To the Editor: Prophylactic or early post-exposure treatments with SARS-CoV-2–specific monoclonal antibodies (mAbs) were useful early in the COVID-19 pandemic. However, the currently circulating SARS-CoV-2 Omicron subvariants (e.g., XBB.1, JN.1 and its derivatives) are resistant to all approved mAb therapies (1). Immunoglobulin products (IGs) manufactured from pooled human plasma are widely used for treatment of patients with several immunodeficiency syndromes. Most IGs are administered intravenously and are called IVIGs.

Polyclonal hyperimmune anti–SARS-CoV-2 IVIGs (pi-hCoV-2IG) were manufactured in 2021 by fractionation of pooled plasma from COVID-19 convalescent patients with virus neutralization titers of 1:320 or greater against the ancestral WA-1 strain and contain IgG at 10-fold higher concentration than in individual convalescent plasma (CP). Vx-hCoV-2IG was generated from pooled plasma of SARS-CoV-2–vaccinated individuals (2021) (2). Some vaccinated individuals also reported prior SARS-CoV-2 infection. Since 2022, more than 90% of the blood donations in the United States had anti–SARS-CoV-2 antibodies, suggesting prior exposure by vaccination, infections, or both (hybrid immunity) (3). Therefore, we hypothesized that IVIG lots manufactured from unscreened plasma donors from 2022 onwards may contain anti–SARS-CoV-2 neutralizing antibodies against circulating Omicron subvariants.

To evaluate therapeutic potential of multiple lots of IVIG, pi-hCoV-2IG, and Vx-hCoV-2IG against circulating Omicron variants (Supplemental Table 1; supplemental material available online with this article; https://doi.org/10.1172/JCI182919DS1), we followed the STROBE reporting guideline (https://www.strobe-statement.org/) for cross-sectional studies. We tested 17 lots of pi-hCoV-2IG prepared from pooled plasma of convalescent individuals infected with SARS-CoV-2 in 2020 and one available Vx-hCoV-2IG lot manufactured from screened pooled plasma with high SARS-CoV-2 neutralization titers of mRNA-vaccinated individuals (hybrid immunity) who reported prior SARS-CoV-2 infection in 2021. Additionally, 20 IVIG preparations manufactured in 2019 from healthy plasma donations (2019-IVIG) before the COVID-19 pandemic, 8 IVIG lots manufactured in 2020 (2020-IVIG), 9 IVIG lots manufactured in 2023 (2023-IVIG), 5 IVIG lots manufactured in 2024 (2024-IVIG), 7 CP from recovered COVID-19 patients in early 2020 (2020-CP), and 8 CP from Omicron vaccine breakthrough infections in 2022 (2022-CP), all collected approximately 30 days after diagnosis, were analyzed for neutralization of SARS-CoV-2 WA-1 and 9 circulating Omicron subvariants (BA.2.86, XBB.1.16, XBB.2.3, EG.5, HV.1, HK.3, JN.1, JN.4, and JD.1.1) in a pseudovirus neutralization assay (PsVNA) (4).

CP collected from recovered COVID-19 patients in 2020 and 2022 as well post-infection hyperimmunoglobulin lots (pi-hCoV-2IG) show high neutralization titers against WA-1, but demonstrated minimal or no PsVNA titers against the current Omicron variants (Figure 1). The 2019-IVIG lots manufactured before the COVID-19 pandemic contained no SARS-CoV-2–neutralizing antibodies (Figure 1). The 2020-IVIG lots manufactured early in the COVID-19 pandemic contained low titers against WA-1, and no neutralizing titers against current Omicron subvariants. On the other hand, 2023-IVIG and 2024-IVIG lots contain high titers against WA-1 (geometric mean titer [GMT]: 16,212 and 30,722, respectively), reflecting the high SARS-CoV-2 seroprevalence in plasma donors. More importantly, these recent IVIG lots have weak to moderate titers against currently circulating variants, even though the donors were exposed to earlier Omicron variants (Supplemental Table 2). The surprising finding was that one lot of Vx-hCov-2IG that was produced in 2021 not only contains the highest titer against the original WA-1 strain (GMT: 69,551), but also high neutralization titers against all the recently circulating Omicron subvariants (GMT ranging between 401 and 11,416) (Figure 1). This finding may be due to vaccination/infection-induced cross-reactive B cells undergoing affinity maturation in germinal centers, resulting in broader high-affinity antibody repertoires that neutralize emerging Omicron subvariants (5).

