SUPPORT-E Consortium: “Covid-19 convalescent plasma should be further investigated”

On December 7^th, the 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, the WHO has stated that even though the evidence surrounding CCP’s benefit for severely ill patients is uncertain, they do recommend that trials focused on subgroups of severe and critically ill patients should continue.

 

As the SUPPORT-E Consortium[1] we wish to respond to these recommendations.

 

In line with the recommendations from the WHO, we agree that there is indeed no firm evidence that CCP is a beneficial therapeutic treatment for COVID-19 patients. However, further research is needed especially within specific patient groups.

 

Recently developments including the rapid transmission of a new SARS-CoV-2 variant, the resistance of this variant to many licensed monoclonals and the uncertainty regarding the potential of antivirals all indicate that the therapeutic potential of CCP is still worth investigating,

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].

 

These observations suggesting efficacy of CCP in early intervention are entirely consistent with the positive results of early intervention with recombinant monoclonal antibodies (MoAbs) targeting against the Spike protein. It may be misleading to draw definitive conclusion regarding the potential effect of CCP based on earlier trials. These studies relied on “low titre” CCP, quite different to CCP currently collected from convalescent vaccinated (or probably vaccinated convalescent) donors that have ten times higher titres, and broad “cross-variant” viral neutralization [9-12]. Indeed, earlier trials reported signals for a dose effect [1].

 

Moreover, the polyclonal antibody content of convalescent plasma would provide an ideal source for hyperimmune immunoglobulin preparation, produced by pooling hundreds or thousands of units of donor plasma, so enabling standardized doses of high titre polyclonal specific antibodies. Although no 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.

 

In case of a new variant, resistant to monoclonal antibodies (MoAbs) and/or existing vaccines, CCP from convalescent vaccinated donors, or if needed from convalescent donors recovering from the given variant, may be one of the rare (early) treatment options, also accessible in low-income countries.

 

The recent introduction of the Omicron variant with a high number of mutations in the Spike protein lead to viral escape and  may completely negate the efficacy of some MoAbs, such as the REGENERON/RONAPREV combination [13]. The efficacy of other MoAbs against the omicron variant remains to be established. 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.

 

Oral antiviral drugs may soon offer another therapeutic option particularly for immunosuppressed patients pending confirmation through clinical trials and published findings.

 

The WHO guideline 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. In addition, the “Pharmacologic treatments for COVID-19 patients”[2] [14] the WHO guidance does not present evidence against the use of CCP in people who do not have severe COVID-19. Guidance for non-severe COVID-19 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 [16]. Among the participants, 99% were enrolled from inpatient setting [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 most recently published TSUNASMI trial [18] documented a trend towards efficacy of CCP versus standard therapy in patients with milder forms of COVID-19. Moreover, it should be emphasized that the positive results with monoclonal antibodies show the great potential of antibody therapy in this subgroup of patients.

 

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].

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.

 

On the mobilization of resources dedicated to collect CCP, it should be noted that research on CCP gave the opportunity to 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[3], for regular (non-COVID-19 related) transfusion or to produce plasma derived medicinal products (PDMPs). There is no waste or overuse of human resources.

 

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 now established feature that monoclonals can 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[4] 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; CCP therapeutics for COVID-19 has only been investigated for a short time and has been explored briefly during this pandemic, nor are there findings showing that this is no longer pertinent. The early CCP trials did not sufficiently consider the importance of antibody titres and dose. In contrast, now donors of very high-titre antibodies can be identified by standardized high-throughput antibody assays.

 

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.

 

The contents of this article reflect only the authors’ view. The Commission is not responsible for any use, that may be made of the information it contains. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 101015756.

 

 

Reference List

 

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(2)    de Candia P., Prattichizzo F, Garavelli S, La GR, De RA, Pontarelli A et al. Effect of time and titer in convalescent plasma therapy for COVID-19. iScience 2021; 24(8):102898.

(3)    Joyner MJ, Carter RE, Senefeld JW, Klassen SA, Mills JR, Johnson PW et al. Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19. N Engl J Med 2021; 384(11):1015-1027.

(4)    Senefeld JW, Klassen SA, Ford SK, Senese KA, Wiggins CC, Bostrom BC et al. Use of convalescent plasma in COVID-19 patients with immunosuppression. Transfusion 2021.

