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 2

IVIG and SCIG products lack neutralizing activity against the circulating SARS-CoV-2 variant at the time of infusion.

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IVIG and SCIG products lack neutralizing activity against the circulatin...
(A) Neutralization activity in healthy donors (blue dots, n = 20) against SARS-CoV-2 WA1/2020 D614G before and 14 and 90 days following completion of 2 doses of COVID-19 mRNA vaccine, and in IVIG (n = 136) 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 median anti–WA1/2020 D614G neutralization activity that was not significantly higher than unvaccinated healthy donor serum neutralization activity. Red dots (marked with a √ below the graph) denote products with median anti–WA1/2020 D614G neutralization activity equivalent to healthy donor serum neutralization activity, 14 days after the second dose of mRNA COVID-19 vaccine. Gray dots indicate products with median anti–WA1/2020 D614G neutralization activity that was higher than unvaccinated healthy donor anti–WA1/2020 D614G neutralization activity, but lower than vaccinated healthy donor anti–WA1/2020 D614G neutralization activity. (B) Neutralization activity against SARS-CoV-2 WA1/2020 D614G in 6 different IVIG and SCIG products separated by manufacturer (Gammagard, orange n = 55; Cuvitru, green n = 19; Hyqvia, purple n = 9; Gamunex-C, red n = 74; Hizentra, blue n = 33; Gamaplex, gray n = 7) infused from August 2021 to November 2022. (C) Neutralizing activity against SARS-CoV-2 WA1/2020 D614G (red dots, n = 197), Delta (blue dots, n = 157), BA.1 (purple, n = 195), and BQ.1.1 (orange, n = 38) in IVIG and SCIG products infused from August 2021 to November 2022. (D) Neutralizing activity against SARS-CoV-2 WA1/2020 D614G (red dots, n = 197), Delta (B.1.617.2; blue dots, n = 157), BA.1 (purple, n = 195), and BQ.1.1 (orange, n = 38) in IVIG and SCIG by manufacture date. (E–G) Comparison of anti–Wuhan-1 spike antibody titer (x axis) and SARS-CoV-2 WA1/2020 D614G (E), Delta (F), and Omicron BA.1 (G) neutralization activity in 157–197 IG products. Bars in A–D indicate median plus interquartile range values. LOD, limit of detection (dotted line) (A–G). The dashed line in A–D represents mean anti–Wuhan-1 neutralizing activity 14 days following the second dose of SARS-CoV-2 mRNA vaccination in healthy donors (n = 20) (A and B) or represents the presumptive protective titer as described in Khoury et al. (19) (C and D). SARS-CoV-2 variant name above the graph in C and D indicates the most prevalent circulating strain in the United States during the month in which IVIG/SCIG was infused (C) or manufactured (D). Numbers above the x axis in C–G indicate the number of lots tested in a specific month (C and D) or the number of lots with a specific anti–Wuhan-1 spike antibody titer (E–G). Significance was assessed using Kruskal-Wallis with Dunn’s post hoc test (A) or mixed effect analysis with Tukey’s posttest correction (B). See also Supplemental Figure 1 and Supplemental Table 1.