Passive immunotherapies for COVID‐19: The subtle line between standard and hyperimmune immunoglobulins is getting invisible

Abstract

During the COVID-19 pandemic, immunoglobulins (IG) have been suggested both as an immunosuppressive treatment in late COVID-19 stages and as an antiviral in pre-exposure prophylaxis, post-exposure prophylaxis, and treatment of early COVID-19 stages. As immunosuppressants in late COVID-19 stages, we and other groups were not able to detect any signal of efficacy.1 On the antiviral side, human neutralising IG (hyperimmune IG, HIG) has been traditionally derived from selected convalescent plasma (CP) donors.2 The Inpatient Treatment of COVID-19 With Anti-Coronavirus Immunoglobulin (ITAC) randomized controlled trial [NCT04546581] of intravenous COVID-HIG (NP-028) (0.4 g/kg) for treatment of COVID-19 inpatients (N = 593) showed no benefit,3 but trials in outpatients are ongoing (INSIGHT 012, NCT04910269). To date, COVID-HIG (NP-028) has been shown to retain neutralising potency against past variant of concern/interest Alpha, Beta, Gamma, Delta/Delta+, Eta, Iota, Kappa, Lambda, Mu, but no data are available for Omicron.4 Furthermore, hyperimmune sera can nowadays be manufactured from naïve vaccinees: for example, Rojas-Jimenez et al. used caprylic acid precipitation to prepare a pilot-scale batch of anti-SARS-CoV-2 HIG from plasma of donors immunised with the BNT162b2 (Pfizer-BioNTech) anti-COVID-19 vaccine, showing higher concentration of anti-RBD and ACE2-RBD neutralizing antibodies (nAbs) than in CCP-derived IVIg.5 But HIG manufacturing suffers from logistical bottlenecks, which hamper scalability. The availability of nAbs within a product which is already scaled up would facilitate large-scale deployment. Despite initial signs of heterologous immunity to SARS-CoV-2 from previous seasonal coronavirus infection in pre-pandemic IG lots of HyQvia® (Baxalta Innovations GmbH), Privigen® (CSL Behring), Intratect® (Biotest AG), IgVena® (Kedrion S.p.A), and Flebogamma® (Grifols S.A.),6-8 pre-pandemic sera have been shown to be devoid of nAb,9, 10 making the occurrence of neutralizing activity extremely unlikely in IG lots manufactured from plasma collected before 2021. However, the situation is rapidly evolving, with most plasma donors worldwide becoming SARS-CoV-2 seropositive because of convalescence and/or COVID-19 vaccination. Karbiener et al. at Baxter reported minimal seropositivity in IG lots released since September 2020: from there, values steadily increased, in correlation with the cumulative COVID-19 incidence, to reach a mean of 36.7 international units (IU)/ml, and 93% of IG lots were positive by January 2021.11 Extrapolating the correlation, the authors estimated that IVIGs could have reached an anti-SARS-CoV-2 potency of ∼400 IU/ml (i.e., a dose similar to that contained in a COVID-19 convalescent plasma (CCP) unit) by July 2021.11 Farcet et al. at Takeda tested 176 IG lots released since March 2020 for SARS-CoV-2 nAbs, 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 COVID-19 incidence, to reach a mean of 31.2 IU/ml and 93% of lots positive by January 2021. Extrapolating the correlation, intravenous immunoglobulins (IVIG) could reach an anti-SARS-CoV-2 potency of ∼345 IU/ml by July 2021. At that stage, prophylactic IVIG treatment for primary/secondary immunodeficiency could contain similar doses of anti-SARS-CoV-2 as CCP.12 Volk et al. investigated SARS-CoV-2 reactivity of US plasma-derived IVIG/subcutaneous IG products from the end of 2020 until June 2021 as well as in CP from May 2020 to August 2020 to determine whether potentially neutralizing antibody titers may be present.13 While approximately 50% of convalescent donations were not/low neutralizing, approximately 10% were at or above 600 IU/ml. 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 nAbs 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 primary immunodeficiency, 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 2021.13 Stinca et al. predicted that anti-SARS-CoV-2 IgG concentration will peak in batches produced in mid-October 2021, containing levels in the vicinity of 190-fold that of the mean (unvaccinated) CCP.14 An elevated concentration (approximately 35-fold CCP) is anticipated to be retained in batches produced well into 2022. Measurement of several Privigen batches using the Phadia™ EliA™ SARS-CoV-2-Sp1 IgG binding assay confirmed the early phase of this model.14 CP and IG (either regular IG or HIG) have different manufacturing times, which makes CP preferrable early in pandemics, while IG take several months to be available.3 Regardless of indication (which is not expected at its best against a respiratory pathogen with marginal systemic spread), the 2 antiviral formulations also differ in composition, with purified IG devoid of IgM and IgA classes. In conclusion, there are encouraging signals that regular IG will equate HIG in terms of efficacy, while granting higher scalability and lower costs. With fast-waning immunity (after either vaccination or natural infections), it is not currently clear how long this opportunity will last. Until this occurs, it is more clear which population subgroups will most benefit from it. In particular, such IG should compete with anti-Spike monolonal antibodies (mAbs) for preexposure prophylaxis in immunocompromised subjects who did not respond to vaccines, but also for post-exposure prophylaxis and early treatment in frail subjects. This is becoming more and more relevant in sight of resistance of Omicron to mAbs (including sotrovimab-resistant BA.215), while, in contrast, CP from vaccinees is getting higher and higher titers of nAbs.16 The results of clinical trials are awaited with interest. (Figure 1) The natural evolution of neutralising antibody-based therapies against an emerging pathogen. VOC, variant of concern We declare we have no conflict of interest related to this manuscript. D.F. conceived the manuscript and wrote the first draft. M.F. revised the manuscript.

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