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The antibody response against SARS-CoV-2 in patients pre- and post-infusion with commercial intravenous immunoglobulin products

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In a recent study posted to the medRxiv* preprint server, researchers comparatively evaluated antibody (Ab) responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among immunodeficient individuals pre- and post-intravenous immunoglobulin (IVIG) product infusions. They also estimated neutralizing antibody (nAb) titers for the SARS-CoV-2 wildtype (WT) strain and the Omicron variant of concern (VOC).

Study: Commercial immunoglobulin products now contain neutralising antibodies against SARS-CoV-2 spike antibody which are detectable in patient serum. Image Credit: Design_Cells/Shutterstock
Study: Commercial immunoglobulin products now contain neutralising antibodies against SARS-CoV-2 spike antibody which are detectable in patient serum. Image Credit: Design_Cells/Shutterstock

Background

Ab-deficient individuals respond poorly to coronavirus disease 2019 (COVID-19) vaccinations and are highly prone to COVID-19 severity outcomes such as hospitalizations and deaths and SARS-CoV-2 infection relapses. For such individuals, other potentially prophylactic agents such as monoclonal antibodies (mAbs) directed against the SARS-CoV-2 spike (S) protein have been considered.

About the study

In the present study, researchers assessed the immunogenicity of several commercially used IVIG products among immunodeficient and healthy individuals.

Thirty-five immunodeficient individuals on immunoglobulin replacement therapy (IRT) and seven healthy controls were recruited for the analysis, and their blood samples were obtained pre- and post-IVIG infusions. All participants had been administered ≥2 SARS-CoV-2 vaccinations. The anti-S titers were assessed using commercial immunoassays, and the SARS-CoV-2 WT and Omicron VOC nAb titers were determined using luminescence-based neutralization assays.

Serum samples were incubated with human immunodeficiency virus (HIV)-based pseudovirus expressing SARS-CoV-2 WT S and Omicron S, and angiotensin-converting enzyme 2 (ACE2)-expressing HeLa cells were used for the cell culture experiments. Further, the anti-SARS-CoV-2 nAb titers of immunodeficient patients undergoing IVIG infusions were compared with those of healthy individuals.

To confirm the induction of SARS-CoV-2 nAb titers by IVIG products, a few batches of IVIG products (except Gammaplex) were tested that were previously used at neat concentrations and five-fold serial dilutions in SARS-CoV-2 neutralization assays. Furthermore, to determine whether the IVIG product differences could reflect in nAb titers of patient sera, post-infusion nAb titers were compared based on the IVIG product administered.

Results

The most commonly reported immunodeficiency diagnoses reported were secondary hypogammaglobulinemia and common variable immunodeficiency (CVID). All patients were on regular IVIG therapy for ≥6 months with immunoglobulin G (IgG) titers usually above 7.0 g/L. Twenty patients reported prior COVID-19 history (two patients were infected twice with SARS-CoV-2), of which approximately half of the infection episodes were treated while the remaining resolved spontaneously. One immunodeficient patient had been treated with sotrovimab mAb in the previous 14 days.

Most patients demonstrated significantly elevated anti-S Ab titers post-IVIG infusion, with median pre-infusion and post-infusion titers being 2123 U/mL and 10,600 U/mL, respectively. The increase was most prominent among patients who received Octagam or Privigen. Post-IVIG infusion titers among Flebogamma recipients were relatively modest, whereas, among Iqymune recipients, the anti-S Ab titers either remained unaltered or reduced marginally.

The sotrovimab-treated patients showed pre-infusion titers >24,999 U/mL, and three Intratect recipients showed similarly elevated pre-infusion titers even on receiving no treatment in recent times. The nAb titers against SARS-CoV-2 WT and Omicron VOC increased significantly post-IVIG infusions; however, baseline pre-infusion nAb titers against SARS-CoV-2 WT were greater than Omicron [median 50% inhibitory concentration (ID50) values for WT vs. Omicron was 1437 versus 925].

The nAb titers against SARS-CoV-2 WT and Omicron were significantly lesser among patients before IVIG infusions than those among healthy individuals (median ID50 values for SARS-Cov-2 WT 1437 versus 27574, and for the Omicron VOC 925 versus 7563) but restored to levels similar to levels observed among healthy individuals post-infusion, although with limited homogeneity (median ID50 values for Omicron VOC 4932 versus 7563; SARS-CoV-2 WT 4985 versus 27574).

Significant differences were not observed between anti-S Ab titers or nAb titers (before or after infusion) between among participants with prior SARS-CoV-2 exposure in the previous six months versus those who developed SARS-CoV-2 infections in more than the previous half-year. All products showed detectable neutralization with ID50 values ranging from 1:25000 to 1:2×107, with higher titers than those detected in patients’ sera; however, the IVIG products showed lower neutralization potency for Omicron than SARS-CoV-2 WT.

Privigen and Intratect batches demonstrated significantly greater neutralization potency against SARS-CoV-2 WT than other IVIG products, particularly Iqymune and Flebogamma. Octagam neutralized Omicron poorly compared to SARS-CoV-2 WT, while Iqymune neutralized Omicron more than SARS-CoV-2 WT despite Iqymune recipients demonstrating lower nAb and anti-SARS-CoV-2 S titers.

Lower SARS-CoV-2 WT neutralization was observed among sera of Iqymune recipients; however, no distinctive differences were observed between the IVIG products for the Omicron VOC, with considerable patient-dependent nAb titer variability. Nevertheless, the overall neutralization enhancements among individuals post-IVIG infusions indicate that the majority of IVIG products conferred immunological benefits against SARS-CoV-2, including the Omicron VOC.

Conclusion

Overall, the study findings showed that several commercially used IVIG products contain SARS-CoV-2 nAbs, which are transferred in good concentrations to immunodeficient individuals, although with significant differences between the products.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

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