Omicron SARS-CoV-2 Neutralization by Immunoglobulin Preparations Manufactured from Plasma Collected in the US and Europe

doi:10.21203/rs.3.rs-1870317/v1

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Omicron SARS-CoV-2 Neutralization by Immunoglobulin Preparations Manufactured from Plasma Collected in the US and Europe

https://doi.org/10.21203/rs.3.rs-1870317/v1

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published 01 Sep, 2022

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After >2 years of the COVID-19 pandemic, immunoglobulins (IG) contain highly potent SARS-CoV-2 neutralizing antibodies, based on the large proportion of US plasma donors who have gone through COVID-19 or vaccination against. Neutralization of Omicron SARS-CoV-2 by antibodies generated after non-Omicron infection or vaccination has been lower though, raising concerns about the potency of IG against this new virus variant. Also, as plasma collected in the US remains the main source of IG, the neutralization of SARS-CoV-2 for plasma collected elsewhere has been less well studied. Here, we confirm Omicron neutralization by US as well as EU plasma-derived IG lots.

Immunology

Virology

Infectious Diseases

Allergy & Immune Disorders

Primary immunodeficiency

Secondary immunodeficiency

SARS-CoV-2

SARS coronavirus 2 antibody potency

neutralizing antibodies

COVID-19

intravenous immune globulin

immunoglobulin

plasma collection

prophylaxis

Omicron

Plasma collected from COVID-19 recovered or vaccinated donors as well as immunoglobulin (IG) preparations produced from it contain SARS-CoV-2 neutralizing antibodies, as primarily demonstrated by studies with the original Wuhan strain of SARS-CoV-2 on US plasma-derived IG. Neutralization of the Wuhan as well as the Omicron virus variants is here confirmed for IG manufactured from plasma collected in the US and EU.

After several months of the COVID-19 pandemic, highly potent SARS-CoV-2 neutralization by intravenous immunoglobulins (IG) manufactured from plasma collected in the US, including post-COVID-19 and COVID-19-vaccinated donors, has been reported [1]. The functional antibody neutralization assay used in this report was based on the original Wuhan SARS-CoV-2 strain. Several other variants of concern have since emerged [2], and the most recent Omicron variant may even have established a new serotype, with – by definition – consequences on the level of virus cross-neutralization [3].

Plasma donors with residence in the US provide a quantitatively dominant contribution to the world’s supply of IG products, and earlier investigations into the potency of IGs against SARS-CoV-2 have thus focused on IG manufactured from US plasma. Several European countries do, however, also contribute sizeable volumes of plasma to the production of IG. The increase of COVID-19 case numbers as well as the number of vaccine doses administered in Europe has, however, been somewhat behind the US [4], with unclear consequences on the development of SARS-CoV-2 neutralization potency in IGs produced from plasma collected there.

As immunocompromised people, either due to their oncological conditions, after organ transplantation, or with certain immunodeficiencies, have a higher risk of severe COVID-19 consequences [5; 6], the levels of SARS-CoV-2 neutralizing antibodies in their IG treatment are of critical importance and were thus revisited in the above context. Beyond the IG preparations for intravenous use tested in earlier studies [7, 1], preparations suitable for the increasingly widely used subcutaneous application were also included in the current investigation.

Measurement of SARS-CoV-2 antibodies

Wuhan SARS-CoV-2 wild type (strain BavPat1/2020) and Omicron SARS-CoV-2 (strain hCoV-19/Netherlands/NH-RIVM-71076/2021, lineage B.1.1.529) neutralizing antibody titers were determined essentially as previously reported [7]. The reciprocal sample dilution resulting in 50% virus neutralization (µNT₅₀) was determined using the Spearman-Kärber formula, and the calculated µNT₅₀ neutralization titer was normalized to an internal assay control, therefore reported as µNT₅₀ [norm. 1:X]. For Wuhan SARS-CoV-2 wild type a qualified analytical method was used that included the National Institute of Biological Standards and Control (NIBSC, Potters Bar, UK) WHO International Standard 20/136 [8] and the concentration of neutralizing antibodies therefore also reported in IU/ml. Both Wuhan SARS-CoV-2 and Omicron neutralization assays included several validity criteria, i.e. confirmatory titration of input virus infectivity, cell viability, and neutralization testing of an internal reference standard, all of which had to comply with defined ranges.

