The commentary by Focosi et al.
1
highlights two key aspects of the patient‐blood management for coronavirus disease
2019 (COVID‐19) convalescent plasma (CCP) therapy in seronegative patients who are
pre‐exposed to B‐cell‐depleting agents. The first one relates to the qualitative composition
of CCP used for patient treatment. The efficacy of CCP is strongly affected by the
titres of neutralising antibodies (nAb) present at the time of donation.
2
,
3
Moreover, there is growing evidence that the nAb activity of plasma units collected
from unvaccinated donors infected during the former COVID‐19 waves is reduced against
novel variants such as Omicron.
4
Hence, the efficacy of collected plasma is likely evolving alongside the exposure
of potential donors to successive variant outbreaks and vaccination campaigns against
severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2).
At the beginning of the pandemic, CCP was used as a front‐line treatment; however,
its wide heterogeneity in nAb titres made it difficult to recruit suitable donors
of high neutralising titres, as defined by the United States Food and drug Administration
(FDA). In contrast, nAb induced after two doses of mRNA vaccination have generally
higher and more homogenous titres, which further remain effective against Omicron
following a booster dose.
5
From March to July 2021, we treated 19 immunosuppressed patients with plasma collected
from COVID‐naive two‐dose mRNA‐vaccinated donors, under a compassionate use protocol,
according to the Swiss regulation rules.
6
No relevant difference was observed between patients receiving CCP (n = 17) versus
vaccinated plasma (VP, n = 19), indicating that VP therapy is safe and effective in
patients with B‐cell lymphopenia. In the meantime, CCP donors are increasingly getting
vaccinated, and three‐dose VP donors are being boosted by a breakthrough infection
(defined as ‘hybrid plasma’, Vax‐CCP or CP/VP). Their plasmas contain higher nAb titres
and broader antibody specificity than CCP,
4
,
7
,
8
as shown by the increase in anti‐spike immunoglobulin G titres between 2021 and 2022
(Figure 1A). Thus, Vax‐CCP is emerging as the most convenient available source of
polyclonal antibody plasma, given the failure of many monoclonal antibody therapies,
due to the Omicron immune escape variants.
9
FIGURE 1
SARS‐CoV‐2 viral load response follow‐up in B‐cell‐depleted patients (n = 11) treated
with plasma therapy (from December 2021 through September 2022). All patients had
received anti‐CD20 therapy and, except of one patient, were hospitalised for moderate
to severe COVID‐19. A favourable clinical outcome was observed in 10 out the 11 plasma‐treated
patients. (A) Anti‐spike (anti‐S) protein IgG titres were collected from COVID‐19‐experienced
only plasma donors (2020, October 2020–February 2021) or COVID‐19‐experienced vaccine‐boosted
(VaxCCP or CP/VP) plasma donors (2021, June–August 2021; 2022, February–September
2022). (B) Comparison of anti‐S IgG antibody titres in each patient before and after
1 × CP/VP or 2 × CP/VP treatment, using an in‐house developed Luminex assay.
11
The maximum reached value is depicted. (C) The PANGO lineage is indicated for each
patient. (D) SARS‐CoV‐2 RNA detection
12
in nasopharyngeal (NP) swabs (copies/ml) before (Day –5 to Day 0) treatment and over‐time
kinetics after treatment with 1 × CP/VP (1×) or 2 × CP/VP (2×). The p value is by
Mann–Whitney test. (E) Time‐to‐negativity of the NP swabs in patients treated with
1 × CP/VP (1×) or 2 × CP/VP (2×). CCP, COVID‐19 convalescent plasma; COVID‐19, coronavirus
disease 2019; IgG, immunoglobulin G; n.s., not significant; PANGO, Phylogenetic Assignment
of Named Global Outbreak; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus‐2;
VP, vaccinated plasma.
The second key aspect commented upon by Focosi et al
1
concerns the best practice for treating immunocompromised seronegative patients with
COVID‐19 with plasma therapy. It still remains to be defined which therapeutic plasma
protocol is optimal to achieve a rapid and complete viral response.
10
In this regard, Focosi et al
1
propose to start with a loading Vax‐CCP dose of 600 ml followed by weekly 600‐ml dose
transfusion, allowing for a faster viral clearance in patients than those receiving
a single‐dose unit. In our centre, we use an initial 400‐ml dose of Vax‐CCP issued
from two vaccinated and recently‐infected donors having recovered from a contemporary
viral strain. In case of insufficient clinical and/or viral load response, we treat
again with the same plasma dose but from other convalescent vaccine‐boosted individuals.
Using this strategy, we recently followed the SARS‐CoV‐2 viral load response in 11
B‐cell‐depleted antibody‐negative patients with a documented onco‐haematological (seven
patients) or autoimmune disorder (four patients), after plasma therapy. Patients were
classified according to whether they had Vax‐CCP treatment once or twice (Figure 1B)
and presented various Phylogenetic Assignment of Named Global Outbreak (PANGO) lineages,
depending on the predominant circulating strain(s) at the time of diagnosis (Figure 1C).
Our data indicate that seven out nine patients were able to clear the virus within
the same time‐range (<35 days, Figure 1D,E) as reported for patients with endogenous
anti‐SARS‐CoV‐2 responses,
6
among them two had received two serial transfusions. Hence, our tailored approach
is consistent with the relative low number of refractory cases (six of 36) previously
observed
6
and enables sparing Vax‐CCP resources of high anti‐SARS‐CoV‐2 titres, which heavily
rely on the continuous collection of donor plasma.
Understanding which parameter(s) may be predictive of complete viral clearance would
likely help adjusting Vax‐CCP treatment. As such, the question of whether basal viral
load is typically higher in B‐cell‐depleted patients than in B‐cell‐undepleted ones
and thus represents a red‐flag could alas not be addressed in the dataset initially
reported,
6
as both cohorts differed substantially in terms of the underlying viral variant (pre‐alpha
vs. alpha predominance respectively). Still, we recently observed that patients transfused
twice with Vax‐CCP had higher levels of initial SARS‐CoV‐2 viral loads than those
receiving only one‐time plasma (Figure 1D). These observations suggest that viral
loads before Vax‐CCP treatment may potentially define those seronegative patients
more at risk of delayed clinical recovery and/or viral clearance, and who would require
additional transfusions. Importantly, randomised controlled trials, like the recently
reopened Randomised, Embedded, Multifactorial, Adaptive Platform Trial for Community‐Acquired
Pneumonia (REMAP‐CAP) trial, specifically focusing on immunocompromised patients treated
with Vax‐CCP, should further help addressing such important points, paving future
guidelines for the use of therapeutic plasma.
AUTHOR CONTRIBUTIONS
Nathalie Rufer wrote the first draft; David Gachoud, Claire Bertelli and Nathalie
Rufer revised the manuscript.
CONFLICT OF INTEREST
The authors declare that they have no competing interests.
PATIENT CONSENT STATEMENT
Each patient provided informed consent for plasma transfusion and data collection.