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 ... -  《-》

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 ... -  《-》

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 ... -  《-》

Convalescent plasma donors show enhanced cross-reactive neutralizing antibody response to antigenic variants of SARS-CoV-2 following immunization.

The therapeutic benefit of convalescent plasma (CP) therapy to treat COVID-19 may derive from neutralizing antibodies (nAbs) to SARS-CoV-2. To investigate the effects of antigenic variation on neutralization potency of CP, we compared nAb titers against prototype and recently emerging strains of SARS-CoV-2, including Delta and Omicron, in CP donors previously infected with SARS-CoV-2 before and after immunization. Samples were assayed from previously SARS-CoV-2 infected donors before (n = 17) and after one (n = 43) or two (n = 71) doses of Astra-Zeneca or Pfizer vaccinations. Ab titers against Wuhan/wild type (WT), Alpha, Beta, and Delta SARS-CoV-2 strains were determined by live virus microneutralization assay while titers to Omicron used a focus reduction neutralization test. Anti-spike antibody was assayed by Elecsys anti-SARS-CoV-2 quantitative spike assay (Roche). Unvaccinated donors showed a geometric mean titer (GMT) of 148 against WT, 80 against Alpha but mostly failed to neutralize Beta, Delta, and Omicron strains. Contrastingly, high GMTs were observed in vaccinated donors against all SARS-CoV-2 strains after one vaccine dose (WT:703; Alpha:692; Beta:187; Delta:215; Omicron:434). By ROC analysis, reactivity in the Roche quantitative Elecsys spike assay of 20,000 U/mL was highly predictive of donations with nAb titers of ≥1:640 against Delta (90% sensitivity; 97% specificity) and ≥1:320 against Omicron (89% sensitivity; 81% specificity). Vaccination of previously infected CP donors induced high levels of broadly neutralizing antibodies against circulating antigenic variants of SARS-CoV-2. High titer donations could be reliably identified by automated quantitative anti-spike antibody assay, enabling large-scale preselection of high-titer convalescent plasma.

Harvala H ，Nguyen D ，Simmonds P ，Lamikanra AA ，Tsang HP ，Otter A ，Maes P ，Webster M ，Clarkson A ，Kaloyirou F ，Hopkins V ，Laidlaw SM ，Carroll M ，Mora A ，Griffiths A ，MacLennan S ，Estcourt L ，Roberts DJ ... -  《-》

Screening for SARS-CoV-2 antibodies in convalescent plasma in Brazil: Preliminary lessons from a voluntary convalescent donor program.

Coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) collection began in two Brazilian hospitals for treatment of severe/critical patients. Mild/moderate COVID-19 convalescents were selected as CCP donors after reverse transcription polymerase chain reaction (RT-PCR) confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and absence of symptoms for ≥14 days plus (a) age (18-60 years), body weight greater than 55 kg; (b) immunohematological studies; (c) no infectious markers of hepatitis B virus, hepatitis C virus, human immunodeficiency virus, human T-lymphotropic virus-1/2, Chagas and syphilis infection; (d) no HLA antibodies (multiparous); (e) second RT-PCR (nasopharyngeal swab and/or blood) negativity; (f) virus neutralization test (cytopathic effect-based virus neutralization test neutralizing antibody) and anti-nucleocapsid protein SARS-CoV-2 IgM, IgG, and IgA enzyme-linked immunosorbent assays. Among 271 donors (41 females, 230 males), 250 presented with neutralizing antibodies. Final RT-PCR was negative on swab (77.0%) or blood (88.4%; P = .46). Final definition of RT-PCR was only defined at more than 28 days after full recovery in 59 of 174 (33.9%) RT-PCR -ve, and 25/69 RT-PCR +ve (36.2%; 13 between 35 and 48 days). Neutralizing antibody titers of 160 or greater were found in 63.6%. Correlation between IgG signal/cutoff of 5.0 or greater and neutralizing antibody of 160 or greater was 82.4%. Combination of final RT-PCR -ve with neutralizing antibody ≥160 was 41.3% (112/271). Serial plasma collection showed decline in neutralizing antibody titers and IgA levels (P < .05), probably denoting a "golden period" for CCP collection (≤28 days after joining the program); IgA might have an important role as neutralizing antibody. Donor's weight, days between disease onset and serial plasma collection, and IgG and IgM levels are important predictors for neutralizing antibody titer. RT-PCR +ve cases are still detected in 36.2% within 28 to 48 days after recovery. High anti-nucleocapsid protein IgG levels may be used as a surrogate marker to neutralizing antibody.

Wendel S ，Kutner JM ，Machado R ，Fontão-Wendel R ，Bub C ，Fachini R ，Yokoyama A ，Candelaria G ，Sakashita A ，Achkar R ，Hamerschlak N ，Scuracchio P ，Amaral M ，Dal Ben M ，Araujo D ，Soares C ，Camargo A ，Kallás E ，Durigon E ，Reis LF ，Rizzo LV ... -  《-》