Therapeutic potential of convalescent plasma and hyperimmune immunoglobulins against SARS-CoV-2 BQ.1, BQ.1.1, and XBB variants

To the Editor: Convalescent plasma (CP) and hyperimmune intravenous immunoglobulins (IVIGs) are routinely used to treat patients with COVID-19. SARS-CoV-2 Omicron variants continue to evolve, generating multiple sublineages with increased transmissibility and antibody-escape mutations (1, 2). Several Omicron lineages that are currently circulating (BA.4, BA.5, BA.2.75, BA.2.75.2, BQ.1, BQ.1.1, and recombinant XBB) contain many mutations in spike protein (Supplemental Table 1; supplemental material available online with this article; https://doi.org/10.1172/JCI168583DS1), resulting in resistance to most therapeutic monoclonal antibodies as well as antibodies generated by SARS-CoV-2 vaccines (1, 2).

Hyperimmune anti–SARS-CoV-2 IVIGs (hCoV-2IG) have been manufactured from pooled plasma units of hundred to thousands of convalescent individuals. hCoV-2IG contain immunoglobulin G at a 10-fold higher concentration compared with that in CP, and they are being evaluated for treatment of COVID-19 (3).

To evaluate their therapeutic potential, 19 lots of hCoV-2IG prepared from convalescent individuals infected with SARS-CoV-2 in 2020, prior to circulation of Omicron; 20 IVIG preparations manufactured in 2019 (2019-IVIG) before the COVID-19 pandemic; and 8 IVIG lots manufactured from healthy plasma donations in 2020 (2020-IVIG) were analyzed for neutralization of SARS-CoV-2 Omicron BA.4/BA.5, BA.2.75, BA.2.75.2, BQ.1, BQ.1.1, and XBB subvariants in a pseudovirus neutralization assay (PsVNA) (Supplemental Methods). For comparison, we evaluated 8 CP samples from recovered patients with COVID-19 in early 2020 (2020-CP) and 9 CP samples from Omicron vaccine-breakthrough infections in 2022 (2022-CP).

2020-CP showed variable PsVNA50 titers against WA-1, ranging between 10 and 1,343 (geometric mean titer [GMT]: 154), but did not neutralize BQ.1, BQ.1.1, or XBB (Figure 1A and Supplemental Table 2). In contrast, 2022-CP demonstrated robust PsVNA50 titers against WA-1 (GMT: 926) and most neutralized BA.2.75, BA.2.75.2, and BA.4/BA.5 (GMT: 50, 59, and 71, respectively). However, only 4 2022-CP showed low neutralization of BQ.1 (GMT: 25), BQ.1.1 (GMT: 22), and XBB (GMT: 21).

Figure 1

Neutralization of SARS-CoV-2 WA-1/2020 strain and Omicron subvariants by IVIG, convalescent plasma, and hCoV-2IG. (A) SARS-CoV-2 neutralization assays were performed using pseudoviruses expressing the spike protein of WA-1/2020 or the Omicron subvariants in 293-ACE2-TMPRSS2 cells. SARS-CoV-2 neutralization titers were determined in each of the prepandemic 2019-IVIG (n = 20; black), 2020-IVIG (n = 8; pink), 2020 convalescent plasma (2020-CP; n = 8; blue), 2022 convalescent plasma (2022-CP; n = 9; turquoise), and hCoV-2IG (n = 19; red) preparations. The assay was performed in duplicate to determine the 50% neutralization titer (PsVNA50). The heights of the bars and the numbers over the bars indicate the geometric mean titers, and the whiskers indicate 95% CIs. The horizontal dashed line indicates the limit of detection for the neutralization assay (PsVNA50 of 20). Differences between SARS-CoV-2 strains were analyzed by ordinary 1-way ANOVA, using Tukey’s pairwise multiple-comparison test in GraphPad Prism version 9.3.1, and P values are shown. (B) Relationship of neutralizing antibodies against SARS-CoV-2 WA-1/2020 and Omicron subvariants. Correlation of SARS-CoV-2 WA-1/2020 neutralizing titer versus Omicron subvariant neutralizing titer for 2020-CP (n = 8; blue), 2022-CP (n = 9; turquoise), and hCoV-2IG (n = 19; red). Correlations show Pearson’s correlation coefficient (r) and 2-tailed P values for all samples. The black lines in the scatter plots depict the linear fit of log₂-transformed PsVNA50 values, with shaded area showing 95% CI.

