Buhre Jana Sophia, Pongracz Tamas, Geisen Ulf Martin, Schubert Mareike, Wang Wenjun, Nouta Jan, Obara Maureen, Lehrian Selina, Rahmöller Johann, Petry Janina, Tran Florian, Schreiber Stefan, Sümbül Melike, Berner Dennis, Gerdes Sascha, Schirmer Jan, Longardt Ann Carolin, Hoff Paula, Kalinke Ulrich, Ludwig Ralf J, Bartsch Yannic C, Hoyer Bimba F, Wuhrer Manfred, Ehlers Marc
Laboratories of Immunology and Antibody Glycan Analysis, Institute of Nutritional Medicine, University of Lübeck and University Medical Center Schleswig-Holstein, Lübeck, Germany.
Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands.
Allergy. 2025 Feb;80(2):423-439. doi: 10.1111/all.16241. Epub 2024 Jul 25.
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.
最近，接受抗肿瘤坏死因子（TNF）治疗的炎症性（自身）免疫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预防突破性感染的能力下降受到了质疑。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IgG Abs的半乳糖基化和唾液酸化水平较低，很可能由主要源自生发中心（GC）反应的长寿浆细胞（PCs）产生。因此，IgG Fc糖基化模式可能适用于区分在抗TNF治疗影响下重复接种疫苗后的短期和长期疫苗反应。
我们以COVID-19疫苗接种为模型，研究了接受抗TNF或其他免疫抑制治疗的患者以及健康个体在接种多达三针疫苗后疫苗诱导的IgG亚类水平、Fc糖基化模式、B细胞亚群以及短期和长期抗体反应的效应功能。利用全球医疗数据库TriNetX，我们确定了接受抗TNF或其他免疫抑制药物治疗的接种疫苗患者发生SARS-CoV-2突破性感染的风险。
抗TNF治疗降低了所有半乳糖基化和唾液酸化水平较低的抗S IgG亚类的长期丰度。潜在记忆B细胞的重新激活最初产生了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，尤其是老年人，每次加强剂量后这些抗体逐渐减少。抗TNF治疗患者短期和长期IgG（1）水平降低与功能活性降低以及发生COVID-19的风险增加相关。
数据表明，抗TNF治疗减少了GC依赖性长寿PCs以及GC依赖性记忆B细胞衍生的短期PCs，从而分别减少了重复接种疫苗后的长期和短期IgG亚类反应。我们提出，抗TNF治疗，尤其是在老年人中，会降低加强疫苗接种的益处。
