B 细胞不是 TT+B 细胞库的一部分。TNF 分泌和效应记忆 CD4 刺突特异性 T 细胞的产生在第三次接种后显著增强。
在初次免疫中存在预先成熟的 MBC 的基础上，RTX 再暴露患者显示出持久但不典型的 GC 免疫反应，同时在 SARS-CoV-2 回忆接种时增强了 Spike 特异性记忆 CD4 T 细胞。
