Lower anti-spike levels in B-cell-depleted patients after convalescent plasma transfusion suggest the need for repeated doses.

Abstract

We read with interest the recent paper by Gachoud et al., shedding light on plasma anti-spike immunoglobulin G (IgG) level kinetics in 36 immunocompromised COVID-19 patients (mostly unvaccinated and seronegative) transfused with plasma at the time of the alpha variant of concern (VOC).1 Seventeen patients received four 200-ml units of convalescent plasma (CP) over 48 h, while 19 patients received two 200-ml units of two-dose mRNA vaccine plasma [either putatively COVID-19-naïve (VP) or COVID-19-experienced (CP/VP, a.k.a. ‘hybrid’ plasma or VaxCCP)] over 24 h. The authors show that, in 17 patients previously treated with anti-CD20 monoclonal antibodies within the last 12 months, who represent a difficult-to-treat COVID-19 patient population, post-transfusion plasma anti-spike IgG levels are lower than in 19 untreated immunocompromised patients. This finding potentially splits the immunocompromised population into two subgroups: the B-cell-depleted and the non-B-cell-depleted. Whether the lower antibody levels are caused by accelerated clearance or delayed endogenous response is not clear at this stage due to the lack of assays discriminating the two sources, but such lower levels translate into delayed SARS-CoV-2 clearance. And clearance is fundamental for immunocompromised patients, given that even low viral loads can lead to symptomatic relapse, or contribute to delays in initiation of further therapy for their underlying condition. In this context, it would help to know whether the baseline viral load (cycle threshold) was higher in the 12 B-cell-depleted than in the five B-cell-undepleted patients. Given that SARS-CoV-2 infection is associated with approximately 109–1011 virions per host, each harbouring 30–40 spike homotrimers2 and that viral neutralization would consume exogenous antibody, IgG half-life would be shorter than expected from conditions where no antigen is present. If higher viral loads are seen in B-cell-depleted versus non-B-cell-depleted patients, repeating doses more frequently than every three weeks and until viral clearance is achieved may be reasonable. In our experience, a single 600-ml high-titre CP/VP unit only induces modest increases in polymerase chain reaction (PCR) cycle thresholds when sampling nasopharyngeal swabs in B-cell-depleted COVID-19 patients. Hence, several centres have started transfusing CP until the patients become PCR-negative. Figure 1 depicts the cycle thresholds from nasopharyngeal swab samples in eight B-cell-depleted patients with antecedent antiviral treatments, after each CP/VP unit: those with repeated CP/VP doses cleared the virus earlier than those who received a single unit, prompting our introduction of weekly 600-ml CP/VP transfusions.3 In a prepublished systematic review of CP use in immunocompromised patients,4 we found an inverse correlation between the cumulative CP volume and mortality, again supporting the position that repeated doses can make a difference. Gachoud et al. show that the serum anti-spike IgG after VP or CP/VP has similar kinetics to that after CP. There is now an abundance of evidence (reviewed here) that CP/VP is superior both to boosted VP as well as CP at neutralizing omicron sublineages.5 In addition, COVID-19-naïve plasma donors have become exceedingly rare (the few being more putative than real, given the absence of anti-N antibody screening), and the use of COVID-19-naïve plasma is not allowed in many countries (e.g., under the emergency use authorization issued by the Food and Drug Administration (FDA) in USA). It is reasonable that the number of antibodies covering variants in hybrid plasma is much higher, thereby lowering the chances for immune escape. Accordingly, the three refractory cases reported in their fig. 2, panel F, show that a negative nasopharyngeal swab (NPS) was promptly achieved after CP/VP transfusion, despite the massive within-host spike evolution. These results would likely not have been achieved with therapeutically authorized anti-spike monoclonal antibodies given their narrow spectrum of action. In short: could a more prompt, stringent schedule of CP/VP have prevented within-host evolution? Thus, ‘hybrid’ plasma may represent an effective strategy that is less prone to immune escape than Evusheld™6 and other monoclonal antibody therapies, and repeated doses may be the key to achieve SARS-CoV-2 clearance in B-cell-depleted COVID-19 patients. Given the comparatively small number of B-cell-depleted patients relative to the high number of vaccinated convalescent donors, this approach is safe and feasible, and warrants evaluation in view of the emergent Spike:R346X-harbouring, fully Evusheld™-resistant omicron sublineages (e.g. BA.4.6 and BA.2.75.2).7 Daniele Focosi and Massimo Franchini wrote the first draft; Jonathon W. Senefeld, Michael J. Joyner, Evan M. Bloch, David Sullivan and Arturo Casadevall revised the final manuscript. We declare we have no conflict of interest related to this manuscript. Dr. Bloch is a member of the U.S. FDA Blood Products Advisory Committee. Any views or opinions expressed in this manuscript are Dr. Bloch's and are based on his own scientific expertise and professional judgement; they do not necessarily represent the views of the Blood Products Advisory Committee or the formal position of the FDA and also do not bind or otherwise obligate or commit either the Advisory Committee or the FDA to the views expressed.