Immunoglobulin replacement products protect against SARS-CoV-2 infection in vivo despite poor neutralizing activity
Ofer Zimmerman, Alexa Michelle Altman Doss, Baoling Ying, Chieh-Yu Liang, Samantha R. Mackin, Hannah G. Davis-Adams, Lucas J. Adams, Laura A. VanBlargan, Rita E. Chen, Suzanne M. Scheaffer, Pritesh Desai, Saravanan Raju, Tarisa L. Mantia, Caitlin C. O’Shaughnessy, Jennifer Marie Monroy, H. James Wedner, Christopher J. Rigell, Andrew L. Kau, Tiffany Biason Dy, Zhen Ren, Jackson S. Turner, Jane A. O’Halloran, Rachel M. Presti, Peggy L. Kendall, Daved H. Fremont, Ali H. Ellebedy, Michael S. Diamond
Ofer Zimmerman, Alexa Michelle Altman Doss, Baoling Ying, Chieh-Yu Liang, Samantha R. Mackin, Hannah G. Davis-Adams, Lucas J. Adams, Laura A. VanBlargan, Rita E. Chen, Suzanne M. Scheaffer, Pritesh Desai, Saravanan Raju, Tarisa L. Mantia, Caitlin C. O’Shaughnessy, Jennifer Marie Monroy, H. James Wedner, Christopher J. Rigell, Andrew L. Kau, Tiffany Biason Dy, Zhen Ren, Jackson S. Turner, Jane A. O’Halloran, Rachel M. Presti, Peggy L. Kendall, Daved H. Fremont, Ali H. Ellebedy, Michael S. Diamond
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Research Article COVID-19 Immunology

Immunoglobulin replacement products protect against SARS-CoV-2 infection in vivo despite poor neutralizing activity

Abstract

Immunoglobulin (IG) replacement products are used routinely in patients with immune deficiency and other immune dysregulation disorders who have poor responses to vaccination and require passive immunity conferred by commercial antibody products. The binding, neutralizing, and protective activity of intravenously administered IG against SARS-CoV-2 emerging variants remains unknown. Here, we tested 198 different IG products manufactured from December 2019 to August 2022. We show that prepandemic IG had no appreciable cross-reactivity or neutralizing activity against SARS-CoV-2. Anti-spike antibody titers and neutralizing activity against SARS-CoV-2 WA1/2020 D614G increased gradually after the pandemic started and reached levels comparable to vaccinated healthy donors 18 months after the diagnosis of the first COVID-19 case in the United States in January 2020. The average time between production to infusion of IG products was 8 months, which resulted in poor neutralization of the variant strain circulating at the time of infusion. Despite limited neutralizing activity, IG prophylaxis with clinically relevant dosing protected susceptible K18-hACE2–transgenic mice against clinical disease, lung infection, and lung inflammation caused by the XBB.1.5 Omicron variant. Moreover, following IG prophylaxis, levels of XBB.1.5 infection in the lung were higher in FcγR-KO mice than in WT mice. Thus, IG replacement products with poor neutralizing activity against evolving SARS-CoV-2 variants likely confer protection to patients with immune deficiency disorders through Fc effector function mechanisms.

Authors

Ofer Zimmerman, Alexa Michelle Altman Doss, Baoling Ying, Chieh-Yu Liang, Samantha R. Mackin, Hannah G. Davis-Adams, Lucas J. Adams, Laura A. VanBlargan, Rita E. Chen, Suzanne M. Scheaffer, Pritesh Desai, Saravanan Raju, Tarisa L. Mantia, Caitlin C. O’Shaughnessy, Jennifer Marie Monroy, H. James Wedner, Christopher J. Rigell, Andrew L. Kau, Tiffany Biason Dy, Zhen Ren, Jackson S. Turner, Jane A. O’Halloran, Rachel M. Presti, Peggy L. Kendall, Daved H. Fremont, Ali H. Ellebedy, Michael S. Diamond

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Figure 1

Lag before the detection of anti-spike antibody titers in IG replacement products.

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Lag before the detection of anti-spike antibody titers in IG replacement...
(A) Anti–Wuhan-1 spike antibody titers were measured in healthy donors (blue dots, n = 20) before and 14 and 90 days following completion of 2 doses of COVID-19 mRNA vaccine and in IVIG (n = 137) and SCIG (n = 61) products infused into patients from August 2021 to November 2022. Black dots (marked with an × above the graph) indicate products with a median anti-spike titer that was not significantly higher than the unvaccinated healthy donor anti-spike titer. Red dots (marked with a √ below the graph) denote products with a median anti-spike titer equivalent to the healthy donor anti-spike titer, 14 days after the second dose of mRNA COVID-19 vaccine. Gray dots indicate products with a median anti-spike titer that was higher than the unvaccinated healthy donor anti-spike titer, but lower than the vaccinated healthy donor anti-spike titer. (B) Anti–Wuhan-1 spike antibody titers in 6 different IVIG and SCIG products (Gammagard, orange n = 55; Cuvitru, green n = 19; Hyqvia, purple n = 9; Gamunex-C, red n = 75; Hizentra, blue n = 33; Gamaplex, gray n = 7) infused from August 2021 to November 2022. (C) Anti–Wuhan-1 spike antibody titers in 198 lots of IVIG and SCIG products by manufacture date. (D) Anti–Wuhan-1 spike antibody titers in 6 different IVIG and SCIG products (Gammagard, orange n = 55; Cuvitru, green n = 19; Hyqvia, purple n = 9; Gamunex-C, red n = 75; Hizentra, blue n = 33; Gamaplex, gray n = 7) by manufacture date. Bars in A–D indicate median and interquartile range values. LOD, limit of detection (dotted line). Dashed line represents mean anti–Wuhan-1 spike antibody end point titer 14 days following the second dose of SARS-CoV-2 mRNA vaccination in healthy donors (n = 20). Numbers above the x axis in C indicate the number of lots tested in a specific month. *P < 0.05, **P < 0.01 by Kruskal-Wallis with Dunn’s post hoc test (A), and mixed effect analysis with Tukey’s posttest correction (B). See also Supplemental Figure 1 and Supplemental Table 1.