Neutralization of SARS-CoV-2 WA1/2020 and circulating Omicron subvariants by IVIG, convalescent plasma, pi-hCoV-2IG, and Vx-hCoV-2IG. SARS-CoV-2 neutralization assays were performed by using pseudoviruses expressing the spike protein of WA1/2020 or the Omicron subvariants in 293-ACE2-TMPRSS2 cells. SARS-CoV-2 neutralization titers were determined in each of the prepandemic 2019-IVIG (n = 20), 2020-IVIG (n = 8), 2020 convalescent plasma (2020-CP; n = 7), 2022 convalescent plasma (2022-CP; n = 8), post-infection hyperimmunoglobulin IVIG (pi-hCoV-2IG; n = 17), 2023-IVIG (n = 9), 2024-IVIG (n = 5), and post-vaccination hyperimmunoglobulin IVIG (Vx-hCoV-2IG; n = 1) preparations. The assay was performed in duplicate to determine the 50% neutralization titer (PsVNA50). The heights of the bars and the numbers over the bars indicate the geometric mean titers, and the whiskers indicate 95% confidence intervals. The horizontal dashed line indicates the limit of detection for the neutralization assay (PsVNA50 of 20). Differences between SARS-CoV-2 strains were analyzed by ordinary 1-way ANOVA with Tukey’s pairwise multiple-comparison test in GraphPad Prism version 9.3.1 and the P values are shown.

Our finding demonstrates that high-titer IVIG lots can be manufactured from plasma screened for high neutralization titers against recent Omicron subvariants. Since the current circulating SARS-CoV-2 Omicron subvariants are resistant to all licensed mAbs, these cross-neutralizing IVIG lots can be an important intervention, particularly for immunocompromised patients and various autoimmune and neurological diseases, including patients with long COVID (6), to prevent or ameliorate the outcome of exposure with circulating and emerging SARS-CoV-2 strains.

Supplemental material

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Acknowledgments

We thank Basil Golding and Keith Peden at the FDA for review of the manuscript. We thank Carol Weiss (FDA) for providing plasmid clones expressing SARS-CoV-2 spike variants. The antibody response study was supported by FDA’s MCMi grants OCET 2022-1746 and OCET 2023-0235 to SK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government.

Address correspondence to: Surender Khurana, CBER, Food and Drug Administration (FDA), Silver Spring, Maryland 20993, USA. Phone: 240.402.9632; Email: Surender.Khurana@fda.hhs.gov.

Footnotes

Conflict of interest: The authors have declared that no conflict of interest exists.

Copyright: © 2024, Bellusci et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

Reference information: J Clin Invest. 2024;134(20):e182919. https://doi.org/10.1172/JCI182919.

References

1. Imai M, et al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med. 2022;385(8):683–694.View this article via: PubMedGoogle Scholar
2. Karbiener M, et al. Highly potent SARS-CoV-2 neutralization by intravenous immunoglobulins manufactured from post-COVID-19 and COVID-19-vaccinated plasma donations. J Infect Dis. 2021;224(10):1707–1711.View this article via: PubMedGoogle Scholar
3. CDC. 2022-2023 Nationwide COVID-19 Infection- and Vaccination-Induced Antibody Seroprevalence (Blood donations). https://covid.cdc.gov/covid-data-tracker/# nationwide-blood-donor-seroprevalence-2022 Accessed September 6, 2024.
4. Awasthi M, et al. Severe acute respiratory syndrome Coronavirus 2 hyperimmune intravenous human immunoglobulins neutralizes omicron subvariants BA.1, BA.2, BA.2.12.1, BA.3, and BA.4/BA.5 for treatment of Coronavirus disease 2019. Clin Infect Dis. 2022;76(3):e503–e506.View this article via: CrossRefPubMedGoogle Scholar
5. Alsoussi WB, et al. SARS-CoV-2 Omicron boosting induces de novo B cell response in humans. Nature. 2023;617(7961):592–598.View this article via: CrossRefPubMedGoogle Scholar
6. Thompson JS, et al. Long-term high-dose immunoglobulin successfully treats Long COVID patients with pulmonary, neurologic, and cardiologic symptoms. Front Immunol. 2022;13:1033651. View this article via: CrossRefPubMedGoogle Scholar

