Systemic light chain (AL) amyloidosis is caused by a usually small plasma cell clone that produces amyloidogenic immunoglobulin light chains. This clone may affect immune competence and immune system fitness but, in addition, organ dysfunction, leading to heart failure, nephrotic range proteinuria, malabsorption, etc. further increases susceptibility to infections and risk of complications. Anti-plasma cell therapies cause immunosuppression and have been associated with increased risk of infectious complications, including COVID-19.^{1, 2} Vaccination against Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the best strategy to avoid severe Coronavirus disease 2019 (COVID-19),³ however, response to vaccines is compromised in patients with plasma cell malignancies or other B-cell lymphoproliferative disorders.^4-8

Data on the humoral responses to vaccination against COVID-19, for patients with AL amyloidosis is limited. Subjects with asymptomatic plasma cell dyscrasias (monoclonal gammopathy of undetermined significance [MGUS] or smoldering myeloma) may have attenuated responses to vaccination,⁶ but although the clones in these patients may be similar in extent to the plasma cell clone in AL amyloidosis, these patients are not receiving active therapy. We reported that after the first dose of vaccine in 59 patients with AL amyloidosis, there was a blunted humoral response; but results following the second dose of the vaccine were not available.⁹ We also observed that patients with transthyretin-related amyloidosis (ATTR^wt), despite their old age could mount a post-vaccination humoral response similar to their matched controls. We prospectively measured the titers of neutralizing antibodies (NAbs) against SARS-CoV-2 after vaccination with the Pfizer-BioNTech BNT162b2 mRNA vaccine and analyzed for factors that were related to seroconversion.

This report is part of larger prospective study (NCT04743388) assessing the kinetics of anti-SARS-CoV-2 antibodies development after COVID-19 vaccination. The major inclusion criteria for this analysis include: (i) a prior diagnosis of AL or ATTR amyloidosis and, (ii) eligibility for vaccination. As a control group, we used volunteers matched for age, gender (1:2), who had (i) no autoimmune or active malignant disease; (ii) no Human Immunodeficiency Virus (HIV) or active hepatitis B, C infection. Serum was separated within 4 h from blood collection and stored at −80°C until the day of measurement. Collected samples refer to day 1 (D1; first BNT162b2 dose), day 22 (D22; second dose), and day 50 (D50; i.e., 4 weeks after the second dose of the vaccine). NAbs against SARS-CoV-2 were measured using an FDA approved surrogate assay (ELISA, cPass™ SARS-CoV-2 NAbs Detection Kit; GenScript, Piscataway, NJ). We used the 30% inhibition cut-off for this surrogate NAbs test as previously suggested¹⁰; a titer of at least 50% is considered a clinically relevant threshold for viral inhibition.¹¹ The study was approved by the respective Ethical Committees in accordance with the Declaration of Helsinki and all patients and controls have provided written informed consent prior to enrollment. The primary end point of the study was the NAbs titer on D50. Details of the analysis are provided in the online supplement.

The final analysis included 126 fully monitored patients who were included in the final analysis (68 males/58 females, median age: 66, and range 35–86). The control group included 252 (ratio 1:2) fully matched controls (for age, gender) (136 male/116 females; median age: 66, and range 35–86 years). The median body mass index (BMI) of patients with AL amyloidosis was 25.4 kg/m² (range 17.9–42.4) and of controls was 26.2 kg/m² (range 17.4–42.7) (p = .704).

At the time of vaccination, 66 (52%) patients with AL amyloidosis were on active therapy, 29 (24%) were on daratumumab-based therapy, 8 had completed therapy but <3 months from the first dose of the vaccine and 52 (43%) had discontinued therapy >3 months from the date of the first vaccine shot, 33 (27%) had prior exposure to daratumumab (at least 3 months had passed since the last dose), and 92 (75%) were in hematologic remission (hematologic Complete response [CR] or hematologic very good partial response [VGPR]). Among those not on therapy, median time since last dose was 26 months (range 3–118). More patients' characteristics are shown in Table S1.

