Highly Potent SARS-CoV-2 Neutralization by Intravenous Immunoglobulins manufactured from Post-COVID-19 and COVID-19-Vaccinated Plasma Donations.

From September 2020, some immunoglobulin lots from US plasma contained neutralizing antibodies against the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Paralleled by the increasing numbers of post-coronavirus disease 2019 (COVID-19) donors, immunoglobulin lot antibody positivity increased to 93% by January 2021, at a mean titer of approximately 30 IU/mL. The correlation predicted that anti-SARS-CoV-2 potency would reach 345 IU/mL by July 2021. In addition to post-COVID-19 donors, the rapidly increasing number of plasma donors vaccinated against COVID-19 resulted in a mean antibody titer of >600 IU/mL in July 2021 immunoglobulin lots, with SARS-CoV-2 antibody titers for several lots even higher than those of earlier produced hyperimmune globulin products.

Karbiener M ，Farcet MR ，Schwaiger J ，Powers N ，Lenart J ，Stewart JM ，Tallman H ，Kreil TR ... -  《-》

SARS-CoV-2 Neutralization in Convalescent Plasma and Commercial Lots of Plasma-Derived Immunoglobulin.

Patients with primary or secondary immunodeficiency (PID or SID) face increased insecurity and discomfort in the light of the COVID-19 pandemic, not knowing if and to what extent their comorbidities may impact the course of a potential SARS-CoV-2 infection. Furthermore, recently available vaccination options might not be amenable or effective for all patients in this heterogeneous population. Therefore, these patients often rely on passive immunization with plasma-derived, intravenous or subcutaneous immunoglobulin (IVIG/SCIG). Whether the ongoing COVID-19 pandemic and/or the progress in vaccination programs lead to increased and potentially protective titers in plasma-derived immunoglobulins (Ig) indicated (e.g., for humoral immunodeficiency) remains a pressing question for this patient population. We investigated SARS-CoV-2 reactivity of US plasma-derived IVIG/SCIG products from the end of 2020 until June 2021 as well as in convalescent plasma (CP) from May 2020 to August 2020 to determine whether potentially neutralizing antibody titers may be present. Final containers of IVIG/SCIG and CP donations were analyzed by commercial ELISA for anti-SARS-CoV-2 S1-receptor binding domain (RBD) IgG as well as microneutralization assay using a patient-derived SARS-CoV-2 (D614G) isolate. Neutralization capacities of 313 single plasma donations and 119 plasma-derived IVIG/SCIG lots were determined. Results obtained from both analytical methods were normalized against the WHO International Standard. Finally, based on dense pharmacokinetic profiles of an IVIG preparation from previously published investigations, possible steady-state plasma levels of SARS-CoV-2 neutralization capacities were approximated based on currently measured anti-SARS-CoV-2 potencies in IVIG/SCIG preparations. CP donations presented with high variability with regards to anti-SARS-CoV-2 reactivity in ELISA as well as in neutralization testing. While approximately 50% of convalescent donations were not/low neutralizing, approximately 10% were at or above 600 IU/mL. IVIG/SCIG lots derived from pre-pandemic plasma donations did not show neutralizing capacities for SARS-CoV-2. Lots produced between December 2020 and June 2021 entailing plasma donations after the emergence of SARS-CoV-2 showed a rapid and constant increase in anti-SARS-CoV-2 reactivity and neutralization capacity over time. While lot-to-lot variability was substantial, neutralization capacity increased from a mean of 21 IU/mL in December 2020 to 506 IU/mL in June 2021 with a maximum of 864 IU/mL for the most recent lots. Pharmacokinetic extrapolations, based on non-compartmental superposition principles using steady-state reference profiles from previously published pharmacokinetic investigations on IVIG in PID, yielded potential steady-state trough plasma levels of 16 IU/mL of neutralizing SARS-CoV-2 IgG based on the average final container concentration from May 2021 of 216 IU/mL. Maximum extrapolated trough levels could reach 64 IU/mL based on the latest maximal final container potency tested in June 2021. SARS-CoV-2 reactivity and neutralization capacity in IVIG/SCIG produced from US plasma rapidly and in part exponentially increased in the first half of 2021. The observed increase of final container potencies is likely trailing the serological status of the US donor population in terms of COVID-19 convalescence and vaccination by at least 5 months due to production lead times and should in principle continue at least until Fall 2021. In summary, the data support rapidly increasing levels of anti-SARS-CoV-2 antibodies in IVIG/SCIG products, implicating that a certain level of protection could be possible against COVID-19 for regularly substituted PID/SID patients. Nevertheless, more research is still needed to confirm which plasma levels are needed to provide protection against SARS-CoV-2 infection in immune-compromised patients.