致编辑：在 COVID-19 大流行的早期，使用 SARS-CoV-2 特异性单克隆抗体 （mAb） 进行预防性或早期暴露后治疗是有用的。然而，目前流行的 SARS-CoV-2 奥密克戎亚变体（例如 XBB.1、JN.1 及其衍生物）对所有已批准的 mAb 疗法均具有耐药性 （1）。由混合人血浆生产的免疫球蛋白产品 （IG） 广泛用于治疗患有多种免疫缺陷综合征的患者。大多数 IG 是通过静脉内给药的，称为 IVIG。

多克隆超免疫抗 SARS-CoV-2 IVIG （pi-hCoV-2IG） 于 2021 年通过分离 COVID-19 恢复期患者的混合血浆制成，这些患者的病毒中和滴度为对祖先 WA-1 菌株的中和滴度为 1：320 或更高，并且含有比单个恢复期血浆 （CP） 高 10 倍的 IgG。Vx-hCoV-2IG 是由接种 SARS-CoV-2 疫苗的个体的混合血浆产生的 （2021） （2）。一些接种疫苗的人还报告了以前的 SARS-CoV-2 感染。自 2022 年以来，美国超过 90% 的献血具有抗 SARS-CoV-2 抗体，这表明之前通过接种疫苗、感染或两者兼而有之（混合免疫）暴露过 （3）。因此，我们假设从 2022 年开始，由未经筛选的血浆捐献者生产的 IVIG 批次可能含有针对循环 Omicron 亚变体的抗 SARS-CoV-2 中和抗体。

为了评估多批次 IVIG、pi-hCoV-2IG 和 Vx-hCoV-2IG 对流行的 Omicron 变体的治疗潜力（补充表 1;本文在线提供的补充材料;https://doi.org/10.1172/JCI182919DS1），我们遵循 STROBE 报告指南 （https://www.strobe-statement.org/） 进行横断面研究。我们测试了 17 批由 2020 年感染 SARS-CoV-2 的恢复期个体的混合血浆制备的 pi-hCoV-2IG，以及一个可用的 Vx-hCoV-2IG 批次，该批次由筛选的混合血浆制造，具有高 SARS-CoV-2 中和滴度的 mRNA 疫苗接种个体（混合免疫）在 2021 年报告了 SARS-CoV-2 感染。此外，2019 年 COVID-19 大流行前使用健康血浆捐献 （2019-IVIG） 生产的 20 个 IVIG 制剂，2020 年生产的 8 个 IVIG 批次（2020-IVIG），2023 年生产的 9 个 IVIG 批次（2023-IVIG），2024 年生产的 5 个 IVIG 批次（2024-IVIG），2020 年初 COVID-19 康复患者的 7 个 CP（2020-CP），以及 2022 年 Omicron 疫苗突破性感染的 8 个 CP（2022-CP）， 在诊断后约 30 天收集的所有病毒均在假病毒中和试验 （PsVNA） 中中中了 SARS-CoV-2 WA-1 和 9 种流行的 Omicron 亚变体（BA.2.86、XBB.1.16、XBB.2.3、EG.5、HV.1、HK.3、JN.1、JN.4 和 JD.1.1） （4）。

