Evolution of SARS-CoV-2 antibody repertoire after successive mRNA vaccinations under immunosuppressive treatment.

IF 10.8 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL EBioMedicine Pub Date : 2025-03-01 Epub Date: 2025-02-25 DOI:10.1016/j.ebiom.2025.105620

Jim B D Keijser, Eileen W Stalman, Luuk Wieske, Maurice Steenhuis, Koos P J van Dam, Laura Y L Kummer, Zoé L E van Kempen, Joep Killestein, Adriaan G Volkers, Sander W Tas, Laura Boekel, Gerrit J Wolbink, Laura Fernandez Blanco, Niels J M Verstegen, Sofie Keijzer, Gerard van Mierlo, Olvi Cristianawati, Arend J Boogaard, Karlijn van der Straten, Jacqueline van Rijswijk, Marit J van Gils, Anja Ten Brinke, S Marieke van Ham, Taco W Kuijpers, Filip Eftimov, Theo Rispens

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Abstract

Background: Repeated antigen exposure can result in a shifting antibody repertoire. The mechanisms by which this occurs and consequences for cross-variant protection against evolving pathogens remain incompletely understood, particularly in the context of immunosuppressive treatments used in patients with immune-mediated inflammatory diseases (IMID).

Methods: To investigate this, we characterised longitudinal changes in the anti-SARS-CoV-2 antibody repertoire over the course of three SARS-CoV-2 mRNA vaccinations in patients with IMIDs treated with methotrexate (MTX) and/or tumour necrosis factor-inhibitors (TNFi), anti-CD20 monoclonal antibodies, no systemic therapy, and healthy controls (total N = 878). We determined serum antibody titres against the receptor-binding domain (RBD) of Wuhan-Hu-1 (WH1) and Omicron BA.1 spike proteins, and assessed ratios thereof between groups as a proxy for cross-reactivity.

Findings: We observe emerging anti-BA.1 RBD reactivity over time, notably following a third vaccination. This may be partly explained by affinity maturation, as evaluated by inhibition of ACE2-RBD interactions. Similar trends were seen in patients treated with MTX and/or TNFi, but not in patients on anti-CD20 therapy. SARS-CoV-2 infection prior to vaccination accelerated these effects initially while leading to comparable results after three vaccinations.

Interpretation: MTX and TNFi do not qualitatively alter the evolution of the antibody repertoire in response to repeated antigen exposure, whereas anti-CD20 does. These insights may help to optimise vaccination strategies for patients with immune-mediated inflammatory diseases.

Funding: This study was supported by ZonMw (The Netherlands Organization for Health Research and Development) and SGF (Collaborating Health Funds).

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免疫抑制治疗下连续mRNA接种后SARS-CoV-2抗体库的进化

背景：重复抗原暴露可导致抗体库的变化。这种情况发生的机制和对不断进化的病原体的交叉变异保护的后果仍然不完全清楚，特别是在免疫介导的炎症性疾病（IMID）患者使用免疫抑制治疗的背景下。方法：为了研究这一点，我们对接受甲氨蝶呤（MTX）和/或肿瘤坏死因子抑制剂（TNFi）、抗cd20单克隆抗体、未接受全身治疗的IMIDs患者和健康对照（总N = 878）进行了三次SARS-CoV-2 mRNA疫苗接种过程中抗SARS-CoV-2抗体库的纵向变化进行了表征。我们测定了武汉- hu -1 （WH1）和Omicron BA.1刺突蛋白受体结合域（RBD）的血清抗体滴度，并评估了组间的比率，作为交叉反应性的代理。结果：我们观察到新出现的抗ba .1RBD随时间的反应性，特别是在第三次接种疫苗后。通过抑制ACE2-RBD相互作用来评估亲和成熟可以部分解释这一现象。在接受MTX和/或TNFi治疗的患者中也发现了类似的趋势，但在接受抗cd20治疗的患者中则没有。疫苗接种前的SARS-CoV-2感染最初加速了这些影响，而在三次疫苗接种后产生了类似的结果。解释：MTX和TNFi在重复抗原暴露时不会定性地改变抗体库的进化，而抗cd20则会。这些见解可能有助于优化免疫介导炎症性疾病患者的疫苗接种策略。资助：本研究由ZonMw（荷兰卫生研究与发展组织）和SGF（合作卫生基金）支持。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.