Prior to the first dose (D1), the NAb titers were similar between patients and controls (median 14.9% [IQR 7.8%–23.1%] vs. 14% [IQR 6.8%–22.9%], p = .439). Eight (6.5%) patients with AL amyloidosis patients had baseline NAbs ≥30% (positivity cutoff), of which five reported a history of prior COVID-19 infection. Among controls, 24 (9.9%) had NAb titers of ≥30% (Figure 1A).

On D22 after the first dose of the BNT162b2 vaccine, there was a significant increase of NAbs titers both in controls and AL patients (both p < .001); however, the median NAbs titer was 23.6% (IQR 12.4%–37.7%) in patients with AL amyloidosis versus 47.5% (IQR 32.1%–62.7%) in the control group (p < .001). Thus, 18% of AL patients versus 44.7% of controls (p < .001) developed NAb titers ≥50%; this level of Nabs is associated with clinically relevant viral inhibition¹¹ (Figure 1A).

On D50 after the initial vaccine shot (4 weeks after the second shot), there was further increase in NAbs titers both in controls and AL patients (for both p < .001) and median NAbs titer for AL patients was 83.1% (IQR 41.5%–94.9%) versus 95.6% (IQR 91.7%–97.2%) in controls (p < .001). Thus, after completion of the two doses, 71% of patients with AL amyloidosis versus 98% of matched controls (p < .001) developed NAb titers ≥50% (Figure 1A).

In univariate analysis, factors associated with NAb titers on D50 included age (p < .001), lymphocyte counts (p < .001), serum albumin (p < .001) and amount of proteinuria at the time of vaccination (p = .047), renal involvement (p = .047), use of steroids (p < .001), active treatment (p < .001), treatment-free interval (p = .001) and remission status (CR/VGPR vs. PR/NR) (p = .018). There was no significant association of D50 Nabs titers with gender (p = .092), BMI (p = .198), serum IgG (0.099), IgA (p = .789), or IgM levels (p = .687) or low (i.e., below lower limit of normal) of at least one of the noninvolved immunoglobulin (p = .179) at the time of vaccination, as well as of liver (p = .521) or heart involvement by amyloidosis (p = .141).

Patients on active therapy had lower NAb titers at D50 (median 51.5% [IQR 25.3%–84.1%] vs. 91.6% [IQR 74.5%–96.5%]) compared to those not on active treatment (p < .001). Specifically, 51% of patients on anti-clonal therapy had a D50 NAb titer ≥50% versus 87% of those who were not on therapy. There was no difference in the baseline NAb titers among those on or off active therapy, while on D22 (i.e., after 1st dose) the NAbs titer was higher among those on therapy but statistical difference was marginal (median 30% vs. 19.6%, p = .052). Thus, after the second dose, the response among those not on therapy was substantially more robust than in patients receiving anti-clonal therapy (Figure 1B). Notably, on D22, NAb titers among AL patients not on active therapy were still significantly lower as compared to non-AL controls (median 27.9 vs. 46.7%, p < .001) as well as on D50 (median 91.6% vs. 95.6%, p < .001). Using receiver operating characteristic (ROC) analysis, we found that at least 3 months since the last dose of therapy were associated with significantly higher probability of ≥50% NAbs on D50 (sensitivity: 62%, specificity: 80%, AUC: 0.690, p = .001).

Among patients on treatment, there was no significant difference between those on bortezomib-based therapy (VCD) versus those on daratumumab-alone therapy, those on daratumumab with VCD or those on IMiDs, or those with current or prior use of cyclophosphamide. Active therapy containing daratumumab did not affect NAbs titers among patients on active therapy (median NAb titer was 52.1% vs. 46.4% for those not receiving treatment with daratumumab, p = .486). Similarly, among patients not on active treatment, prior exposure to daratumumab did not affect D50 NAb titers (92.1% vs. 91.2%, p = .966) (Figure 1C). Six (5%) patients had a history of prior autologous stem cell transplantation (ASCT) with a median time since transplant of 61 months, (range 6–184); median NAb titer at D50 was 89% for this group of patients with two patients having NAbs titers below 50%.