在 2020 年和 2022 年从康复的 COVID-19 患者以及感染后高免疫球蛋白批次 （pi-hCoV-2IG） 中收集的 CP 显示对 WA-1 的高中和滴度，但对当前 Omicron 变体的 PsVNA 滴度极低或没有（图 1）。在 COVID-19 大流行之前生产的 2019-IVIG 批次不含 SARS-CoV-2 中和抗体（图 1）。在 COVID-19 大流行早期生产的 2020-IVIG 批次含有针对 WA-1 的低滴度，并且对当前的 Omicron 亚变体没有中和滴度。另一方面，2023-IVIG 和 2024-IVIG 批次含有针对 WA-1 的高滴度（几何平均滴度 [GMT]：分别为 16,212 和 30,722），反映了血浆供体中的 SARS-CoV-2 血清阳性率高。更重要的是，这些最近的 IVIG 批次对当前流行的变体具有弱到中等滴度，即使供体暴露于早期的 Omicron 变体（补充表 2）。令人惊讶的发现是，2021 年生产的一批 Vx-hCov-2IG 不仅含有对原始 WA-1 毒株的最高滴度（GMT：69,551），而且对所有最近流行的 Omicron 亚变体（GMT 范围在 401 到 11,416 之间）具有高中和滴度（图 1）。这一发现可能是由于疫苗接种/感染诱导的交叉反应性 B 细胞在生发中心经历亲和成熟，从而产生更广泛的高亲和力抗体库，可中和新出现的 Omicron 亚变体 （5）。

通过 IVIG、恢复期血浆、pi-hCoV-2IG 和 Vx-hCoV-2IG 中和 SARS-CoV-2 WA1/2020 和流行的 Omicron 亚变体。通过在 293-ACE2-TMPRSS2 细胞中使用表达 WA1/2020 刺突蛋白或 Omicron 亚变体的假病毒进行 SARS-CoV-2 中和试验。在大流行前 2019-IVIG （n = 20）、2020-IVIG （n = 8）、2020 年恢复期血浆 （2020-CP;n = 7）、2022 恢复期血浆 （2022-CP;n = 8）、感染后高免疫球蛋白 IVIG （pi-hCoV-2IG;n = 17）、2023-IVIG （n = 9）、2024-IVIG （n = 5） 和疫苗接种后高免疫球蛋白 IVIG （Vx-hCoV-2IG;n = 1） 制剂。测定一式两份，以确定 50% 的中和滴度 （PsVNA50）。条形的高度和条形上的数字表示几何平均滴度，须线表示 95% 置信区间。水平虚线表示中和测定的检测限（PsVNA50 为 20）。在 GraphPad Prism 9.3.1 版中，通过普通的 1 因子方差分析和 Tukey 的成对多重比较检验分析 SARS-CoV-2 毒株之间的差异，并显示 P 值。

我们的研究结果表明，高滴度 IVIG 批次可以由针对最近的 Omicron 亚变体的高中和滴度的血浆筛选制成。由于当前流行的 SARS-CoV-2 Omicron 亚变体对所有获得许可的 mAb 均具有耐药性，因此这些交叉中和 IVIG 批次可能是一种重要的干预措施，特别是对于免疫功能低下的患者和各种自身免疫和神经系统疾病，包括长期 COVID 患者 （6），以预防或改善暴露于循环和新出现的 SARS-CoV-2 毒株的结果。

 补充资料

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 确认

我们感谢 FDA 的 Basil Golding 和 Keith Peden 对手稿的审查。我们感谢 Carol Weiss （FDA） 提供表达 SARS-CoV-2 刺突变体的质粒克隆。抗体反应研究得到了 FDA 的 MCMi 拨款 OCET 2022-1746 和 OCET 2023-0235 的支持。资助者在研究设计、数据收集和分析、发表决定或手稿准备方面没有任何作用。本出版物的内容不一定反映美国卫生与公众服务部的观点或政策，提及商品名称、商业产品或组织也不意味着美国政府的认可。

通信地址：Surender Khurana，CBER，食品和药物管理局 （FDA），美国马里兰州银泉 20993。电话：240.402.9632;电子邮件：Surender.Khurana@fda.hhs.gov。

 脚注

利益冲突：作者已声明不存在利益冲突。

版权所有：© 2024，Bellusci 等人。这是一篇根据 Creative Commons Attribution 4.0 International License 条款发布的开放获取文章。

Reference information: J Clin Invest. 2024;134(20):e182919. https://doi.org/10.1172/JCI182919.

 引用

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