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

Plain Language Summary People with deficiencies in their immune system often have an insufficient antibody response to antigens such as bacteria, viruses, or vaccines. These patients therefore often receive antibodies from healthy people to replace the missing antibodies and build a first line of defense against infections. These antibodies (also called immunoglobulins [Ig]) are prepared from plasma, the liquid fraction of the blood without cells, of healthy donors. This plasma is then split up during pharmaceutical production into its protein components. One of these is immunoglobulin G (IgG), which is the protein family that neutralizes/inactivates infectious agents as well as marks these infectious agents so they can be recognized by other parts of the immune system. With the ongoing COVID-19 pandemic and the severe to fatal outcomes for certain patient groups, especially people with impaired immunity, these patients and their physicians are interested in whether their antibody replacement therapy also confers protection against SARS-CoV-2 infection. We analyzed the capability of plasma-derived Ig lots to (i) recognize SARS-CoV-2 protein by ELISA method as well as (ii) neutralize SARS-CoV-2 by neutralization studies using the actual virus under biosafety level 3 (BSL-3) conditions. Here we show increasing anti-SARS-CoV-2 activity over time of manufactured Ig lots produced between December 2020 and June 2021. The most recent lots had a neutralizing activity of up to 864 IU/mL. Considering that the US represents Octapharma's main plasma source, the progress in vaccination levels together with the evolution of the COVID-19 pandemic in this country suggests that the intravenous or subcutaneous immunoglobulin (IVIG/SCIG) neutralization capacities against SARS-CoV-2 might still increase and could potentially reach a level where antibody plasma concentrations in the patient confer immune protection. Introduction 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. Purpose 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. Methods 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. Results 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. Conclusions 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.