Generalized linear models after normalization of NAb titers, were used for evaluation of multiple factors associated with D50 NAb titers (Table S3). Specifically, at least 3 months since the last dose of anticlonal therapy (p < .001), lymphocyte counts (p = .001) and serum albumin levels at the time of vaccination (p = .020) were independent predictors of NAb titers on D50.

Focusing on significant (i.e., protective) seroconversion (defined as NAbs titer ≥50% at D50), we performed a multiple logistic regression analysis. In this analysis, >3 months of treatment-free interval (OR: 7.75, p < .001), was the strongest predictive factor associated with activation of humoral immune responses (Table S2).

Among the patients in the study, one was infected and developed very mild symptoms after the first and before the second dose and two patients were infected but remained completely asymptomatic more than 2 weeks after the second dose (in both testing was performed because of close home contact with an infected individual).

We also compared NAbs titers of patients with ATTR^wt (N = 22) to age and gender matched controls (N = 44, 1:2 matching, median age 84, range 72–92 in both) (Table S4) that were vaccinated with BNT162b2; 18 (82%) of the patients were receiving tafamidis (61 mg dose). The median baseline NAb titers were similar (23% for patients with ATTR^wt vs. 16% for controls, p = .717) as well as on D22 (40.5% for ATTR^wt vs. 41.2% for controls, p = .596) and on D50 (92.2% vs. 94.2%, p = .546) (Figure S1).

The data presented in this report indicate that patients with AL amyloidosis have an attenuated humoral response to vaccination with BNT162b2, as compared to matched controls. Our analysis indicates that the most important factor that negatively affects the development of NAbs after vaccination for COVID-19 is the administration of active anti-clonal therapy. This data point to the major immunosuppressive role of anti-plasma cell therapy but also to the immunosuppressive effect of the underlying plasma cell clone, even though the impact may be low. Thus, patients with AL amyloidosis do not differ significantly in their response to vaccination than patients with myeloma (data published from our group^{5, 6} and others^{7, 8}). Specifically, we recently reported that antibody response after vaccination with BNT162b2 in patients with myeloma depends on the type of anti-myeloma treatment.⁶ In the current study, in patients with AL amyloidosis, we observed that the use of daratumumab as part of the treatment regimen did not significantly affect antibody response, among those on active therapy, while prior exposure to daratumumab, also did not have any additive immunosuppressive effect. Data from our group in patients with myeloma indicated that daratumumab-based therapy was associated with lower NAb titers⁶; however, myeloma patients were more heavily pretreated than patients with AL amyloidosis and with more extensive and aggressive clones. In addition, weekly bortezomib with cyclophosphamide (the most widely used regimen in AL amyloidosis) is also associated with significant immunosuppression. Time from the last dose of therapy was a significant factor to predict an adequate antibody response; however, some patients may require more time to restore a fully functional immune system. We observed that a duration of at least 3 months after last dose of anti-clonal therapy before vaccination may affect humoral immune response. In support, in an exploratory analysis, not all patients had recovered lymphocyte counts at the time of vaccination (10% of those not in therapy had lymphocyte counts <1000/μL). Although it is recommended that a treatment-free period should precede and follow vaccination, this may not be feasible; in fact, although vaccination is an urgent need for those most vulnerable subjects, it may not be possible to hold treatment for a disease like AL amyloidosis. Nevertheless, patients on therapy who are in deep hematologic remission may still mount adequate NAbs titers. We also evaluated a small number of elderly patients with non-AL amyloidosis and no clonal disease (i.e., patients with ATTR^wt amyloidosis) and observed that they developed an antibody response that was similar to their age/gender-matched controls.

