Wieske Luuk, van Dam Koos P J, Steenhuis Maurice, Stalman Eileen W, Kummer Laura Y L, van Kempen Zoé L E, Killestein Joep, Volkers Adriaan G, Tas Sander W, Boekel Laura, Wolbink Gerrit J, van der Kooi Anneke J, Raaphorst Joost, Löwenberg Mark, Takkenberg R Bart, D'Haens Geert R A M, Spuls Phyllis I, Bekkenk Marcel W, Musters Annelie H, Post Nicoline F, Bosma Angela L, Hilhorst Marc L, Vegting Yosta, Bemelman Frederike J, Voskuyl Alexandre E, Broens Bo, Sanchez Agner Parra, van Els Cécile A C M, de Wit Jelle, Rutgers Abraham, de Leeuw Karina, Horváth Barbara, Verschuuren Jan J G M, Ruiter Annabel M, van Ouwerkerk Lotte, van der Woude Diane, Allaart Renée C F, Teng Y K Onno, van Paassen Pieter, Busch Matthias H, Jallah Papay B P, Brusse Esther, van Doorn Pieter A, Baars Adája E, Hijnen Dirk Jan, Schreurs Corine R G, van der Pol W Ludo, Goedee H Stephan, Keijzer Sofie, Keijser Jim B D, Boogaard Arend, Cristianawati Olvi, Ten Brinke Anja, Verstegen Niels J M, Zwinderman Koos A H, van Ham S Marieke, Kuijpers Taco W, Rispens Theo, Eftimov Filip
Department of Neurology and Neurophysiology, Amsterdam Neuroscience, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, Amsterdam, Netherlands.
Lancet Rheumatol. 2022 May;4(5):e338-e350. doi: 10.1016/S2665-9913(22)00034-0. Epub 2022 Mar 17.
Disease-specific studies have reported impaired humoral responses after SARS-CoV-2 vaccination in patients with immune-mediated inflammatory disorders treated with specific immunosuppressants. Disease-overarching studies, and data on recall responses and third vaccinations are scarce. Our primary objective was to investigate the effects of immunosuppressive monotherapies on the humoral immune response after SARS-CoV-2 vaccination in patients with prevalent immune-mediated inflammatory disorders.
We did a cohort study in participants treated in outpatient clinics in seven university hospitals and one rheumatology treatment centre in the Netherlands as well as participants included in two national cohort studies on COVID-19-related disease severity. We included patients aged older than 18 years, diagnosed with any of the prespecified immune-mediated inflammatory disorders, who were able to understand and complete questionnaires in Dutch. Participants with immune-mediated inflammatory disorders who were not on systemic immunosuppressants and healthy participants were included as controls. Anti-receptor binding domain IgG responses and neutralisation capacity were monitored following standard vaccination regimens and a three-vaccination regimen in subgroups. Hybrid immune responses-ie, vaccination after previous SARS-CoV-2 infection-were studied as a proxy for recall responses.
Between Feb 2 and Aug 1, 2021, we included 3222 participants in our cohort. Sera from 2339 participants, 1869 without and 470 participants with previous SARS-CoV-2 infection were analysed (mean age 49·9 years [SD 13·7]; 1470 [62·8%] females and 869 [37·2%] males). Humoral responses did not differ between disorders. Anti-CD20 therapy, sphingosine 1-phosphate receptor (S1P) modulators, and mycophenolate mofetil combined with corticosteroids were associated with lower relative risks for reaching seroconversion following standard vaccination (0·32 [95% CI 0·19-0·49] for anti-CD20 therapy, 0·35 [0·21-0·55] for S1P modulators, and 0·61 [0·40-0·90] for mycophenolate mofetil combined with corticosteroids). A third vaccination increased seroconversion for mycophenolate mofetil combination treatments (from 52·6% after the second vaccination to 89·5% after the third) but not significantly for anti-CD20 therapies (from 36·8% to 45·6%) and S1P modulators (from 35·5% to 48·4%). Most other immunosuppressant groups showed moderately reduced antibody titres after standard vaccination that did not increase after a third vaccination, although seroconversion rates and neutralisation capacity were unaffected. In participants with previous SARS-CoV-2 infection, SARS-CoV-2 antibodies were boosted after vaccination, regardless of immunosuppressive treatment.