Volk A ，Covini-Souris C ，Kuehnel D ，De Mey C ，Römisch J ，Schmidt T ... -  《-》

Rapidly Increasing Severe Acute Respiratory Syndrome Coronavirus 2 Neutralization by Intravenous Immunoglobulins Produced From Plasma Collected During the 2020 Pandemic.

Immunoglobulin lots (N = 176) released since March 2020 were tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibodies, with first positive results for September 2020 lots (mean, 1.7 IU/mL; 46% of lots positive). From there, values steadily increased, in correlation with the cumulative coronavirus disease 2019 (COVID-19) incidence, to reach a mean of 31.2 IU/mL and 93% of lots positive by January 2021. Extrapolating the correlation, immunoglobulins could reach an anti-SARS-CoV-2 potency of approximately 345 IU/mL by July 2021. At that stage, prophylactic immunoglobulin treatment for primary/secondary immunodeficiency could contain similar doses of anti-SARS-CoV-2 as convalescent plasma that is used for treatment of COVID-19.

Farcet MR ，Karbiener M ，Schwaiger J ，Ilk R ，Kreil TR ... -  《-》

Development and characterization of anti-SARS-CoV-2 intravenous immunoglobulin from COVID-19 convalescent plasma.

Razumikhin M ，Smolyanova T ，Nikolaeva A ，Orlova E ，Ivanov A ，Belyakova O ，Vyaznikova T ，Selezneva N ，Perevozchikov A ，Sokolova A ，Zubkova N ，Efimova I ，Dolzhikova I ，Logunov D ，Sakanjan E ... -  《-》

Longitudinal analysis of SARS-CoV-2 antibodies in 8000 U.S. first-time convalescent plasma donations.

Coronavirus disease 2019 (COVID-19) convalescent individuals carry antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that, through a plasma donation, can be used as a potential therapeutic either in direct transfusion or for the manufacture of hyperimmune globulin (HIG). The success of such interventions depends on the antibody potency in such plasma donations, but little information on the collection of potent units is currently available. A total of 8749 plasma units, collected from April until September 2020 from first-time U.S. COVID-19 convalescent plasma donors, were characterized for SARS-CoV-2 immunoglobulin G (IgG) antibodies by Abbott chemiluminescent microparticle immunoassay (CMIA). The period between COVID-19 onset until donation and donor age, ethnicity, sex, and COVID-19 severity were evaluated against the obtained signal (index S/C). A marked decrease in mean index S/C was seen over the plasma collection period surveyed, which was significantly correlated to decreases in mean plasma donor age (p < .0001; R2 = .726) and percentage of donations obtained from COVID-19 convalescent patients who had been hospitalized (p = .001; R2 = .4426). The highest titer plasma units were obtained soon after convalescence from COVID-19 patients who required hospitalization, from advanced age donors, and from Black/African/Hispanic American versus White/Caucasian ethnicities, whereas there was no effect of donor sex on the values obtained with the Abbott CMIA. Since the onset of the pandemic, the average SARS-CoV-2 IgG values of first-time U.S. COVID-19 convalescent plasma donations have significantly dropped, mainly due to donations from progressively younger aged donors who tend to experience less severe COVID-19.

Karbiener M ，Farcet MR ，Ilk R ，Schreiner J ，Lenart J ，Powers N ，Stewart JM ，Tallman H ，Kreil TR ... -  《-》