Vaccine Efficacy after Rituximab Exposure: First Interim Analysis of Virtue Project on Behalf of West Midlands Research Consortium, UK
Vaccine Efficacy after Rituximab Exposure: First Interim Analysis of Virtue Project on Behalf of West Midlands Research Consortium, UK
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DOI：
10.1182/blood-2021-150220
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发表时间：
2021-12-24
期刊：
影响因子：
20.3
通讯作者：
Basu S
中科院分区：
文献类型：
--
作者：
Shields AM;Venkatachalam S;Paneesha S;Ford M;Sheeran T;Kelly M;Karim F;Qureshi I;Salhan B;DeSilva N;Stones J;Lee S;Khawaja J;Kaudlay PK;Whitmill R;Nabikakepoto G;Faustini SE;Richter AG;Drayson MT;Basu S
背景：抗cd20b细胞消耗剂是血液恶性肿瘤和自身免疫性疾病治疗中最常用的免疫疗法之一。通过诱导外周B细胞发育不全，假设抗cd20消耗剂显著损害对新抗原的血清学反应，包括SARS-CoV-2疫苗中的SARS-CoV-2刺突糖蛋白。SARS-CoV-2后血清阳性是预防严重COVID-19的最强、可测量的相关性。了解暴露于B细胞消耗剂后B细胞重构和疫苗反应的动力学对于最大限度地提高疫苗对严重COVID-19易感患者的效力至关重要。方法：对80例基础血液病恶性肿瘤患者和38例基础风湿病患者在第二次接种SARS-CoV-2疫苗后（平均采样时间：46.5d, IQR: 33.8-63.3）进行研究。采用六色流式细胞术（BD Trucount）进行淋巴细胞亚群（CD4、CD8、CD19、CD56/16）计数。采用酶联免疫吸附法（The Binding Site, Human Anti-IgG/A/M sars - cov -2 elisa）测定抗sars - cov -2刺突糖蛋白抗体总水平。探讨了B细胞耗竭后免疫重建与疫苗反应性的关系。结果：在血液学队列中（中位年龄70岁，IQR为60.3-76.0，男性62.5%），接种疫苗后总体血清阳性为60.0%。化疗结束后，接受积极化疗的个体血清阳性率明显低于接种疫苗的个体（22.7% vs 74.1%, p<0.0001）。在风湿病队列中（中位年龄65岁，IQR 58.3-70.8，男性39.9%），总体血清阳性为69.4%。在这两个队列中，疫苗无应答者的外周血CD19+ B细胞明显较少（血液学：0.20 vs 0.02 x10 9/L, p=0.004，风湿病学：0.07 vs 0.01 x10 9/L, p=0.03）。在两个队列中，接种Tozinameran和Vaxzeveria后的抗体应答程度没有差异。在B细胞耗竭治疗后的前6个月，疫苗反应性较低；在血液学队列中为42.9%，在风湿病队列中为33.3%，在B细胞消耗后6-12个月接受第二次剂量的个体中分别增加到100%和75%（图1）。与风湿病患者相比，血液病患者在B细胞耗损后的7-12个月内B细胞重建更快（77.8% vs 22.2%达到正常B细胞计数，p=0.005），并且与疫苗反应性提高相关。然而，一些血液病患者在完成治疗后出现了持续的免疫缺陷：至少36个月前完成治疗的患者中有25%未能对疫苗接种产生反应。在这组疫苗无应答者中，83.3%的个体B细胞数量在正常范围内。这些患者以前都接受过滤泡性淋巴瘤的治疗，这表明这些患者的长期继发性免疫缺陷具有特定的机制。结论：在血液学恶性肿瘤的积极化疗期间和B细胞耗竭后的前6个月，无论潜在疾病如何，对SARS-CoV-2疫苗的血清学反应性较差。在B细胞耗竭后的7-12个月内，疫苗反应性显著提高。与血液病患者相比，风湿病患者的B细胞重构较慢，并且与疫苗反应性降低有关，这可能是由于同时使用额外的疾病改善抗风湿病治疗所致。此外，长期继发性免疫缺陷发生在少数血液病患者中。为了最大限度地发挥SARS-CoV-2加强疫苗接种的效力并优化现有疫苗剂量的利用，应在使用抗cd20消耗药物后至少6个月进行免疫接种。图1：血液病和风湿病患者B细胞耗竭后疫苗反应性恢复的动力学。Paneesha: Roche; Honoraria；詹森:谢礼;基:谢礼;百时美施贵宝：荣誉；AbbVie:谢礼;Celgene公司:谢礼。Abingdon Health：目前持有一家私人控股公司的个股。
Background: Anti-CD20 B cell depleting agents are amongst the most commonly used immunotherapeutics employed in the treatment of haematological malignancy and autoimmune diseases. By inducing peripheral B cell aplasia, anti-CD20 depleting agents are hypothesised to significantly impair serological responses to neoantigens, including the SARS-CoV-2 spike glycoprotein within SARS-CoV-2 vaccines. Seropositivity following SARS-CoV-2 is the strongest, measurable correlate of protection from severe COVID-19. Understanding the kinetics of B cell reconstitution and vaccine responsiveness following exposure to B cell depleting agents is essential to maximise vaccine efficacy in patients vulnerable to severe COVID-19. Methods: 80 patients with underlying haematological malignancy and 38 patients with underlying rheumatological disease previously treated with anti-CD20 B cell depleting agents were studied following their second dose of a SARS-CoV-2 vaccine (median time to sampling: 46.5d, IQR: 33.8-63.3). Lymphocyte subset (CD4, CD8, CD19, CD56/16) enumeration was performed using 6 colour flow cytometry (BD Trucount). Total anti-SARS-CoV-2 spike glycoprotein antibodies were measured by enzyme-linked immunosorbent assay (The Binding Site, Human Anti-IgG/A/M SARS-CoV-2-ELISA). The relationship between immune reconstitution following B cell depletion and vaccine responsiveness was explored. Results: In the haematology cohort (median age 70y, IQR 60.3-76.0, 62.5% male), overall seropositivity following vaccination was 60.0%. Individuals on active chemotherapy had significantly lower seroprevalence than those vaccinated following the completion of chemotherapy (22.7% vs 74.1%, p<0.0001). In the rheumatology cohort (median age 65y, IQR 58.3-70.8, 39.9% male), overall seropositivity was 69.4%. In both cohorts, vaccine non-responders had significantly smaller populations of peripheral CD19+ B cells (haematology: 0.20 vs 0.02 x10 9/L, p=0.004, rheumatology: 0.07 vs 0.01 x10 9/L, p=0.03). The magnitude of the antibody response following vaccination did not differ between recipients of Tozinameran and Vaxzeveria in either cohort. Vaccine responsiveness was lower in the first 6 months following B cell depletion therapy; 42.9% in the haematology cohort and 33.3% in the rheumatology cohort, increasing to 100% and 75% respectively in individuals receiving their second dose 6-12 months following B cell depletion (Figure 1). B cell reconstitution in the 7-12 month window following B cell depletion was faster in haematology compared to rheumatology patients (77.8% v 22.2% achieving normal B cell count, p=0.005) and associated with improved vaccine responsiveness. However, persistent immunodeficiency occurred in some haematology patients following completion of treatment: 25% of patients who had completed therapy at least 36 months previously failed to respond to vaccination. In this cohort of vaccine non-responders, 83.3% of individuals had B cell numbers within the normal range. These patients had all previously been treated for follicular lymphoma suggesting a specific mechanism for long-range secondary immunodeficiency in these patients. Conclusions: Serological responsiveness to SARS-CoV-2 vaccines is poor during active chemotherapy for haematological malignancy and in the first 6 months following B cell depletion, regardless of underlying disease. Vaccine responsiveness significantly improves in the 7-12 month window following B cell depletion. Compared to haematology patients, B cell reconstitution is slower in rheumatology patients and associated with reduced vaccine responsiveness, possibly due to the use of additional concurrent disease-modifying anti-rheumatic therapies. Furthermore, long-term secondary immunodeficiency occurs in a minority of haematology patients. To maximise the efficacy from SARS-CoV-2 booster vaccination and optimal utilisation of available vaccine doses, immunisations should be delivered at least 6 months following the administration of anti-CD20 depleting drugs. Figure 1: Kinetics of return of vaccine responsiveness following B cell depletion in haematology and rheumatology patients. Paneesha: Roche: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Bristol Myers Squibb: Honoraria; AbbVie: Honoraria; Celgene: Honoraria. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company.