Introduction

Patients with primary or secondary immunodeficiency (PID or SID) face increased insecurity and discomfort in the light of the COVID-19 pandemic, not knowing if and to what extent their comorbidities may impact the course of a potential SARS-CoV-2 infection. Furthermore, recently available vaccination options might not be amenable or effective for all patients in this heterogeneous population. Therefore, these patients often rely on passive immunization with plasma-derived, intravenous or subcutaneous immunoglobulin (IVIG/SCIG).

Whether the ongoing COVID-19 pandemic and/or the progress in vaccination programs lead to increased and potentially protective titers in plasma-derived immunoglobulins (Ig) indicated (e.g., for humoral immunodeficiency) remains a pressing question for this patient population.

Purpose

We investigated SARS-CoV-2 reactivity of US plasma-derived IVIG/SCIG products from the end of 2020 until June 2021 as well as in convalescent plasma (CP) from May 2020 to August 2020 to determine whether potentially neutralizing antibody titers may be present.

Methods

Final containers of IVIG/SCIG and CP donations were analyzed by commercial ELISA for anti-SARS-CoV-2 S1-receptor binding domain (RBD) IgG as well as microneutralization assay using a patient-derived SARS-CoV-2 (D614G) isolate. Neutralization capacities of 313 single plasma donations and 119 plasma-derived IVIG/SCIG lots were determined. Results obtained from both analytical methods were normalized against the WHO International Standard. Finally, based on dense pharmacokinetic profiles of an IVIG preparation from previously published investigations, possible steady-state plasma levels of SARS-CoV-2 neutralization capacities were approximated based on currently measured anti-SARS-CoV-2 potencies in IVIG/SCIG preparations.

Results

CP donations presented with high variability with regards to anti-SARS-CoV-2 reactivity in ELISA as well as in neutralization testing. While approximately 50% of convalescent donations were not/low neutralizing, approximately 10% were at or above 600 IU/mL. IVIG/SCIG lots derived from pre-pandemic plasma donations did not show neutralizing capacities for SARS-CoV-2. Lots produced between December 2020 and June 2021 entailing plasma donations after the emergence of SARS-CoV-2 showed a rapid and constant increase in anti-SARS-CoV-2 reactivity and neutralization capacity over time. While lot-to-lot variability was substantial, neutralization capacity increased from a mean of 21 IU/mL in December 2020 to 506 IU/mL in June 2021 with a maximum of 864 IU/mL for the most recent lots. Pharmacokinetic extrapolations, based on non-compartmental superposition principles using steady-state reference profiles from previously published pharmacokinetic investigations on IVIG in PID, yielded potential steady-state trough plasma levels of 16 IU/mL of neutralizing SARS-CoV-2 IgG based on the average final container concentration from May 2021 of 216 IU/mL. Maximum extrapolated trough levels could reach 64 IU/mL based on the latest maximal final container potency tested in June 2021.

Conclusions

SARS-CoV-2 reactivity and neutralization capacity in IVIG/SCIG produced from US plasma rapidly and in part exponentially increased in the first half of 2021. The observed increase of final container potencies is likely trailing the serological status of the US donor population in terms of COVID-19 convalescence and vaccination by at least 5 months due to production lead times and should in principle continue at least until Fall 2021. In summary, the data support rapidly increasing levels of anti-SARS-CoV-2 antibodies in IVIG/SCIG products, implicating that a certain level of protection could be possible against COVID-19 for regularly substituted PID/SID patients. Nevertheless, more research is still needed to confirm which plasma levels are needed to provide protection against SARS-CoV-2 infection in immune-compromised patients.

中文翻译：

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恢复期血浆中的 SARS-CoV-2 中和作用和大量血浆衍生免疫球蛋白

介绍

鉴于 COVID-19 大流行，原发性或继发性免疫缺陷（PID 或 SID）患者面临着更多的不安全感和不适感，他们不知道他们的合并症是否以及在多大程度上会影响潜在的 SARS-CoV-2 感染的进程。此外，最近可用的疫苗接种方案可能不适用于这一异质人群中的所有患者或有效。因此，这些患者通常依赖于使用血浆来源、静脉内或皮下免疫球蛋白 (IVIG/SCIG) 进行被动免疫。

持续的 COVID-19 大流行和/或疫苗接种计划的进展是否会导致血浆衍生免疫球蛋白 (Ig) 的指示滴度增加和潜在的保护性滴度（例如，体液免疫缺陷）仍然是该患者群体的一个紧迫问题。

目的

我们研究了 2020 年底至 2021 年 6 月期间美国血浆衍生 IVIG/SCIG 产品以及 2020 年 5 月至 2020 年 8 月恢复期血浆 (CP) 中的 SARS-CoV-2 反应性，以确定是否可能存在潜在的中和抗体滴度.

方法

IVIG/SCIG 和 CP 捐赠的最终容器通过商业 ELISA 分析抗 SARS-CoV-2 S1 受体结合域 (RBD) IgG 以及使用患者来源的 SARS-CoV-2 (D614G) 分离物进行微中和测定. 测定了 313 个单次血浆捐赠和 119 个血浆衍生的 IVIG/SCIG 批次的中和能力。两种分析方法获得的结果均根据 WHO 国际标准进行了标准化。最后，基于先前发表的研究中 IVIG 制剂的密集药代动力学特征，基于目前在 IVIG/SCIG 制剂中测量的抗 SARS-CoV-2 效力，估计了 SARS-CoV-2 中和能力的可能稳态血浆水平。

结果

CP 捐赠在 ELISA 和中和测试中的抗 SARS-CoV-2 反应性方面呈现出高度可变性。虽然大约 50% 的恢复期捐赠没有中和/低中和，但大约 10% 达到或高于 600 IU/mL。来自大流行前血浆捐赠的 IVIG/SCIG 批次未显示出对 SARS-CoV-2 的中和能力。在 SARS-CoV-2 出现后，2020 年 12 月至 2021 年 6 月期间生产的需要血浆捐赠的批次显示，随着时间的推移，抗 SARS-CoV-2 反应性和中和能力迅速且持续增加。虽然批次间差异很大，但中和能力从 2020 年 12 月的平均 21 IU/mL 增加到 2021 年 6 月的 506 IU/mL，最近批次的最大值为 864 IU/mL。药代动力学外推，基于非隔室叠加原理，使用先前发表的关于 PID 中 IVIG 的药代动力学研究的稳态参考曲线，基于平均最终容器，产生 16 IU/mL 中和 SARS-CoV-2 IgG 的潜在稳态谷血浆水平从 2021 年 5 月开始，浓度为 216 IU/mL。根据 2021 年 6 月测试的最新最大最终容器效力，推断的最大谷值水平可能达到 64 IU/mL。

结论

从美国血浆生产的 IVIG/SCIG 中的 SARS-CoV-2 反应性和中和能力在 2021 年上半年迅速并部分呈指数增长。观察到的最终容器效力的增加可能落后于美国供体人群的血清学状态由于生产提前期，COVID-19 恢复期和疫苗接种至少提前 5 个月，原则上应至少持续到 2021 年秋季。总之，数据支持 IVIG/SCIG 中抗 SARS-CoV-2 抗体水平迅速增加产品，这意味着对于定期更换的 PID/SID 患者，可以对 COVID-19 提供一定程度的保护。尽管如此，仍需要更多的研究来确认需要哪些血浆水平来保护免疫受损患者免受 SARS-CoV-2 感染。