These results clearly support the need for further evaluation of possible booster doses in patients that fail to develop adequate antibody responses. Across these lines of possible interventions, recent data¹² from a small randomized study support that among transplant recipients receiving immunosuppression a third dose of the mRNA-1273 vaccine (Moderna) triggered substantially higher immunogenicity than placebo. Since there are similarities in the level of immunosuppression caused by anti-clonal therapies for AL amyloidosis (as well as for myeloma and lymphomas), a similar strategy is probably a likely indication, but has not yet been approved by the authorities. Nonetheless, our data provide evidence that there is an urgent need to adopt strategies that can enhance a clinically meaningful protective seroconversion in patients with AL amyloidosis (either on therapy or after therapy). Given the ongoing spread of the SARS-CoV-2 B.1.617.2 (or delta) variant with increased infectivity, this need becomes urgent. Recently, a booster dose has been recommended for immunocompromised patients in many countries, including those who had been vaccinated with BNT162b2. Our data indicate that such a strategy could indeed be beneficial for many patients who failed to achieve seroconversion, or who may have waning antibody levels.

Our study was not designed to assess clinical efficacy of vaccination in patients with AL amyloidosis. Among the 126 vaccinated patients, there were only two cases of asymptomatic infection, despite the increasing infection rates in Greece. For the evaluation of efficacy, we used the previously reported threshold of at least 50% titer for neutralizing antibodies. However, even lower levels of NAb titers may be protective against severe infection,¹³ while new variants of SARS-CoV-2 may be associated with resistance to antibodies requiring higher Nab titers for effective clinical protection. There is evidence that NAbs against Wuhan strain, elicited after vaccination with current vaccines display significant activity against other variants of concern, including the delta variant, although neutralizing serum responses may be weaker.^{14, 15} In a recent paper by Rosati et al.,¹⁶ the authors found that anti-spike antibodies from the vaccine recipients (naïve and convalescent) and SARS-CoV-2 convalescent patients show a strong ability to recognize and neutralize the autologous WA1, as well as the Alpha and Delta Spike variants but that they show greatly impaired recognition of Beta, in agreement with others. Furthermore, they found a strong direct correlation between NAbs against WA1 and Delta variant, supporting the notion that individuals with robust NAb against WA1 also strongly neutralize Delta. This data indicates that a title of NAb >50% may not be as protective against delta variant infection, but the clinically relevant threshold is difficult to define. Finally, in the current study, we did not evaluate the antiviral T and B cell memory responses after vaccination, which may also be affected in patients with AL amyloidosis, and which are also important for protection from the infection.In conclusion, patients with AL amyloidosis have a less robust response to anti-SARS-CoV-2 vaccination as compared to matched controls. Our data point to the critical role of concomitant anti-clonal therapy, which significantly reduced the probability of an adequate antibody response and protective seroconversion. Moreover, our data support the need for additional booster doses, especially for those on active therapy.

全身性轻链 (AL) 淀粉样变性是由产生淀粉样蛋白原免疫球蛋白轻链的通常较小的浆细胞克隆引起的。这种克隆可能会影响免疫能力和免疫系统健康，但此外，器官功能障碍，导致心力衰竭、肾病范围蛋白尿、吸收不良等，进一步增加了感染的易感性和并发症的风险。抗浆细胞疗法会导致免疫抑制，并与感染并发症（包括 COVID-19）的风险增加有关。^{1, 2}针对严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 的疫苗接种是避免 2019 年严重冠状病毒病 (COVID-19) 的最佳策略，³然而，浆细胞恶性肿瘤或其他 B 细胞淋巴增生性疾病患者对疫苗的反应受到损害。^4-8

