Neutralising antibody potency against SARS-CoV-2 wild-type and omicron BA.1 and BA.4/5 variants in patients with inflammatory bowel disease treated with infliximab and vedolizumab after three doses of COVID-19 vaccine (CLARITY IBD): an analysis of a prospective multicentre cohort study.
Neutralising antibody potency against SARS-CoV-2 wild-type and omicron BA.1 and BA.4/5 variants in patients with inflammatory bowel disease treated with infliximab and vedolizumab after three doses of COVID-19 vaccine (CLARITY IBD): an analysis of a prospective multicentre cohort study.
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DOI：
10.1016/s2468-1253(22)00389-2
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发表时间：
2023-02
影响因子：
35.7
通讯作者：
Powell, Nick
中科院分区：
文献类型：
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作者：
Liu, Zhigang;Le, Kaixing;Zhou, Xin;Alexander, James L.;Lin, Simeng;Bewshea, Claire;Chanchlani, Neil;Nice, Rachel;McDonald, Timothy J.;Lamb, Christopher A.;Sebastian, Shaji;Kok, Klaartje;Lees, Charlie W.;Hart, Ailsa L.;Pollok, Richard C.;Boyton, Rosemary J.;Altmann, Daniel M.;Pollock, Katrina M.;Goodhand, James R.;Kennedy, Nicholas A.;Ahmad, Tariq;Powell, Nick
抗肿瘤坏死因子药物，如英夫利昔单抗，与SARS-CoV-2疫苗接种后的抗体反应减弱有关。我们的目的是确定抗tnf药物英夫利昔单抗和抗整合素药物vedolizumab如何影响疫苗诱导的针对高传染性组粒（B.1.1.529） BA.1和BA.4和BA.5（以下简称BA.4/5） SARS-CoV-2变体的中和抗体，这些变体具有逃避宿主免疫的能力，并且与新出现的亚谱系一起，现在是引起当前感染浪潮的主要变体。CLARITY IBD是一项前瞻性、多中心、观察性队列研究，研究英夫利昔单抗和维多单抗对炎症性肠病（IBD）患者SARS-CoV-2感染和疫苗接种的影响。从英国92家医院的输液部门招募了5岁及以上诊断为IBD并接受英夫利昔单抗或维多单抗治疗6周或更长时间的患者。在本分析中，我们纳入了自招募以来一直接受不间断生物治疗且先前没有SARS-CoV-2感染的参与者。主要结果是在接种三剂SARS-CoV-2疫苗后，针对SARS-CoV-2野生型和组粒亚变体BA.1和BA.4/5的抗体反应中和。我们构建了Cox比例风险模型来研究突破性感染的风险与中和抗体滴度的关系。该研究已在ISRCTN注册中心注册，编号为ISRCTN45176516，并已结束。2020年9月22日至12月23日，CLARITY IBD研究招募了7224名IBD患者，其中1288名患者在接种了三剂SARS-CoV-2疫苗后没有感染SARS-CoV-2，并接受了英夫利昔单抗（n=871）或维多单抗（n=417）的治疗，纳入了本研究（中位年龄为46.1岁[IQR 33.6 - 58.2]，女性610名[47.4%]，男性671名[52.1%]，白人1209名[93.9%]，亚洲人46名[3.6%]）。在三剂SARS-CoV-2疫苗后，英夫利昔单抗治疗的患者50%中和效价（NT50s）显著低于vedolizumab治疗的患者，针对野生型（几何平均2062 [95% CI 1720-2473]对3440 [2939-4026]，p< 0.0001）， ba1（107·3[86.4 - 133·2]对648·9[523·5 - 804.5],p< 0.0001）和ba4 /5（40·63[31·99-51·60]对223·0[183·1-271·4]，p< 0.0001）变异。英夫利昔单抗治疗患者的突破感染发生率（119 [13.7%;95% CI 11.5 - 16.2] / 871）明显高于韦多单抗治疗患者（29 [7.0%]/ 417 [4.8 - 10.0];p= 0.00040）。第三剂疫苗后突破感染时间的Cox比例风险模型显示，英夫利昔单抗治疗的风险高于韦多单抗治疗（风险比[HR] 1.71 [95% CI 1.08 - 2.71]; p= 0.022）。在突破性感染的参与者中，我们发现针对BA.4/5的高中和抗体滴度与较低的危害风险相关，因此，突破感染的时间较长（HR 0.87 [0.79 - 0.95]; p= 0.0028）。我们的研究结果强调了持续进行SARS-CoV-2疫苗接种计划的重要性，包括第二代二价疫苗，特别是在疫苗免疫原性和效力可能降低的患者亚组中，例如抗tnf治疗的患者。皇家德文大学医疗保健NHS基金会信托；赫尔大学教学医院NHS信托；帝国生物医学研究中心；英国克罗恩病和结肠炎；英国勇气;联合王国研究和创新国家核心研究免疫方案；以及F - Hoffmann-La Roche、Biogen、Celltrion Healthcare、武田和Galapagos的无限制教育资助。
Anti-TNF drugs, such as infliximab, are associated with attenuated antibody responses after SARS-CoV-2 vaccination. We aimed to determine how the anti-TNF drug infliximab and the anti-integrin drug vedolizumab affect vaccine-induced neutralising antibodies against highly transmissible omicron (B.1.1.529) BA.1, and BA.4 and BA.5 (hereafter BA.4/5) SARS-CoV-2 variants, which possess the ability to evade host immunity and, together with emerging sublineages, are now the dominating