Humoral responses following vaccination are impaired by specific immunosuppressants. After standard vaccination regimens, patients with immune-mediated inflammatory disorders taking most immunosuppressants show similar seroconversion to controls, although antibody titres might be moderately reduced. As neutralisation capacity and recall responses are also preserved in these patients, this is not likely to translate to loss of (short-term) protection. In patients on immunosuppressants showing poor humoral responses after standard vaccination regimens, a third vaccination resulted in additional seroconversion in patients taking mycophenolate mofetil combination treatments, whereas the effect of a third vaccination in patients on anti-CD20 therapy and S1P modulators was limited.
ZonMw (The Netherlands Organization for Health Research and Development).
疾病特异性研究报告称，在接受特定免疫抑制剂治疗的免疫介导性炎症疾病患者中，接种严重急性呼吸综合征冠状病毒2（SARS-CoV-2）疫苗后体液免疫反应受损。针对多种疾病的研究以及关于回忆反应和第三次疫苗接种的数据很少。我们的主要目的是研究免疫抑制单一疗法对常见免疫介导性炎症疾病患者接种SARS-CoV-2疫苗后体液免疫反应的影响。
我们进行了一项队列研究，研究对象包括在荷兰七家大学医院和一个风湿病治疗中心的门诊接受治疗的参与者，以及两项关于新型冠状病毒肺炎（COVID-19）相关疾病严重程度的全国性队列研究中的参与者。我们纳入了年龄超过18岁且被诊断患有任何一种预先指定的免疫介导性炎症疾病、能够理解并完成荷兰语问卷的患者。未接受全身免疫抑制剂治疗的免疫介导性炎症疾病参与者和健康参与者被纳入作为对照。在标准疫苗接种方案和亚组的三次疫苗接种方案后，监测抗受体结合域免疫球蛋白G（IgG）反应和中和能力。混合免疫反应（即先前感染SARS-CoV-2后接种疫苗）被作为回忆反应的替代指标进行研究。
在2021年2月2日至8月1日期间，我们的队列中纳入了3222名参与者。分析了2339名参与者的血清，其中1869名无先前SARS-CoV-2感染，470名有先前SARS-CoV-2感染（平均年龄49.9岁[标准差13.7]；女性1470名[62.8%]，男性869名[37.2%]）。不同疾病之间的体液免疫反应没有差异。抗CD20疗法、鞘氨醇1-磷酸受体（S1P）调节剂以及霉酚酸酯联合糖皮质激素与标准疫苗接种后血清转化的相对风险较低相关（抗CD20疗法为0.32[95%置信区间0.19-0.49]，S1P调节剂为0.35[0.21-0.55]，霉酚酸酯联合糖皮质激素为0.61[0.40-0.90]）。第三次疫苗接种增加了霉酚酸酯联合治疗的血清转化率（从第二次接种后的52.6%增至第三次接种后的89.5%），但抗CD20疗法（从36.8%增至45.6%）和S1P调节剂（从35.5%增至48.4%）的血清转化率增加不显著。大多数其他免疫抑制剂组在标准疫苗接种后抗体滴度适度降低，第三次疫苗接种后未增加，尽管血清转化率和中和能力未受影响。在先前感染过SARS-CoV-2的参与者中，无论免疫抑制治疗如何，接种疫苗后SARS-CoV-2抗体均得到增强。
特定免疫抑制剂会损害疫苗接种后的体液免疫反应。在标准疫苗接种方案后，大多数免疫抑制剂治疗的免疫介导性炎症疾病患者的血清转化率与对照组相似，尽管抗体滴度可能会适度降低。由于这些患者的中和能力和回忆反应也得以保留，这不太可能转化为（短期）保护作用的丧失。在标准疫苗接种方案后体液免疫反应较差的免疫抑制剂治疗患者中，第三次疫苗接种使接受霉酚酸酯联合治疗的患者产生了额外的血清转化，而第三次疫苗接种对接受抗CD20疗法和S1P调节剂治疗的患者的效果有限。
荷兰卫生研究与发展组织（ZonMw）
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