AL 淀粉样变性患者对 COVID-19 疫苗接种的体液反应数据有限。患有无症状浆细胞恶液质（意义不明的单克隆丙种球蛋白病 [MGUS] 或冒烟性骨髓瘤）的受试者可能对疫苗接种的反应减弱，⁶但尽管这些患者的克隆可能与 AL 淀粉样变性的浆细胞克隆的程度相似，但这些患者没有接受积极治疗。我们报道了 59 名 AL 淀粉样变性患者在接种第一剂疫苗后，出现了迟钝的体液反应；但无法获得第二剂疫苗后的结果。⁹我们还观察到转甲状腺素蛋白相关淀粉样变性（ATTR ^wt)，尽管他们年纪大了，但接种后的体液反应与他们匹配的对照组相似。在接种 Pfizer-BioNTech BNT162b2 mRNA 疫苗后，我们前瞻性地测量了针对 SARS-CoV-2 的中和抗体 (NAb) 的滴度，并分析了与血清转化相关的因素。

本报告是评估 COVID-19 疫苗接种后抗 SARS-CoV-2 抗体发展动力学的大型前瞻性研究 (NCT04743388) 的一部分。该分析的主要纳入标准包括：(i) AL 或 ATTR 淀粉样变性的先前诊断，以及 (ii) 接种疫苗的资格。作为对照组，我们使用年龄、性别 (1:2) 匹配的志愿者，他们 (i) 没有自身免疫性疾病或活动性恶性疾病；(ii) 没有人类免疫缺陷病毒 (HIV) 或活动性乙型、丙型肝炎感染。在 4 小时内从血液收集中分离血清并储存在 -80°C 直至测量当天。收集的样本是指第 1 天（D1；第一剂 BNT162b2）、第 22 天（D22；第二剂）和第 50 天（D50；即第二剂疫苗后 4 周）。使用 FDA 批准的替代检测（ELISA，cPass™ SARS-CoV-2 NAbs 检测试剂盒；金斯瑞，新泽西州皮斯卡塔韦）。如前所述，我们使用 30% 的抑制临界值来进行此替代 NAb 测试¹⁰ ; 至少 50% 的滴度被认为是病毒抑制的临床相关阈值。¹¹根据赫尔辛基宣言，该研究得到了各自的伦理委员会的批准，所有患者和对照在入组前均已提供书面知情同意书。该研究的主要终点是第 50 天的 NAb 滴度。在线补充提供了分析的详细信息。

最终分析包括 126 名完全监测的患者，他们被纳入最终分析（68 名男性/58 名女性，中位年龄：66，范围 35-86）。对照组包括 252 名（比例为 1:2）完全匹配的对照（年龄、性别）（136 名男性/116 名女性；中位年龄：66 岁，范围 35-86 岁）。AL 淀粉样变性患者的中位体重指数 (BMI) 为 25.4 kg/m ²（范围 17.9–42.4），对照组为 26.2 kg/m ²（范围 17.4–42.7）（p  = .704）。

在接种疫苗时，66 名 (52%) AL 淀粉样变性患者正在接受积极治疗，29 名 (24%) 正在接受基于达雷妥尤单抗的治疗，8 名已完成治疗但距离第一剂疫苗不到 3 个月，52 ( 43%) 自第一次接种疫苗之日起 3 个月以上停止治疗，33 (27%) 名之前曾接触过达雷妥尤单抗（自最后一次接种以来至少已过去 3 个月），92 名 (75%) 处于血液学状态缓解（血液学完全缓解 [CR] 或血液学非常好的部分缓解 [VGPR]）。在未接受治疗的患者中，自上次给药后的中位时间为 26 个月（范围 3-118）。更多患者的特征见表S1。

在第一次给药 (D1) 之前，患者和对照之间的 NAb 滴度相似（中位数 14.9% [IQR 7.8%–23.1%] 与 14% [IQR 6.8%–22.9%]，p  = .439）。8 名 (6.5%) AL 淀粉样变性患者的基线 NAb ≥ 30%（阳性截止值），其中 5 名报告了既往 COVID-19 感染史。在对照中，24 个 (9.9%) 的 NAb 滴度≥30%（图 1A）。

