Production of anti-SARS-CoV-2 hyperimmune globulin from convalescent plasma

Peter Vandeberg, Maria Cruz, Jose Maria Diez, W Keither Merritt, Benjamin Santos, Susan Trukawinski, Andrea Wellhouse, Marta Jose, Todd Willis, Peter Vandeberg, Maria Cruz, Jose Maria Diez, W Keither Merritt, Benjamin Santos, Susan Trukawinski, Andrea Wellhouse, Marta Jose, Todd Willis

Abstract

Background: In late 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus emerged in China and quickly spread into a worldwide pandemic. Prior to the development of specific drug therapies or a vaccine, more immediately available treatments were sought including convalescent plasma. A potential improvement from convalescent plasma could be the preparation of anti-SARS-CoV-2 hyperimmune globulin (hIVIG).

Study design and methods: Convalescent plasma was collected from an existing network of plasma donation centers. A caprylate/chromatography purification process was used to manufacture hIVIG. Initial batches of hIVIG were manufactured in a versatile, small-scale facility designed and built to rapidly address emerging infectious diseases.

Results: Processing convalescent plasma into hIVIG resulted in a highly purified immunoglobulin G (IgG) product with more concentrated neutralizing antibody activity. hIVIG will allow for the administration of greater antibody activity per unit of volume with decreased potential for several adverse events associated with plasma administration. IgG concentration and IgG specific to SARS-CoV-2 were increased over 10-fold from convalescent plasma to the final product. Normalized enzyme-linked immunosorbent assay activity (per mg/ml IgG) was maintained throughout the process. Protein content in these final product batches was 100% IgG, consisting of 98% monomer and dimer forms. Potentially hazardous proteins (IgM, IgA, and anti-A, anti-B, and anti-D) were reduced to minimal levels.

Conclusions: Multiple batches of anti-SARS-CoV-2 hIVIG that met regulatory requirements were manufactured from human convalescent plasma. The first clinical study in which the hIVIG will be evaluated will be Inpatient Treatment with Anti-Coronavirus Immunoglobulin (ITAC) [NCT04546581].

Keywords: COVID-19; COVID-19 convalescent hyperimmune; convalescent plasma; hIVIG; immune globulin.

Conflict of interest statement

The authors are employees of Grifols, which provided financial support for this study and is a manufacturer of COVID‐19 Immune Globulin.

© 2021 The Authors. Transfusion published by Wiley Periodicals LLC. on behalf of AABB.