As expected, the 2019-IVIG lots did not neutralize any SARS-CoV-2 strain. The 2020-IVIG lots (made from plasma units that were not screened for anti–SARS-CoV-2 neutralizing antibodies) had low PsVNA50 titers against WA-1 (GMT: 35) and did not neutralize Omicron variants (Figure 1A and Supplemental Table 2).

The 19 hCoV-2IG lots demonstrated robust neutralization of WA-1 (GMT: 1,615) (Figure 1A). Surprisingly, all 19 lots exhibited neutralization titers against BA.4/BA.5, ranging from 47 to 205 (GMT: 83). Importantly, 15 of the 19 hCoV-2IG lots also neutralized BA.2.75 and BA.2.75.2, with PsVNA50 titers of 22–430 (GMT: 37 and 32, respectively). At least 10 hCoV-2IG lots demonstrated presence of antibodies against BQ.1, BQ.1.1, and XBB subvariants, but the neutralization titers were further reduced (GMT: 21–25; Figure 1A and Supplemental Table 2). Strong correlations were observed between PsVNA50 titers against WA-1/2020 and BA.4/BA.5, BA.2.75, and BA.2.75.2 (P < 0.0001) for CP and hCoV-2IG (Figure 1B). In contrast, weak insignificant correlations were observed between PsVNA50 titers against WA-1/2020 and BQ.1, BQ.1.1, and XBB (Figure 1B).

Our study demonstrates that some hyperimmune COVID-IVIG lots manufactured in 2020 (2020-hCoV-2IG) neutralized several Omicron variants, similar to CP, from Omicron breakthrough infections in individuals with prior vaccination (2022-CP), at a level (PsVNA50 titer of >1:40) predicted to provide protection against severe COVID-19 (4). Nevertheless, evolution of the variant landscape can increase resistance to antibodies elicited by prior SARS-CoV-2 infections and vaccination, especially against the newly emerged BQ.1, BQ.1.1, and XBB subvariants (5). Therefore, high-titer hCoV-2IG batches could be generated from donors who have been boosted recently with Omicron-containing bivalent vaccine and/or recovered from infection with Omicron following vaccination (hybrid immunity) (6). While there are logistical challenges to hyperimmune globulin production (e.g., long lead time), hCoV-2IG have notable advantages over CP, including standardization of dose, pathogen reduction, and measurements of anti–SARS-CoV-2 neutralizing titers prior to release. This could improve the hCoV-2IG therapeutic effectiveness against severe COVID-19 caused by circulating and emerging SARS-CoV-2 variants.

Author contributions

SK and HG designed research. HG provided clinical specimens and unblinded clinical data. LB and SK performed assays. SK and HG contributed to manuscript writing.

Supplemental material

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Acknowledgments

We thank Basil Golding and Keith Peden at the FDA for review of the manuscript. We thank Carol Weiss at the FDA for providing plasmid clones expressing SARS-CoV-2 spike variants. The antibody response study was supported by the FDA’s Medical Countermeasures Initiative grant (OCET 2021-1565 to SK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government.

Address correspondence to: Surender Khurana, 10903 New Hampshire Avenue, Silver Spring, Maryland 20993, USA. Phone: 240.402.9632; Email: Surender.Khurana@fda.hhs.gov.

Footnotes

Conflict of interest: The authors have declared that no conflict of interest exists.

Copyright: © 2023, Bellusci et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

Submitted: January 5, 2023; Accepted: February 13, 2023; Published: April 17, 2023.

Reference information: J Clin Invest. 2023;133(8):e168583. https://doi.org/10.1172/JCI168583.

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