在第一剂 BNT162b2 疫苗后的第 22 天，对照组和 AL 患者的 NAb 滴度均显着增加（均p  < .001）；然而，AL 淀粉样变性患者的 NAb 滴度中位数为 23.6%（IQR 12.4%–37.7%），而对照组为 47.5%（IQR 32.1%–62.7%）（p  < .001）。因此，18% 的 AL 患者与 44.7% 的对照组 ( p  < .001) 的 NAb 滴度≥50%；这种 Nabs 水平与临床相关的病毒抑制相关¹¹（图 1A）。

在第一次疫苗注射后的第 50 天（第二次注射后 4 周），对照组和 AL 患者的 NAb 滴度进一步增加（p  < .001），AL 患者的 NAb 滴度中位数为 83.1%（IQR 41.5 %–94.9%) 与对照组的 95.6% (IQR 91.7%–97.2%) ( p  < .001)。因此，在完成两个剂量后，71% 的 AL 淀粉样变性患者与 98% 的匹配对照 ( p  < .001) 的 NAb 滴度≥50%（图 1A）。

在单变量分析中，与第50 天 NAb 滴度相关的因素包括年龄 ( p  < .001)、淋巴细胞计数 ( p  < .001)、血清白蛋白 ( p  < .001) 和疫苗接种时的蛋白尿量 ( p  = .001) 。 047)、肾脏受累 ( p  = .047)、使用类固醇 ( p  < .001)、积极治疗 ( p  < .001)、无治疗间隔 ( p  = .001) 和缓解状态（CR/VGPR vs. PR/NR) ( p  = .018)。D50 Nabs 滴度与性别 ( p  = .092)、BMI ( p  = .198)、血清 IgG (0.099)、IgA ( p  = .789) 或 IgM 水平没有显着相关性（p  = .687) 或低（即低于正常下限）至少一种非 受累免疫球蛋白 ( p = .179) 以及肝脏 ( p  = .521) 或心脏受累通过淀粉样变性 ( p  = .141)。

与未接受积极治疗的患者相比，接受积极治疗的患者在第 50 天的 NAb 滴度较低（中位数 51.5% [IQR 25.3%–84.1%] vs. 91.6% [IQR 74.5%–96.5%]）（p  < .001）。具体而言，51% 接受抗克隆治疗的患者的 D50 NAb 滴度≥50%，而未接受治疗的患者则为 87%。接受或不接受积极治疗的患者的基线 NAb 滴度没有差异，而在第 22 天（即第 1 次给药后），接受治疗的患者的 NAb 滴度更高，但统计学差异很小（中位数 30% 对 19.6%，p = .052）。因此，在第二次给药后，未接受治疗的患者的反应明显强于接受抗克隆治疗的患者（图 1B）。值得注意的是，在第 22 天，未接受积极治疗的 AL 患者的 NAb 滴度仍显着低于非 AL 对照组（中位数 27.9 对 46.7%，p  < .001）以及第 50 天（中位数 91.6% 对 95.6） %，p  < .001）。使用受试者工作特征 (ROC) 分析，我们发现自最后一剂治疗以来至少 3 个月与 D50 ≥50% NAb 的显着更高概率相关（敏感性：62%，特异性：80%，AUC：0.690，p  = .001）。

在接受治疗的患者中，接受基于硼替佐米治疗 (VCD) 的患者与接受达雷妥尤单抗单药治疗的患者、接受达雷妥尤单抗联合 VCD 治疗的患者或接受 IMiD 治疗的患者，或目前或之前使用过环磷酰胺的患者之间没有显着差异。含有达雷妥尤单抗的积极治疗不影响接受积极治疗的患者的 NAb 滴度（中位 NAb 滴度为 52.1% 对未接受达雷妥尤单抗治疗的患者为 46.4%，p  = .486）。同样，在未接受积极治疗的患者中，先前暴露于达雷妥尤单抗不影响 D50 NAb 滴度（92.1% 与 91.2%，p = .966)（图 1C）。6 名 (5%) 患者有既往自体干细胞移植 (ASCT) 史，移植后中位时间为 61 个月（范围 6-184）；这组患者在 D50 时的中位 NAb 滴度为 89%，其中两名患者的 NAb 滴度低于 50%。

