Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
JAMA Netw Open. 2022 May 2;5(5):e2211497. doi: 10.1001/jamanetworkopen.2022.11497.
B-cell-depleting monoclonal antibodies are widely used for treatment of multiple sclerosis but are associated with an impaired response to vaccines.
To identify factors associated with a favorable vaccine response to tozinameran.
DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study was conducted in a specialized multiple sclerosis clinic at a university hospital from January 21 to December 1, 2021. Of 75 patients evaluated for participation who received a diagnosis of multiple sclerosis with planned or ongoing treatment with rituximab, 69 were included in the study, and data from 67 were analyzed.
Sex, age, number of previous rituximab infusions, accumulated dose of rituximab, previous COVID-19 infection, time since last rituximab treatment, CD19+ B-cell count before vaccination, CD4+ T-cell count, and CD8+ T-cell count were considered potential factors associated with the main outcome.
Serological vaccine responses were measured by quantitation of anti-spike immunoglobulin G (IgG) antibodies, anti-receptor-binding domain (RBD) IgG antibodies, and their neutralizing capacities. Cellular responses to spike protein-derived SARS-CoV-2 peptide pools were assessed by counting interferon gamma spot-forming units in a FluoroSpot assay.
Among 60 patients with ongoing rituximab treatment (49 women [82%]; mean (SD) age, 43 [10] years), the median (range) disease duration was 9 (1-29) years, and the median (range) dose of rituximab was 2750 (500-10 000) mg during a median (range) time of 2.8 (0.5-8.3) years. The median (range) follow-up from the first vaccination dose was 7.3 (4.3-10.0) months. Vaccine responses were determined before vaccination with tozinameran and 6 weeks after vaccination. By using established cutoff values for anti-spike IgG (264 binding antibody units/mL) and anti-RBD IgG (506 binding antibody units/mL), the proportion of patients with a positive response increased with the number of B cells, which was the only factor associated with these outcomes. A cutoff for the B-cell count of at least 40/μL was associated with an optimal serological response. At this cutoff, 26 of 29 patients (90%) had positive test results for anti-spike IgG and 21 of 29 patients (72%) for anti-RBD IgG, and 27 of 29 patients (93%) developed antibodies with greater than 90% inhibition of angiotensin-converting enzyme 2. No factor associated with the cellular response was identified. Depending on the peptide pool, 21 of 25 patients (84%) to 22 of 25 patients (88%) developed a T-cell response with interferon gamma production at the B-cell count cutoff of at least 40/μL.
This cohort study found that for an optimal vaccine response from tozinameran, rituximab-treated patients with multiple sclerosis may be vaccinated as soon as possible, with rituximab treatment delayed until B-cell counts have reached at least 40/μL. An additional vaccination with tozinameran should be considered at that point.
B 细胞耗竭性单克隆抗体广泛用于多发性硬化症的治疗，但与疫苗反应受损有关。
确定与 tozinameran 疫苗良好反应相关的因素。
设计、地点和参与者：这项前瞻性队列研究于 2021 年 1 月 21 日至 12 月 1 日在一家大学医院的专门多发性硬化症诊所进行。在评估的 75 名计划或正在接受利妥昔单抗治疗的多发性硬化症患者中，有 69 名符合研究条件，其中 67 名的数据进行了分析。
性别、年龄、利妥昔单抗输注次数、利妥昔单抗累积剂量、既往 COVID-19 感染、上次利妥昔单抗治疗后时间、接种前 CD19+B 细胞计数、CD4+T 细胞计数和 CD8+T 细胞计数被认为是与主要结局相关的潜在因素。
通过定量检测抗刺突 IgG（IgG）抗体、抗受体结合域（RBD）IgG 抗体及其中和能力来测量血清学疫苗反应。通过计算 FluoroSpot 测定中干扰素 γ斑点形成单位来评估针对 Spike 蛋白衍生 SARS-CoV-2 肽池的细胞反应。
在 60 名正在接受利妥昔单抗治疗的患者（49 名女性[82%]；平均[标准差]年龄 43[10]岁）中，中位（范围）疾病持续时间为 9（1-29）年，中位（范围）利妥昔单抗剂量为 2750（500-10000）mg，中位（范围）时间为 2.8（0.5-8.3）年。从第一次接种剂量到 7.3（4.3-10.0）个月的中位随访时间。在接种 tozinameran 之前和接种后 6 周测定疫苗反应。使用抗刺突 IgG（264 结合抗体单位/mL）和抗 RBD IgG（506 结合抗体单位/mL）的既定临界值，随着 B 细胞数量的增加，阳性反应的比例增加，这是唯一与这些结果相关的因素。B 细胞计数至少为 40/μL 的临界值与最佳血清学反应相关。在此临界值下，29 名患者中有 26 名（90%）抗 Spike IgG 检测结果阳性，29 名患者中有 21 名（72%）抗 RBD IgG 检测结果阳性，29 名患者中有 27 名（93%）产生了大于 90%抑制血管紧张素转换酶 2 的抗体。未发现与细胞反应相关的因素。根据肽池的不同，25 名患者中有 21 名（84%）至 22 名（88%）在 B 细胞计数至少为 40/μL 的临界值下产生具有干扰素 γ产生的 T 细胞反应。
这项队列研究发现，对于接受 tozinameran 的最佳疫苗反应，接受利妥昔单抗治疗的多发性硬化症患者可能尽快接种疫苗，直到 B 细胞计数达到至少 40/μL 时再延迟利妥昔单抗治疗。此时应考虑再接种一次 tozinameran。
