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 3

Contemporary IG products protect K18-hAE2–transgenic mice from XBB.1.5 infection despite lacking neutralizing activity.

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Contemporary IG products protect K18-hAE2–transgenic mice from XBB.1.5 i...
(A) Anti–Wuhan-1 or –XBB.1.5 spike human antibody end point titers in naive K18-hACE2–transgenic mice 24 hours after treatment with PBS (black dots, n = 3), 600 mg/kg prepandemic IG (blue dots, n = 3), or contemporary IG (red dots, n = 3). (B) Neutralizing activity against SARS-CoV-2 WA1/2020 D614G or XBB.1.5 of serum obtained from naive K18-hACE2–transgenic mice 24 hours after treatment with PBS (black dots, n = 3), 600 mg/kg prepandemic IG (blue dots, n = 3), or contemporary IG (red dots, n = 3). (C and D) Percentage change in initial body weight in mice treated with PBS (black dots, n = 10, 2 independent experiments), prepandemic G (blue dots, n = 10), or contemporary IG (red dots, n = 10) and challenged with WA1/2020 D614G (C) or XBB.1.5 (D). (E–H) Lung SARS-CoV-2 WA1/2020 D614G (E and G) or XBB.1.5 (F and H) RNA titers (E and F) or infectious virus (G and H) 6 days after infection, in mice treated with PBS (black dots, n = 10), prepandemic IG (blue dots, n = 10), or contemporary IG (red dots, n = 10) 24 hours before intranasal virus challenge. Bars indicate median with interquartile range (A and B), mean ± SEM (C and D), or mean (E–H). **P < 0.01, ***P < 0.001, ****P < 0.0001 by mixed effect analysis with Tukey’s posttest correction (C and D) or 1-way ANOVA with Tukey’s posttest correction (E–H).