Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Oct 5;77(7):950-960.
doi: 10.1093/cid/ciad368.

Commercial Immunoglobulin Products Contain Neutralizing Antibodies Against Severe Acute Respiratory Syndrome Coronavirus 2 Spike Protein

Vinit Upasani  1 , Katie Townsend  2 , Mary Y Wu  3 , Edward J Carr  4   5 , Agnieszka Hobbs  3 , Giulia Dowgier  3 , Martina Ragno  3 , Lou S Herman  3 , Sonal Sharma  6 , Devesh Shah  6 , Simon F K Lee  7 , Neil Chauhan  8 , Julie M Glanville  8 , Lucy Neave  8 , Steven Hanson  8 , Sriram Ravichandran  8 , Aoife Tynan  9 , Mary O'Sullivan  2 , Fernando Moreira  2 , Sarita Workman  2 , Andrew Symes  2 , Siobhan O Burns  1   2 , Susan Tadros  2 , Jennifer C L Hart  10 , Rupert C L Beale  3   5 , Sonia Gandhi  3   11 , Emma C Wall  3   11 , Laura McCoy  1 , David M Lowe  1   2
Affiliations

Commercial Immunoglobulin Products Contain Neutralizing Antibodies Against Severe Acute Respiratory Syndrome Coronavirus 2 Spike Protein

Vinit Upasani et al. Clin Infect Dis. .

Abstract

Background: Patients with antibody deficiency respond poorly to coronavirus disease 2019 (COVID-19) vaccination and are at risk of severe or prolonged infection. They are given long-term immunoglobulin replacement therapy (IRT) prepared from healthy donor plasma to confer passive immunity against infection. Following widespread COVID-19 vaccination alongside natural exposure, we hypothesized that immunoglobulin preparations will now contain neutralizing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike antibodies, which confer protection against COVID-19 disease and may help to treat chronic infection.

Methods: We evaluated anti-SARS-CoV-2 spike antibody in a cohort of patients before and after immunoglobulin infusion. Neutralizing capacity of patient samples and immunoglobulin products was assessed using in vitro pseudovirus and live-virus neutralization assays, the latter investigating multiple batches against current circulating Omicron variants. We describe the clinical course of 9 patients started on IRT during treatment of COVID-19.

Results: In 35 individuals with antibody deficiency established on IRT, median anti-spike antibody titer increased from 2123 to 10 600 U/mL postinfusion, with corresponding increase in pseudovirus neutralization titers to levels comparable to healthy donors. Testing immunoglobulin products directly in the live-virus assay confirmed neutralization, including of BQ1.1 and XBB variants, but with variation between immunoglobulin products and batches.Initiation of IRT alongside remdesivir in patients with antibody deficiency and prolonged COVID-19 infection (median 189 days, maximum >900 days with an ancestral viral strain) resulted in clearance of SARS-CoV-2 at a median of 20 days.

Conclusions: Immunoglobulin preparations now contain neutralizing anti-SARS-CoV-2 antibodies that are transmitted to patients and help to treat COVID-19 in individuals with failure of humoral immunity.

Keywords: IVIG; SARS-CoV-2; immunodeficiency; neutralization; spike antibody.