NAb 滴度标准化后的广义线性模型用于评估与 D50 NAb 滴度相关的多个因素（表 S3）。具体而言，自最后一剂抗克隆治疗 ( p  < .001)起至少 3 个月 ，接种疫苗时的淋巴细胞计数 ( p = .001) 和血清白蛋白水平 ( p  = .020) 是 NAb 滴度的独立预测因子D50。

关注显着（即保护性）血清转化（定义为 D50 时 NAb 滴度≥50%），我们进行了多元逻辑回归分析。在该分析中，>3 个月的无治疗间隔（OR：7.75，p  < .001）是与体液免疫反应激活相关的最强预测因素（表 S2）。

在研究中的患者中，一名患者在第一次和第二次给药后被感染并出现非常轻微的症状，两名患者被感染但在第二次给药后超过 2 周仍完全无症状（在两次测试中，由于居家隔离而进行了两次测试）与感染者接触）。

我们还比较了 ATTR ^wt（N  = 22）患者与年龄和性别匹配的对照（N  = 44，1:2 匹配，中位年龄 84，两者的范围均为 72-92）（表 S4）的 NAb 滴度，后者接种了BNT162b2；18 (82%) 名患者正在接受 tafamidis（61 毫克剂量）。中值基线 NAb 滴度相似（ATTR ^wt患者为 23%，对照组为 16%，p  = .717）以及 D22（ATTR ^wt为40.5 %，对照组为 41.2%，p  = .596）和 D50（92.2% 对 94.2%，p  = .546）（图 S1）。

本报告中提供的数据表明，与匹配的对照相比，AL 淀粉样变性患者对接种 BNT162b2 的体液反应减弱。我们的分析表明，对 COVID-19 疫苗接种后 NAb 的发展产生负面影响的最重要因素是给予积极的抗克隆治疗。该数据表明抗浆细胞疗法的主要免疫抑制作用以及潜在浆细胞克隆的免疫抑制作用，尽管影响可能很小。因此，AL 淀粉样变性患者对疫苗接种的反应与骨髓瘤患者相比没有显着差异（数据来自我们组^5、6和其他^7、8）。具体而言，我们最近报道了骨髓瘤患者接种 BNT162b2 后的抗体反应取决于抗骨髓瘤治疗的类型。⁶在目前的研究中，在 AL 淀粉样变性患者中，我们观察到，在接受积极治疗的患者中，使用达雷妥尤单抗作为治疗方案的一部分并未显着影响抗体反应，而先前使用达雷妥妥单抗的患者也没有任何添加剂免疫抑制作用。我们小组在骨髓瘤患者中的数据表明，基于达雷妥尤单抗的治疗与较低的 NAb 滴度相关⁶; 然而，与 AL 淀粉样变性患者相比，骨髓瘤患者接受了更严格的预处理，并且具有更广泛和更具侵袭性的克隆。此外，每周一次硼替佐米联合环磷酰胺（AL 淀粉样变性最广泛使用的方案）也与显着的免疫抑制有关。从最后一剂治疗开始的时间是预测足够抗体反应的重要因素；然而，一些患者可能需要更多时间来恢复功能齐全的免疫系统。我们观察到，在接种前最后一剂抗克隆治疗后至少 3 个月的持续时间可能会影响体液免疫反应。作为支持，在一项探索性分析中，并非所有患者在接种疫苗时都恢复了淋巴细胞计数（10% 未接受治疗的患者淋巴细胞计数 <1000/μL）。虽然建议在接种疫苗之前和之后有一段无治疗期，但这可能不可行；事实上，尽管对那些最脆弱的受试者来说，接种疫苗是一种迫切需要，但可能无法对像 AL 淀粉样变性这样的疾病进行治疗。尽管如此，处于血液学深度缓解的接受治疗的患者仍可能获得足够的 NAb 滴度。我们还评估了少数患有非 AL 淀粉样变性和无克隆性疾病的老年患者（即 ATTR 患者^wt淀粉样变性）并观察到他们产生了与年龄/性别匹配的对照组相似的抗体反应。

