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On December 7th, WHO updated its living guideline on COVID-19 therapeutics, including convalescent plasma (CCP). This led to their recommendation against the use of CCP for COVID-19 patients, adding that it should only be used within clinical trials for severely and critically ill COVID-19 patients. In addition to their recommendation, WHO has stated that even though the evidence surrounding CCP’s benefit for severely ill patients is uncertain, they do recommend that trials focusing on subgroups of severe and critically ill patients should continue.
As the SUPPORT-E Consortium* we wish to respond to these recommendations.
In line with the recommendations from WHO, we agree that there is no firm evidence that CCP is a beneficial therapeutic treatment for COVID-19 patients, but we firmly believe that, given the rate of SARS-CoV-2 infection in Europe, as well as the existing therapeutic means and treatments, CCP is still worth investigating, in particular within specific patient groups.
There is no evidence that randomized clinical trials should focus only on severely ill COVID-19 patients: in fact the strongest data suggest efficacy of CCP in early intervention 1-3 among seronegative patients and immunosuppressed patients 4;5 Also, a significant antibody dose response has been reported 3;6-8. A large number of earlier trials relied on “low titre” CCP, this is very different to CCP currently collected from vaccinated convalescent donors that have ten times higher titres, and broad “cross-variants” viral neutralization 9-12.
Moreover, the polyclonal antibody content of convalescent plasma could make this product an ideal source for hyperimmune immunoglobulin preparation, which require pooling large numbers of units of donor plasma, so standardizing the dose of high titre polyclonal specific antibodies. Although studies pertaining to the use of hyperimmune globulin have yet to be published, it is clear that CCP availability is a prerequisite in case of need for specific Ig preparation.
Other treatment options, notably recombinant monoclonal antibodies (MoAb) are not always available, especially in low and middle-income countries. These are expensive and prone to potential reduced efficacy against variants of concern.
The recent introduction of the Omicron variant with a high number of mutations in the Spike protein lead to viral escape and challenge existing MoAb 13. Conversely, CCP collected among recently infected donors would contain Ig produced after infection with current variants. Additionally, this treatment would also be available in low-income countries.
WHO guidance does not present evidence against the use of CCP in people who do not have severe COVID-19 14. For non-severe COVID-19 it is based inter alia on the RECOVERY trial 15 which only provides good evidence for severely or critically ill patients, or on the PLACID trial which assessed CCP with low to undetectable levels of anti-SARS-CoV-2 antibodies to those randomised to receive convalescent plasma 16. Among the participants, 99% were enrolled from inpatient settings 14, i.e., the significant subgroup of non-hospitalized, vulnerable patients at risk of hospitalization were not adequately represented in this analysis. Positive signals of CCP efficacy were detected in subgroup analyses of some negative RCTs. For instance, in patients with immunodeficiency enrolled in the REMAP-CAP trial 17, or in patients with milder COVID-19 in the recently published TSUNAMI trial 18. The WHO provides recommendations for the whole spectrum of COVID-19 disease, while the available evidence is limited. Knowledge gaps must be clearly identified and investigated in further trials, e.g., very early treatment in non-hospitalized patients, immunocompromised patients, antibody-negative patients.
WHO latest guidance on CCP also refers to potential harm of transfusion, whilst also stating that there is no evidence of an increase of risks of transfusion-associated complications. The SUPPORT-E Consortium is therefore questioning the three-times repeated assertion of CCP associated to transfusion harm and its evidence. A recent meta-analysis on 30 randomized and non-randomized trials documented the safety of CCP compared to standard therapy, even when thromboembolic complications were considered 19.
On the mobilization of resources dedicated to collect CCP, it should be noted that there is no waste or overuse of human resources. Research on CCP allowed blood establishments to increase their collection of plasma that, if not used for treating COVID-19 patients, is nevertheless kept and stored for future usage, for regular (non-COVID-19 related) transfusion or to produce plasma derived medicinal products (PDMPs).
The SUPPORT-E Consortium notes that the WHO guidance on CCP highlights high cost and limited availability, when for monoclonals (or antivirals) these logistic arguments are not emphasized in the same manner. In particular, the conclusion drawn from these practical issues is peculiar since it is presented as if the above practical issues contribute to the recommendation not to administer CCP while it leads to recommending monoclonals – despite the even higher cost and very limited availability, and the increased risk that monoclonals lose their activity against newly emerging variants.
In Europe, a big part of research on CCP is based on data collected and shared through the SUPPORT-E EU CCP database 20 containing data on 153,000 CCP donations; analysing the data and drawing conclusions from them is ongoing and results will be presented at the end of the project. It therefore seems premature to draw firm conclusions on the use of CCP, at this stage.
We believe that research on CCP use should only stop or be discouraged in either of two situations: (i) when a therapy is showing harm to the patients or (ii) when the question explored is no longer pertinent or worth exploring. We do not think that this is the case.
We further wish to underline the importance of the scientific community to keep exploring the potential of CCP. It still is a promising, inexpensive, and well tolerated therapy that actively involves communities to care for those who suffer from acute infection by those who have recovered thus valuing the contribution of donors in this fight against a pandemic.
The SUPPORT-E Consortium is very much grateful for the ongoing financial support of the European Commission funding this research.
Hubert Schrezenmeier
Vincenzo de Angelis
Stéphane Bégué
Livia Cannata
Christian Erikstrup
Lise Escourt
Hendrik Feys
Catherine Hartmann
Marcello Lembo
Gaia Mori
David Roberts
Ellen van der Schoot
Daphne Thijssen-Timmer
Pierre Tiberghien
On behalf of the SUPPORT-E Consortium: * SUPPORT-E is an EU funded project dedicated to research on COVID19 convalescent plasma; https://www.support-e.eu/
Reference List
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(15) RECOVERY Collaborative Group. Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial. Lancet 2021; 397(10289):2049-2059.
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(20) DG SANTE: EU CCP Database. 10-12-2021.
Ref Type: Online Source. https://ec.europa.eu/health/blood_tissues_organs/covid-19_en