抗TNF治疗削弱反复接种疫苗后的短期和长期IgG应答

近年来，关于抗肿瘤坏死因子（TNF）治疗下感染性（自身免疫）疾病患者接种疫苗是否影响疫苗诱导的免疫应答和突破性感染保护的问题引起关注。然而，TNF阻断对反复接种后短期和长期免疫应答的影响尚不明确。疫苗研究显示，初期的短期IgG抗体（Abs）携带高度半乳糖基化和唾液酸化的Fc糖基，而长期的IgG抗体则具有较低的半乳糖化和唾液酸化水平，且很可能由起源于生发中心（GC）反应的长寿命浆细胞（PCs）产生。因此，IgG Fc糖基化模式可能用于区分抗TNF治疗影响下的反复接种后短期与长期疫苗反应。我们以新冠疫苗为模型，研究了在抗TNF或其他免疫抑制治疗患者与健康志愿者中，最多接受三剂疫苗后，疫苗诱导的IgG亚类水平、Fc糖基化模式、B细胞亚群及效应功能的变化。通过全球医疗数据库TriNetX分析，评估了在抗TNF或其他免疫抑制药物治疗下接种疫苗的患者的SARS-CoV-2突破性感染风险。结果显示，抗TNF治疗显著降低所有抗S IgG亚类的长期水平，伴随低半乳糖化和唾液酸化。初期生成的高度半乳糖化和唾液酸化的IgG抗体在再次激活记忆B细胞后逐渐减少，尤其在老年患者中更为明显。抗TNF治疗患者的短期和长期IgG（1）水平降低，相关功能活性减弱，COVID-19发生风险增加。数据表明，抗TNF治疗同时抑制了依赖于生发中心的长寿命浆细胞和记忆B细胞的短寿命浆细胞，从而影响了反复接种后的IgG亚类应答。我们建议，尤其在老年患者中，抗TNF治疗可能削弱加强针疫苗的益处。

Recently, it has been questioned whether vaccination of patients with inflammatory (auto)immune diseases under anti-tumor necrosis factor (TNF) treatment leads to impaired vaccine-induced immune responses and protection against breakthrough infections. However, the effects of TNF blockade on short- and long-term immune responses after repeated vaccination remain unclear. Vaccination studies have shown that initial short-term IgG antibodies (Abs) carry highly galactosylated and sialylated Fc glycans, whilst long-term IgG Abs have low levels of galactosylation and sialylation and are most likely generated by long-lived plasma cells (PCs) derived primarily from the germinal center (GC) response. Thus, IgG Fc glycosylation patterns may be applicable to distinguish short- and long-term vaccine responses after repeated vaccination under the influence of anti-TNF treatment.We used COVID-19 vaccination as a model to investigate vaccine-induced IgG subclass levels and Fc glycosylation patterns, B cell subsets, and effector functions of short- and long-term Ab responses after up to three vaccinations in patients on anti-TNF or other immunosuppressive treatments and in healthy individuals. Using TriNetX, a global healthcare database, we determined the risk of SARS-CoV-2 breakthrough infections in vaccinated patients treated with anti-TNF or other immunosuppressive drugs.Anti-TNF treatment reduced the long-term abundance of all anti-S IgG subclasses with low levels of galactosylation and sialylation. Re-activation of potential memory B cells initially generated highly galactosylated and sialylated IgG antibodies, which were progressively reduced after each booster dose in anti-TNF-treated patients, especially in the elderly. The reduced short- and long-term IgG (1) levels in anti-TNF-treated patients correlated with diminished functional activity and an increased risk for the development of COVID-19.The data suggest that anti-TNF treatment reduces both GC-dependent long-lived PCs and GC-dependent memory B cell-derived short-lived PCs, hence both the long- and short-term IgG subclass responses, respectively, after repeated vaccination. We propose that anti-TNF therapy, especially in the elderly, reduces the benefit of booster vaccination.