Immunoglobulin preparations and anti-SARS-CoV-2 hyperimmune globulin

To determine Wuhan SARS-CoV-2 wild type and Omicron SARS-CoV-2 neutralization by immunoglobulin, six IG, 10% lots fractionated from US plasma collected prior to the pandemic (prepandemic; Gammagard Liquid; Baxalta US Inc., Lexington, MA), ten COVID-19 hyperimmune globulin (HIG) preparations manufactured exclusively from COVID-19 convalescent donors [1] and 100 IG, 10% lots fractionated from US or EU plasma collected during the pandemic (Gammagard Liquid, Baxalta US Inc., Lexington, MA or KIOVIG, Takeda Manufacturing Austria AG, respectively; released March till April 2022) were tested. To evaluate the development of SARS-CoV-2 neutralizing antibody content in IG lots manufactured from US and EU sourced plasma over time, all IG, 10% lots and all lots of immunoglobulin for subcutaneous application, i.e. SCIG, 20% (Cuvitru; Baxalta US Inc., Lexington, MA; US plasma) released between May 2021 and April 2022 were analyzed for original Wuhan SARS-CoV-2 wild type neutralization potency. Of these, the IG, 10% lots released between November 2021 and April 2022 were also analyzed for Omicron SARS-CoV-2 neutralization.

Graphs and Statistical Analysis

Graphical illustrations and statistical analysis (paired and unpaired t tests) were done in GraphPad Prism v9.2.0 software.

Wuhan and Omicron SARS-CoV-2 neutralization by immunoglobulin preparations from plasma collected before the pandemic, or after COVID-19 caused by Wuhan-like virus variants

IG lots that were fractionated from plasma collected prior to the COVID-19 pandemic (prepandemic; n=6) had no neutralizing activity against either of the two SARS-CoV-2 strains (Figure 1), fully consistent with earlier findings [9]. The investigational COVID-19 hyperimmune (HIG; n=10) preparations had high neutralization capacity (GMT±SEM µNT₅₀[norm. 1:X]) against the Wuhan SARS-CoV-2 wild type (947±109), yet a significantly (p<0.0001) lower neutralization titer against the recent Omicron strain (24±1), i.e. an approximately 40-fold difference in potency. Regular IG lots released in March and April 2022, produced from US plasma (5057±281; n=85) or from EU plasma (3214±382; n=15), had 3-5 fold greater Wuhan SARS-CoV-2 wild type neutralization capacity than even the HIG. These IG lots also had a quite potent neutralization capacity for the Omicron strain (US: 394±27; EU: 116±19) (Figure 1), although this was on average 20-fold lower than their respective Wuhan neutralization titer.

Wuhan and Omicron SARS-CoV-2 neutralization by immunoglobulin preparations from plasma collected during the course of the pandemic and vaccination campaigns, in the US and EU

Regular IG, 10% released to the US market between May 2021 and April 2022, had continuously and quite rapidly increasing neutralization titers against the Wuhan SARS-CoV-2 wild type, which seemed to reach plateau levels towards the end of 2021, at levels approx. 25-fold higher than in May 2021 (Figure 2 A). This increase in titers was somewhat delayed for EU plasma derived IG lots, that did finally reach antibody levels approximately within only a factor of 2 from the US lots, i.e. a single dilution step as used in the neutralization assay. By April 2022, consistent and high neutralization capacity for the Wuhan SARS-CoV-2 wild type virus was seen for all IG lots (US: 6168±511; EU: 4476±430), with Omicron neutralization 12- (US: 510±50) and 22- (EU: 199±14) fold lower (Figure 2 A).

SARS-CoV-2 antibody levels in IG preparations for intravenous versus subcutaneous application

When normalized to 10% protein content, lots of SCIG, 20% for subcutaneous application, released to the US market between May 2021 and April 2022, had near equivalent and similarly increasing neutralization potency against the Wuhan SARS-CoV-2 wild type as seen for lots of IG, 10% for intravenous application (Figure 2 B). IG preparations for subcutaneous application also reached similar consistent plateau levels towards the end of 2021, at approx. 25-fold higher potency than in May 2021 (Figure 2 B). There was no difference (p=0.71) in anti-SARS-CoV-2 potency development over time nor at levels reached between these two classes of IG preparations.

In line with a previous report for Wuhan SARS-CoV-2 wild type virus [9], IG fractionated from plasma collected prior to the COVID-19 pandemic did also not neutralize the Omicron SARS-CoV-2 variant (Fig. 1). COVID-19 HIG preparations, fractionated from COVID-19 convalescent donor plasma collected at the beginning of the pandemic and therefore representative of the antibody response to infection only, provided for some Wuhan as well as Omicron neutralization, with the latter however considerably lower than against the Wuhan SARS-CoV-2 wild type, in line with previous reports of 16-fold and up to 32-fold lower neutralization of the Omicron vs. Wuhan strain by post COVID-19 sera, tested with a pseudovirus system [10, 11].

