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DOI: 10.1002/rmv.2341
EDITORIAL
Passive immunotherapies for COVID‐19: The subtle line
between standard and hyperimmune immunoglobulins is
getting invisible
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 Behr-
ing), Intratect
®
(Biotest AG), IgVena
®
(Kedrion S.p.A), and Flebo-
gamma
®
(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 immu-
noglobulins (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 reac-
tivity and nAbs over time. While lot‐to‐lot variability was sub-
stantial, 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 extrapola-
tions, based on non‐compartmental superposition principles using
steady‐state reference profiles from previously published pharma-
cokinetic 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 extrapo-
lated 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
Rev Med Virol. 2022;e2341. wileyonlinelibrary.com/journal/rmv © 2022 John Wiley & Sons Ltd.
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https://doi.org/10.1002/rmv.2341
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 pan-
demics, while IG take several months to be available.
3
Regardless
of indication (which is not expected at its best against a respira-
tory pathogen with marginal systemic spread), the 2 antiviral for-
mulations 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 resis-
tance of Omicron to mAbs (including sotrovimab‐resistant BA.2
15
),
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)
KEYWORDS
COVID19, immunosuppressants, intravenous immunoglobulins,
polyclonal antibodies, SARS‐CoV‐2
CONFLICT OF INTEREST
We declare we have no conflict of interest related to this manuscript.
AUTHOR CONTRIBUTIONS
D.F. conceived the manuscript and wrote the first draft. M.F. revised
the manuscript.
Daniele Focosi
1
Massimo Franchini
2
1
North‐Western Tuscany Blood Bank, Pisa University Hospital,
Pisa, Italy
2
Department of Hematology and Transfusion Medicine, Carlo
Poma Hospital, Mantua, Italy
Correspondence
Daniele Focosi, North‐Western Tuscany Blood Bank, Pisa University
Hospital, 56124 Pisa, Italy.
Email: daniele.focosi@gmail.com
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