BackgroundRecently, 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.MethodsWe 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.ResultsAnti‐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.ConclusionsThe 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.

中文翻译：

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抗 TNF 疗法会损害重复接种疫苗后的短期和长期 IgG 反应


背景最近，有人质疑接受抗肿瘤坏死因子（TNF）治疗的炎症（自身）免疫性疾病患者接种疫苗是否会导致疫苗诱导的免疫反应和针对突破性感染的保护受损。然而，TNF 阻断对重复接种疫苗后短期和长期免疫反应的影响仍不清楚。疫苗研究表明，最初的短期 IgG 抗体 (Ab) 携带高度半乳糖基化和唾液酸化的 Fc 聚糖，而长期 IgG Abs 的半乳糖基化和唾液酸化水平较低，很可能是由长寿命浆细胞 (PC) 产生的主要来自生发中心（GC）反应。因此，IgG Fc 糖基化模式可能适用于区分在抗 TNF 治疗的影响下重复接种疫苗后的短期和长期疫苗反应。方法我们使用 COVID-19 疫苗接种作为模型来研究疫苗诱导的 IgG 亚类水平和 Fc在接受抗 TNF 或其他免疫抑制治疗的患者和健康个体中，最多接种 3 次疫苗后，糖基化模式、B 细胞亚群以及短期和长期抗体反应的效应器功能。使用全球医疗保健数据库 TriNetX，我们确定了接受抗 TNF 或其他免疫抑制药物治疗的疫苗接种患者中 SARS-CoV-2 突破性感染的风险。结果抗 TNF 治疗降低了所有抗 S IgG 亚类的长期丰度具有低水平的半乳糖基化和唾液酸化。潜在记忆 B 细胞的重新激活最初会产生高度半乳糖基化和唾液酸化的 IgG 抗体，在接受抗 TNF 治疗的患者中，尤其是老年人，每次加强剂量后，这些抗体逐渐减少。 接受抗 TNF 治疗的患者短期和长期 IgG (1) 水平降低与功能活动减弱和发生 COVID-19 的风险增加相关。结论数据表明，抗 TNF 治疗可降低 GC 依赖性长寿命 PC 和 GC 依赖性记忆 B 细胞衍生的短寿命 PC，因此在重复接种疫苗后分别产生长期和短期 IgG 亚类反应。我们建议，抗 TNF 治疗，尤其是老年人，会降低加强疫苗接种的益处。