Year: 2023
Type: article
Abstract: To the Editor—We congratulate Maor and colleagues for their unprecedented randomized clinical trial (RCT) comparing convalescent plasma (CP) with CP-derived immunoglobulin G (cIgG) in hospitalized coronavirus disease 2019 (COVID-19) patients [1], which represents one of the very few head-to-head RCTs done during the pandemic. cIgG is devoid of immunoglobulin A and immunoglobulin M, which have a prominent role in virus neutralization [2], although each has a shorter half-life than IgG. Consequently, their finding that CP and cIgG have comparable efficacy at day 14, but not day 28 [1], has a potential pharmacokinetic explanation, as neutralizing antibody provided by CP would be cleared faster. The CP used in their RCT was qualified based on high-throughput serology (Abbott anti-Spike IgG >1050 AU/mL), with the US Food and Drug Administration recommending at least >1280 AU/mL [3]. Despite both arms receiving 4 g total antibody, anti-spike IgG in the 2 CP units (0.42 million AU) was estimated to be 25% the anti–spike 1 IgG in cIgG (1.35 million AU), which could also explain the trends to greater efficacy at day 14 and superiority at day 28. The superiority of cIgG at day 14 provides additional evidence for the importance of high antibody dosing in COVID-19. CP has consistently been shown to be safe and effective when used in the first 5 days since onset of COVID-19 symptoms [4], so the authors’ findings that there was no difference in response between those treated before versus after 7 days since onset of symptoms [1] is likely due to low titers in CP or late treatment, since those requiring hospitalization in the first 7 days from symptom onset likely had a more severe disease course. Finally, a subgroup analysis for the 67 immunocompromised patients (27 in the cIgG arm and 40 in the CP arm) could be informative. The authors conclude that “In the face of new variants, cIgG is a viable option for treating COVID-19,” but this statement needs to be qualified logistically. cIgG manufacturing is more expensive than CP and, most importantly, requires 6–12 months between initiation of CP collections and distribution of lots; accordingly, the first CP collection occurred on May 2020 and the first patient within the RCT was transfused in January 2021 (and the last one in October 2021). During that time, the dominant SARS-CoV-2 variant changed from wild-type to Delta, against which the neutralization capacity likely changed. Today in a postvaccine pandemic era, when hybrid exposure (infection and vaccination) leads to high-titer (>40 000 AU/mL) heterologous immunity and provides cross-protection against even future variants [5, 6], cIgG has a 6- to 12-month lag in variant match compared to CP. Standard intravenous immunoglobulin bulks already stem mostly from CP donations, reducing the logistical feasibility, regulatory hurdles, and cost-effectiveness of a dedicated manufacturing chain [7]. Given that in immunocompetent hospitalized patients cIgG has failed to show superiority against placebo in a large RCT [8] and that anti-spike monoclonal antibodies are no longer effective against new Omicron variants, we feel that future RCTs should be designed with biological plausibility (eg, seronegative immunocompromised patients [9]) and logistic feasibility in mind.
Source: Clinical Infectious Diseases
DOI: 10.1093/cid/ciad406
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4382918591