The difference in Wuhan versus Omicron neutralization potency was somewhat less pronounced for pandemic IG preparations (Fig. 1), manufactured from plasma collected from a mixed convalescent, COVID-19 vaccinated and partially even re-exposed donor population. The highly potent and heterogeneous SARS-CoV-2 antibody specificities contained in these commercial IG lots apparently provide for better Omicron neutralization, reflective of the greater antibody response to COVID-19 vaccination rather than SARS-CoV-2 infection only [1, 12] and broader Omicron neutralization following repeat vaccination and infection exposures [11, 13]. Still, the observed differences in SARS-CoV-2 variant cross-neutralization by the IG preparations support the proposal to consider the Omicron SARS-CoV-2 variant a distinct serotype [3].

A dramatic upward change in anti-SARS-CoV-2 potency was previously reported for US plasma-derived IG lots released in May 2021 [1], a trend that continued until the end of 2021 and seems to have plateaued since then (Fig. 2A), irrespective whether IG preparations for intravenous or subcutaneous application were analyzed (Fig. 2B). Analysis of EU plasma-derived IG lots indicated that SARS-CoV-2 neutralization titers against the Wuhan virus strain were lower in May 2021, reflective of the lower COVID 19 incidence as well as slower uptake of vaccination in Europe as compared to the US [4]. By the end of 2021, Wuhan SARS-CoV-2 wild type neutralizing titers in EU-plasma derived IG lots had reached equivalently high levels as in US-plasma derived IG lots.

First Omicron cases were reported in November 2021 from the US and EU [14] and the variant then rapidly became dominant in both geographies. With a typical period of approximately 6 months between plasma collection and IG lot release [7], Omicron-induced antibodies are not yet likely present in the IG preparations investigated here, although an increase in (cross-)neutralization titer also against the new variant is evident in US- and EU-plasma derived IG lots released in March and April 2022, which is expected to further increase significantly in the IG lots released in the upcoming months.

This outlook is of relevance for people with immunodeficiencies or immunosuppression, who depend on the antibody specificities contained in their IG treatment for protection from COVID-19. In the US, the COVID-NET has analyzed factors associated with severe outcomes in over 22,000 adults hospitalized with COVID-19. Of these, 12.2% were immunocompromised, although they only constitute an estimated 2.7% of the entire US population [6].

More specifically to the Omicron virus variant, plasma samples from patients with X-linked agammaglobulinemia, who receive regular IG as prophylaxis, were found to contain relatively low plasma concentrations of SARS-CoV-2 antibodies, with no potential to neutralize the Omicron variant in vitro, and three out of four patients had symptomatic COVID-19 during the Omicron wave [15]. The most current IG lot used in this study was produced in August 2021, i.e., at a time when SARS-CoV-2 neutralization titers of US plasma-derived lots were 4–5 times lower than reported here for current IG lots, and lower yet for EU plasma-derived lots (Fig. 2A). Whether these more potent antibody levels, now also against the Omicron virus variant, driven by additional COVID-19 cases and even more so effective vaccination campaigns, will be able to afford clinically meaningful levels of protection remains to be determined.

Funding

No additional financial support was received.

Acknowledgments

The contributions of the entire Global Pathogen Safety team, most notably Brigitte Kainz, Jasmin de Silva, Stefan Pantic, Elisabeth List, Nicole Rameder, Petra Gruber (neutralization assays), Veronika Sulzer, Sabrina Brandtner (cell culture), Eva Ha and Alexandra Schlapschy-Danzinger (virus culture), Kathrin Nagl (IG logistics) are gratefully acknowledged. Wild type (Wuhan) SARS-CoV-2 strain BavPat1/2020 and Omicron SARS-CoV-2 strain hCoV-19/Netherlands/NH-RIVM-71076/2021, lineage B.1.1.529 were sourced via the European Virus Archive GLOBAL (EVA-GLOBAL) project that has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement no. 871029 and were kindly provided by Christian Drosten and Victor Corman (Charité Universitätsmedizin, Institute of Virology, Berlin, Germany) and Chantal Reusken (National Institute for Public Health and the Environment, RIVM, Bilthoven, Netherlands), respectively.

Potential conflicts of interest

Authors are employees of Takeda Manufacturing Austria AG, Vienna, Austria. MRF, MK, and TRK have Takeda stock interest.

Financial support

This study was funded by Takeda Manufacturing Austria AG.

Presented in part

The results have not been presented.

Correspondence and requests for reprints

Thomas R. Kreil, PhD

Takeda, Benatzkygasse 2-6, 1221 Vienna, Austria.

Phone: +43 1 20100 247 3860. Fax: +43 1 20100 247 5783.

E-mail: [email protected]

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Omicron SARS-CoV-2 Neutralization by Immunoglobulin Preparations Manufactured from Plasma Collected in the US and Europe

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