PubMed Disclaimer

Conflict of interest statement

Potential conflicts of interest. A. T. has received personal fees from CSL Behring and reports payment for attendance to an advisory board from CSL. S. W. has received personal fees from UCB and LFB Biopharmaceuticals; sponsorship to attend meetings from Biotest, CSL Behring, and Octapharma; grants or contracts from CSL Behring–International Nursing Group for Immunodeficiencies (INGID) for translation of INGID immunoglobulin administration guidelines and from BioCryst, Octapharma, CSL Behring, HIS, and Takeda for support for INGID conference 2022; honoraria from CSL Behring for clinicians’ experience using prefilled syringes; payment or honoraria from UCB for providing training for subcutaneous pump usage; support from Kenes–European Society of Immunodeficiency (ESID) conference organizers for attending ESID/INGID/International Patient Organisation for Primary Immunodeficiencies (IPOPI) conference; support from IPOPI for attending International Primary Immundoeficiencies Congress meeting; support from World Primary Immunodeficiencies Week (WPIW) for attending WPIW opening ceremony; and roles as board member of INGID, organizing committee for the International Primary Immunodeficiencies Congress, and steering committee for World PI Week. A. S. has received personal fees for a webinar from CSL Behring and sponsorship for conference from Takeda. S. O. B. has received grant support from CSL Behring to Royal Free London NHS Foundation Trust; grant funding to UCL from UCL Hospitals NHS Foundation Trust Biomedical Research Centers, Wellcome Trust, Medical Research Council, National Institute of Health Research, UK Research Institute, and Jeffrey Modell Foundation; consulting fees paid to UCL Consulting from GSK; personal honoraria for talks from Biotest; medicolegal fees related to primary immunodeficiency from various solicitor firms; personal fees or travel expenses from Immunodeficiency Canada/Israel Association of Allergy and Clinical Immunology, CSL Behring, Baxalta US, and Biotest; fees as an external expert for GSK; support for attending stakeholder meeting from IPOPI; participation on a data and safety monitoring board or advisory board for GSK (consultant fees paid to UCL Consulting) and NHS SCID Newborn Screening Diagnostic Reference Panel (unremunerated expert member); and unremunerated roles as Chair of the ESID clinical working party, board member of ESID, Chair for the European Reference Network for Rare Immunodeficiency, Autoinflammatory and Autoimmune diseases Transition Working Group, Chronic Granulomatous Disease Society research advisory panel, Associate Editor for Frontiers in Immunology, and Chronic Granulomatous Disease Society research advisory panel. D. M. L. has received personal fees from Gilead for an educational video on COVID-19 in immunodeficiency and from Merck for a roundtable discussion on risk of COVID-19 in immunosuppressed patients; speaker’s fees from Biotest; support to attend a conference from Octapharma; research grants from GSK and Bristol Myers Squibb, outside the current work, paid to institution; consulting fees from GSK, paid to institution; payment or honoraria for roundtable discussion on COVID-19 in immunosuppressed patients from Merck; speaker’s fees from Biotest; travel and accommodation fees for ESID conference 2022 from Octapharma; and a role as member of NHS England Expert Working group on COVID-19 therapeutics and independent advisory group on high-risk patients. R. C. L. B. reports ad hoc consultancy fees paid to author, unrelated to this manuscript, from Immunos Therapeutics, and unremunerated participation as member of an independent advisory group on COVID Therapeutics (and other similar advisory groups). E. J. C. reports unsalaried membership of the UK Kidney Association Infection Prevention and Control Committee. S. T. reports support for attending a conference including travel to meeting from CSL and support for attending a meeting from Takeda. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Humoral immune responses in patients with primary immunodeficiencies receiving intravenous immunoglobulin (IVIG) products. A–B, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike antibody titers in serum samples taken from patients pre- and postinfusion with IVIG products; results are presented from all patients (A) and according to product received (B). Note that 1 patient in the Privigen group had received sotrovimab within the previous 2 weeks and had a titer >25 000 U/mL even before infusion. C–D, Comparison of neutralizing antibody titers (Inhibitory Dilution 50 (ID50) against SARS-CoV-2 ancestral and Omicron viruses in serum samples from patients pre- and postinfusion with IVIG products. E–F, Neutralizing antibody titers in comparison with healthy donors. P values were calculated using Wilcoxon paired t test for comparing 2 groups and Kruskal-Wallis test with Dunn post hoc test for comparing 3 groups (**P < .01; ***P < .001; ****P < .0001). Abbreviations: HDs, healthy donors; ID50, Inhibitory Dilution 50; IVIG, intravenous immunoglobulin; ns, not significant; S Ab, spike antibody.
Figure 2.
Figure 2.
Intravenous immunoglobulin (IVIG) products have neutralizing activity against circulating variants BQ.1.1 and XBB. Batches of 6 different IVIG products were assessed using a high-throughput live-virus microneutralization assay against Omicron BA.1 and subvariants, including BA.4/5, BQ.1.1, and XBB. The half maximal effective concentration (EC50) values were calculated fitting a 4-parameter dose-response curve to 4 replicate runs of an 8-point dilution series of each product (Supplementary Figure 3) and represents the concentration of the product (µg/mL) that effectively inhibits viral infection and replication by 50%.
Figure 3.
Figure 3.
C-reactive protein, severe acute respiratory syndrome coronavirus 2 diagnostic tests, and serum spike antibody results over time during prolonged coronavirus disease 2019 infection with treatment intervention. Abbreviations: Abx, antibiotics; COVID-19, coronavirus disease 2019; CRP, C-reactive protein; IVIG, intravenous immunoglobulin; NPS, nasopharyngeal swab; PCR, polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; S Ab, spike antibody.
See this image and copyright information in PMC

Comment in

References

    1. McCusker C, Upton J, Warrington R. Primary immunodeficiency. Allergy Asthma Clin Immunol 2018; 14:61. - PMC - PubMed
    1. Shields AM, Faustini SE, Hill HJ, et al. . SARS-CoV-2 vaccine responses in individuals with antibody deficiency: findings from the COV-AD study. J Clin Immunol 2022; 42:923–34. - PMC - PubMed
    1. Brown LK, Moran E, Goodman A, et al. . Treatment of chronic or relapsing COVID-19 in immunodeficiency. J Allergy Clin Immunol 2022; 149:557–61.e1. - PMC - PubMed
    1. Shields AM, Anantharachagan A, Arumugakani G, et al. . Outcomes following SARS-CoV-2 infection in patients with primary and secondary immunodeficiency in the UK. Clin Exp Immunol 2022; 209:247–58. - PMC - PubMed
    1. Nguyen Y, Flahault A, Chavarot N, et al. . Pre-exposure prophylaxis with tixagevimab and cilgavimab (Evusheld) for COVID-19 among 1112 severely immunocompromised patients. Clin Microbiol Infect 2022; 28:1654.e1–4. - PMC - PubMed

Publication types

Supplementary concepts