Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：最近，有人质疑,在抗肿瘤坏死因子(TNF)治疗下,对炎性(自身)免疫疾病患者接种疫苗是否会导致疫苗诱导的免疫反应受损,以及对突破性感染的保护作用.然而,TNF阻断对反复接种疫苗后短期和长期免疫反应的影响尚不清楚.疫苗接种研究表明，初始短期IgG抗体（Abs）携带高度半乳糖基化和唾液酸化的Fc聚糖，而长期IgGAb的半乳糖基化和唾液酸化水平较低，并且很可能是由主要来自生发中心（GC）反应的长寿命浆细胞（PC）产生的。因此，IgGFc糖基化模式可适用于区分在抗TNF治疗的影响下重复接种后的短期和长期疫苗应答。
方法：我们使用COVID-19疫苗作为模型来研究疫苗诱导的IgG亚类水平和Fc糖基化模式，B细胞亚群,在接受抗TNF或其他免疫抑制治疗的患者和健康个体中，接种多达三次疫苗后，短期和长期Ab反应的效应子功能。使用TriNetX，全球医疗保健数据库，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发生SARS-CoV-2突破性感染的风险.
结果：抗TNF治疗降低了所有抗SIgG亚类的长期丰度，半乳糖基化和唾液酸化水平较低。重新激活潜在的记忆B细胞最初产生高度半乳糖基化和唾液酸化的IgG抗体，在抗TNF治疗的患者中，每次加强剂量后逐渐减少，尤其是老年人。抗TNF治疗患者的短期和长期IgG(1)水平降低与功能活性降低和COVID-19发展风险增加相关。
结论：数据表明，抗TNF治疗既减少了GC依赖性长寿命PCs，也减少了GC依赖性记忆B细胞衍生的短寿命PCs，因此，长期和短期的IgG亚类反应，分别,反复接种疫苗后。我们建议抗TNF治疗，尤其是老年人，减少加强疫苗接种的好处。
方法：我们使用COVID-19疫苗作为模型来研究疫苗诱导的IgG亚类水平和Fc糖基化模式，B细胞亚群,在接受抗TNF或其他免疫抑制治疗的患者和健康个体中，接种多达三次疫苗后，短期和长期Ab反应的效应子功能。使用TriNetX，全球医疗保健数据库，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发生SARS-CoV-2突破性感染的风险.
结果：抗TNF治疗降低了所有抗SIgG亚类的长期丰度，半乳糖基化和唾液酸化水平较低。重新激活潜在的记忆B细胞最初产生高度半乳糖基化和唾液酸化的IgG抗体，在抗TNF治疗的患者中，每次加强剂量后逐渐减少，尤其是老年人。抗TNF治疗患者的短期和长期IgG(1)水平降低与功能活性降低和COVID-19发展风险增加相关。
结论：数据表明，抗TNF治疗既减少了GC依赖性长寿命PCs，也减少了GC依赖性记忆B细胞衍生的短寿命PCs，因此，长期和短期的IgG亚类反应，分别,反复接种疫苗后。我们建议抗TNF治疗，尤其是老年人，减少加强疫苗接种的好处。
