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. 2024 Feb 8;9(3):e176359.
doi: 10.1172/jci.insight.176359.

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

Ofer Zimmerman  1 , Alexa Michelle Altman Doss  2 , Baoling Ying  1 , Chieh-Yu Liang  3 , Samantha R Mackin  3 , Hannah G Davis-Adams  1 , Lucas J Adams  3 , Laura A VanBlargan  1 , Rita E Chen  3 , Suzanne M Scheaffer  1 , Pritesh Desai  1 , Saravanan Raju  3 , Tarisa L Mantia  1 , Caitlin C O'Shaughnessy  1 , Jennifer Marie Monroy  1 , H James Wedner  1 , Christopher J Rigell  1 , Andrew L Kau  1   4   5 , Tiffany Biason Dy  1 , Zhen Ren  1 , Jackson S Turner  3 , Jane A O'Halloran  1 , Rachel M Presti  1   6   7 , Peggy L Kendall  1 , Daved H Fremont  3 , Ali H Ellebedy  3   4   6   7 , Michael S Diamond  1   3   4   6   7
Affiliations

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

Ofer Zimmerman et al. JCI Insight. .

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.

Keywords: COVID-19; Immunoglobulins; Immunology.

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Figures

Figure 1
Figure 1. Lag before the detection of anti-spike antibody titers in IG replacement products.
(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.
Figure 2
Figure 2. IVIG and SCIG products lack neutralizing activity against the circulating SARS-CoV-2 variant at the time of infusion.
(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.
Figure 3
Figure 3. Contemporary IG products protect K18-hAE2–transgenic mice from XBB.1.5 infection despite lacking neutralizing activity.
(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).
Figure 4
Figure 4. Prophylaxis with contemporary IG was associated with reductions in lung cytokines and chemokines after SARS-CoV-2 challenge of K18-hACE2–transgenic mice.
(A–C) Cytokine and chemokine levels from lung homogenates of K18-hACE2–transgenic mice treated with IG (blue dots, prepandemic, n = 10; red dots, contemporary, n =10) or PBS (black dots, n = 10) and challenged with SARS-CoV-2 WA1/2020 D614G or XBB.1.5. Samples were obtained 6 days after infection. (A) For each analyte, fold change was calculated compared to mock-inoculated mice, and log2 values were plotted in the color-coded heatmap. (B and C) Individual cytokine levels were measured in the lung homogenates of WA1/2020 D614G (B) or XBB.1.5 (C) SARS-CoV-2–infected mice after prophylaxis with prepandemic IG (blue) or contemporary IG (red) or treatment with PBS (black) compared to naive mice (gray). Mean values ± SEM are shown. *P < 0.05, **P < 0.01, ****P < 0.0001 by 1-way ANOVA with Tukey’s posttest correction (B and C).
Figure 5
Figure 5. The reduction in XBB.1.5 lung infection following IG prophylaxis is Fc effector function dependent.
(A and B) Levels of XBB.1.5 RNA (A) and infectious virus (B) in the lungs of C57BL/6J (n = 10, black dots) and FcγR I/III/IV–KO mice (n = 10, red dots) challenged with SARS-CoV-2 XBB.1.5, 24 hours following administration of PBS or IG prophylaxis. Lungs were collected 2 days after inoculation for virological analysis. Mean values are shown (2 experiments). ****P < 0.0001 by 1-way ANOVA with Tukey’s posttest correction (A and B).
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