variants causing current waves of infection. CLARITY IBD is a prospective, multicentre, observational cohort study investigating the effect of infliximab and vedolizumab on SARS-CoV-2 infection and vaccination in patients with inflammatory bowel disease (IBD). Patients aged 5 years and older with a diagnosis of IBD and being treated with infliximab or vedolizumab for 6 weeks or longer were recruited from infusion units at 92 hospitals in the UK. In this analysis, we included participants who had received uninterrupted biological therapy since recruitment and without a previous SARS-CoV-2 infection. The primary outcome was neutralising antibody responses against SARS-CoV-2 wild-type and omicron subvariants BA.1 and BA.4/5 after three doses of SARS-CoV-2 vaccine. We constructed Cox proportional hazards models to investigate the risk of breakthrough infection in relation to neutralising antibody titres. The study is registered with the ISRCTN registry, ISRCTN45176516, and is closed to accrual. Between Sept 22 and Dec 23, 2020, 7224 patients with IBD were recruited to the CLARITY IBD study, of whom 1288 had no previous SARS-CoV-2 infection after three doses of SARS-CoV-2 vaccine and were established on either infliximab (n=871) or vedolizumab (n=417) and included in this study (median age was 46·1 years [IQR 33·6–58·2], 610 [47·4%] were female, 671 [52·1%] were male, 1209 [93·9%] were White, and 46 [3·6%] were Asian). After three doses of SARS-CoV-2 vaccine, 50% neutralising titres (NT50s) were significantly lower in patients treated with infliximab than in those treated with vedolizumab, against wild-type (geometric mean 2062 [95% CI 1720–2473] vs 3440 [2939–4026]; p<0·0001), BA.1 (107·3 [86·40–133·2] vs 648·9 [523·5–804·5]; p<0·0001), and BA.4/5 (40·63 [31·99–51·60] vs 223·0 [183·1–271·4]; p<0·0001) variants. Breakthrough infection was significantly more frequent in patients treated with infliximab (119 [13·7%; 95% CI 11·5–16·2] of 871) than in those treated with vedolizumab (29 [7·0% [4·8–10·0] of 417; p=0·00040). Cox proportional hazards models of time to breakthrough infection after the third dose of vaccine showed infliximab treatment to be associated with a higher hazard risk than treatment with vedolizumab (hazard ratio [HR] 1·71 [95% CI 1·08–2·71]; p=0·022). Among participants who had a breakthrough infection, we found that higher neutralising antibody titres against BA.4/5 were associated with a lower hazard risk and, hence, a longer time to breakthrough infection (HR 0·87 [0·79–0·95]; p=0·0028). Our findings underline the importance of continued SARS-CoV-2 vaccination programmes, including second-generation bivalent vaccines, especially in patient subgroups where vaccine immunogenicity and efficacy might be reduced, such as those on anti-TNF therapies. Royal Devon University Healthcare NHS Foundation Trust; Hull University Teaching Hospital NHS Trust; NIHR Imperial Biomedical Research Centre; Crohn's and Colitis UK; Guts UK; National Core Studies Immunity Programme, UK Research and Innovation; and unrestricted educational grants from F Hoffmann-La Roche, Biogen, Celltrion Healthcare, Takeda, and Galapagos.