这些结果清楚地支持进一步评估未能产生足够抗体反应的患者可能的加强剂量的必要性。在这些可能的干预措施中，最近的数据¹²一项小型随机研究表明，在接受免疫抑制的移植受者中，第三剂 mRNA-1273 疫苗（Moderna）引发的免疫原性显着高于安慰剂。由于 AL 淀粉样变性（以及骨髓瘤和淋巴瘤）的抗克隆疗法引起的免疫抑制水平相似，因此类似的策略可能是一种可能的适应症，但尚未得到当局的批准。尽管如此，我们的数据提供的证据表明，迫切需要采用可以增强 AL 淀粉样变性患者（治疗中或治疗后）具有临床意义的保护性血清转换的策略。鉴于 SARS-CoV-2 B.1.617.2（或 delta）变体的持续传播以及传染性的增加，这一需求变得紧迫。最近，许多国家已建议对免疫功能低下的患者进行加强剂量，包括已接种 BNT162b2 的患者。我们的数据表明，这种策略确实对许多未能实现血清转换或抗体水平下降的患者有益。

我们的研究并非旨在评估疫苗接种对 AL 淀粉样变性患者的临床疗效。尽管希腊的感染率不断上升，但在 126 名接种疫苗的患者中，只有两例无症状感染者。为了评估功效，我们使用先前报告的中和抗体滴度至少为 50% 的阈值。然而，即使是较低水平的 NAb 滴度也可能对严重感染有保护作用，¹³而 SARS-CoV-2 的新变体可能与对需要更高 Nab 滴度以提供有效临床保护的抗体的抗性有关。有证据表明，在用当前疫苗接种疫苗后引发的针对武汉毒株的 NAb 显示出对其他关注变体（包括 delta 变体）的显着活性，尽管中和血清反应可能较弱。^{14, 15}在 Rosati 等人最近的一篇论文中，¹⁶作者发现，来自疫苗接受者（初治和恢复期）和 SARS-CoV-2 恢复期患者的抗刺突抗体显示出强大的识别和中和自体 WA1 以及 Alpha 和 Delta Spike 变体的能力，但它们显示与他人一致，大大削弱了对 Beta 的认可。此外，他们发现 NAb 与 WA1 和 Delta 变体之间存在很强的直接相关性，支持具有强大 NAb 的个体也能强烈中和 Delta 的观点。该数据表明，NAb > 50% 的标题可能不会对 delta 变体感染起到保护作用，但临床相关阈值很难定义。最后，在目前的研究中，我们没有评估疫苗接种后的抗病毒 T 和 B 细胞记忆反应，这也可能在 AL 淀粉样变性患者中受到影响，这对于防止感染也很重要。 总之，与匹配的对照相比，AL 淀粉样变性患者对抗 SARS-CoV-2 疫苗的反应较弱。我们的数据指出伴随抗克隆治疗的关键作用，它显着降低了充分抗体反应和保护性血清转换的可能性。此外，我们的数据支持需要额外的加强剂量，特别是对于那些接受积极治疗的人。这显着降低了充分抗体反应和保护性血清转化的可能性。此外，我们的数据支持需要额外的加强剂量，特别是对于那些接受积极治疗的人。这显着降低了充分抗体反应和保护性血清转化的可能性。此外，我们的数据支持需要额外的加强剂量，特别是对于那些接受积极治疗的人。