References

    1. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506.
    1. World Health Organization . Timeline of WHO's response to COVID‐19: last updated 28 December 2020 [monograph on the internet]. Geneva: World Health Organization; 2020. . Accessed January 14, 2021.
    1. Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, et al. Treatment of 5 critically ill patients with COVID‐19 with convalescent plasma. JAMA. 2020;323:1582–9.
    1. Luke TC, Kilbane EM, Jackson JL, Hoffman SL. Meta‐analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment? Ann Intern Med. 2006;145:599–609.
    1. Soo YO, Cheng Y, Wong R, Hui DS, Lee CK, Tsang KK, et al. Retrospective comparison of convalescent plasma with continuing high‐dose methylprednisolone treatment in SARS patients. Clin Microbiol Infect. 2004;10:676–8.
    1. Ko JH, Seok H, Cho SY, Eun Ha Y, Baek JY, Kim SH, et al. Challenges of convalescent plasma infusion therapy in Middle East respiratory coronavirus infection: a single centre experience. Antivir Ther. 2018;23:617–22.
    1. Jungbauer C, Weseslindtner L, Weidner L, Gänsdorfer S, Farcet MR, Gschaider‐Reichhart E, et al. Characterization of 100 sequential SARS‐CoV‐2 convalescent plasma donations. Transfusion. 2020;61(1):12–6.
    1. 21 CFR 630 ‐ General requirements for blood and blood components intended for transfusion or further manufacturing use. In: Code of Federal Regualtions, US Department of Health and Human Services, Washington, DC: United States Government Printing Office, 2010.
    1. Plasma Protein Therapeutics Association . Safety and quality [monograph on the internet]. 2020. . Accessed October 1, 2020.
    1. U.S. Department of Health and Human Services Food and Drug Administration Center for Biologics Evaluation and Research . Investigational COVID‐19 convalescent plasma: guidance for industry. Bethesda, MD: United States Food and Drug Administration, Department of Health and Human Services; 2020. . Accessed November 16, 2020.
    1. Lebing W, Remington KM, Schreiner C, Paul HI. Properties of a new intravenous immunoglobulin (IGIV‐C, 10%) produced by virus inactivation with caprylate and column chromatography. Vox Sang. 2003;84:193–201.
    1. Alonso W, Vandeberg P, Lang J, Yuziuk J, Silverstein R, Stokes K, et al. Immune globulin subcutaneous, human 20% solution (Xembify(R)), a new high concentration immunoglobulin product for subcutaneous administration. Biologicals. 2020;64:34–40.
    1. Gamunex‐C [immune globulin injection (human) 10% Caprylate/chromatography purified]‐package insert [monograph on the internet]. Research Triangle Park, NC: Grifols Therapeutics LLC; 2020. . Accessed September 15, 2020.
    1. Chapter 1. Injections and implanted drug products (parenterals) – Product quality tests. In: United States Pharmacopeia 43 – National Formulary 38. United States Pharmacopeial Convention, North Bethesda, MD, USA. Available from: . Accessed November 16, 2020.
    1. Boonyaratanakornkit J, Morishima C, Selke S, Zamora D, McGuffin S, Shapiro AE, et al. Clinical, laboratory, and temporal predictors of neutralizing antibodies to SARS‐CoV‐2 among COVID‐19 convalescent plasma donor candidates. J Clin Invest. 2020;131(3):e144930.
    1. Garratty G, Glynn SA, McEntire R. ABO and Rh(D) phenotype frequencies of different racial/ethnic groups in the United States. Transfusion. 2004;44:703–6.
    1. McVey J, Baker D, Parti R, Berg R, Gudino M, Teschner W. Anti‐A and anti‐B titers in donor plasma, plasma pools, and immunoglobulin final products. Transfusion. 2015;55(Suppl 2):S98–104.
    1. European Directorate for the Quality of Medicines and Healthcare . Monograph 0918: Human normal immunoglobulin for intravenous administration. In: European Pharmacopeia 10.0, Strasbourg, France: Council of Europe; 2019. p. 2862–2863.
    1. European Directorate for the Quality of Medicines and Healthcare . General Chapter 2.6.20: Anti‐A and anti‐B haemagglutinins (indirect method). In: European Pharmacopeia 10.0, Strasbourg, France: Council of Europe; 2019. p. 218–219.
    1. Sewell WAC, Kerr J, Behr‐Gross ME, Peter HH, on behalf of the Kreuth Ig Working Group. European consensus proposal for immunoglobulin therapies. Eur J Immunol. 2014;44:2207–14.
    1. Flegel WA. Pathogenesis and mechanisms of antibody‐mediated hemolysis. Transfusion. 2015;55(Suppl 2):S47–58.
    1. Pineda AA, Taswell HF. Transfusion reactions associated with anti‐IgA antibodies: report of four cases and review of the literature. Transfusion. 1975;15:10–5.
    1. Liu L, Wang P, Nair MS, Yu J, Rapp M, Wang Q, et al. Potent neutralizing antibodies against multiple epitopes on SARS‐CoV‐2 spike. Nature. 2020;584:450–6.
    1. Li Q, Wu J, Nie J, Zhang L, Hao H, Liu S, et al. The impact of mutations in SARS‐CoV‐2 spike on viral infectivity and antigenicity. Cell. 2020;182(5):1284–94.
    1. Inpatient treatment with anti‐coronavirus immunoglobulin (ITAC) [monograph on the internet]. ; 2020. . Accessed September 25, 2020.

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