(5)    Thompson MA, Henderson JP, Shah PK, Rubinstein SM, Joyner MJ, Choueiri TK et al. Association of Convalescent Plasma Therapy With Survival in Patients With Hematologic Cancers and COVID-19. JAMA Oncol 2021.

(6)    Körper S, Weiss M, Zickler D, Wiesmann T, Zacharowski K, Corman VM et al. Results of the CAPSID randomized trial for high-dose convalescent plasma in patients with severe COVID-19. J Clin Invest 2021; 131(20).

(7)    O`Donnell MR, Grinsztein B, Cummings MJ, Justman J, Lamb MR, Eckhardt CM et al. A randomized, double-blind, controlled trial of convalescent plasma in adults with severe COVID-19. medRxiv 2021;2021.

(8)    Salazar E, Christensen PA, Graviss EA, Nguyen DT, Castillo B, Chen J et al. Significantly Decreased Mortality in a Large Cohort of Coronavirus Disease 2019 (COVID-19) Patients Transfused Early with Convalescent Plasma Containing High-Titer Anti-Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike Protein IgG. Am J Pathol 2021; 191(1):90-107.

(9)    Wang Z, Muecksch F, Schaefer-Babajew D, Finkin S, Viant C, Gaebler C et al. Naturally enhanced neutralizing breadth against SARS-CoV-2 one year after infection. Nature 2021.

(10)    Lustig Y, Nemet I, Kliker L, Zuckerman N, Yishai R, Alroy-Preis S et al. Neutralizing Response against Variants after SARS-CoV-2 Infection and One Dose of BNT162b2. N Engl J Med 2021.

(11)    Stamatatos L, Czartoski J, Wan YH, Homad LJ, Rubin V, Glantz H et al. mRNA vaccination boosts cross-variant neutralizing antibodies elicited by SARS-CoV-2 infection. Science 2021.

(12)    Jahrsdörfer B, Fabricius D, Scholz J, Ludwig C, Grempels A, Lotfi R et al. BNT162b2 Vaccination Elicits Strong Serological Immune Responses Against SARS-CoV-2 Including Variants of Concern in Elderly Convalescents. Front Immunol 2021; 12:743422. doi: 10.3389/fimmu.2021.743422. eCollection;%2021.:743422.

(13)    Wilhelm A, Widera M, Grikscheit K, Toptan T, Schenk B, Pallas C et al. Reduced Neutralization of SARS-CoV-2 Omicron Variant by Vaccine Sera and monoclonal antibodies. medRxiv 2021;2021.

(14)    Siemieniuk RA, Bartoszko JJ, Diaz Martinez JP, Kum E, Qasim A, Zeraatkar D et al. Antibody and cellular therapies for treatment of covid-19: a living systematic review and network meta-analysis. BMJ 2021; 374:n2231.

(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.

(16)    Agarwal A, Mukherjee A, Kumar G, Chatterjee P, Bhatnagar T, Malhotra P. Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial). BMJ 2020; 371:m3939. doi: 10.1136/bmj.m3939.:m3939.

(17)    Estcourt LJ, Turgeon AF, McQuilten ZK, McVerry BJ, Al-Beidh F, Annane D et al. Effect of Convalescent Plasma on Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial. JAMA 2021; 326(17):1690-1702.

(18)    Menichetti F, Popoli P, Puopolo M, Spila AS, Tiseo G, Bartoloni A et al. Effect of High-Titer Convalescent Plasma on Progression to Severe Respiratory Failure or Death in Hospitalized Patients With COVID-19 Pneumonia: A Randomized Clinical Trial. JAMA Netw Open 2021; 4(11):e2136246.

(19)    Franchini M, Cruciani M. How Safe Is COVID-19 Convalescent Plasma? Mayo Clin Proc 2021; 96(8):2279-2281.

(20)    DG SANTE: EU CCP Database.  10-12-2021.

Ref Type: Online Source

 

[1] SUPPORT-E is an EU funded project dedicated to research on COVID19 convalescent plasma https://www.support-e.eu/

[2] https://covid-ma.com/living_data/index.php?treatment1=Convalescent+plasma&submit=Validate#comparisons_div

[3] E.g, in the UK, NL and in Germany [19;20]

[4] Hosted by the European Commission, DG SANTE: https://ec.europa.eu/health/blood_tissues_organs/covid-19_en