Plasma from donors recovered from the new Coronavirus 2019 as therapy for critical patients with COVID-19 (COVID-19 plasma study): a multicentre study protocol

Abstract

Since the end of 2019, a new coronavirus strain has been reported in the Chinese province of Wuhan, indicated as 2019-nCoV or SARS-CoV-2. In February 2020, the first case of transmission on Italian soil was reported. On March 09, 2020, at the time of protocol design, the Italian Ministry of Health reported 10,149 people who had contracted the virus; of these, 8514 were positive, of which 5038 were hospitalized with symptoms (59.2%) and 877 in intensive care (10.3%), while the remaining 2599 were in home isolation; 631 were deceased (6.2%) and 1004 healed (9.9%). To date there are no studies in the literature that demonstrate its feasibility and efficacy in the context of the worldwide SARS-CoV-2 epidemic. Based upon the little existing evidence, we planned to assess the efficacy of the infusion of hyperimmune plasma in COVID-19 patients in a one-arm proof-of-concept clinical trial. The primary objective of our study is to evaluate the efficacy of the administration of plasma taken from convalescent donors of COVID-19 to critically ill patients with COVID-19 in terms of their survival. Death from any cause will be considered. The main limit of this study is its one-arm proof-of-concept design with only 43 patients enrolled. However, in the absence of previous evidence, larger and/or randomized trials did not appear to be ethically acceptable. Moreover, the results from this study, if encouraging, will allow us to plan further informed large clinical trials. Trial registration: NCT 04321421 March 23, 2020. Keywords COVID-19 • Hyperimmune plasma • Plasmapheresis Background and rationale* Claudia Del Fante

SARS-CoV-2 neutralizing human recombinant antibodies selected from pre-pandemic healthy donors binding at RBD-ACE2 interface

“…It was also used for a very limited number of patients without significant results for MERS 43 . The approach was also used for COVID-19 with promising results 44 . The mode of action of these polyclonal antibody preparations can be virus neutralization, Fcγ receptor binding mediated phagocytosis or antibody dependent cellular cytotoxicity as well as complement activation 45,46 .…”

“…A convalescent patient can provide 400-800 mL plasma, with 250-300 mL of plasma typically needed per treatment. With two rounds of treatment per patient, this is a grave limitation since one donor can only provide material for 1-2 patients 44,45 . Human or humanized monoclonal antibodies are a powerful alternative to polyclonal antibodies derived from convalescent plasma.…”

Challenges in the Production of Convalescent Hyperimmune Plasma in the Age of COVID-19

“…16 With this background, 17 considering the dramatic situation and the high lethality rate of COVID-19 in Italy, we have planned a multicenter interventional single-arm trial (Clinicaltrials.gov:NCT04321421) to produce hyperimmune plasma for treating critical patients with COVID-19. 18 Briefly, 500 to 600 mL plasmaphereses are collected from adult male donors, recovered from COVID-19 (defined as two consecutive nasopharyngeal swabs negative for reverse transcriptase-polymerase chain reaction [RT-PCR] testing), aged 18 years or older, through a cell separator device and evaluated for transmissible diseases (human immunodeficiency virus, hepatitis C virus, hepatitis B virus, and syphilis) according to Italian laws. Additional molecular tests for detection of hepatitis A virus, hepatitis E virus, and parvovirus B19, and neutralizing titer for SARS-CoV-2 will be performed according to the recommendations from Italian National Blood Center (CNS) for donation of anti-COVID-19 convalescent plasma.…”

“…The sample size calculation involves the enrolment of 43 patients. 18 Patients are continuously monitored for adverse events; these will be communicated to the local published online June 8, 2020 Transfusion Service staff, who in turn will notify them to the national electronic system for hemovigilance (SISTRA; https:// www.centronazionalesangue.it). In addition, according to directives from CNS, 20 donors are advised to inform their Transfusion Service in the case of reappearance of symptoms compatible with SARS-CoV-2 infection within 14 days after donation (postdonation information).…”

“…In addition, candidates for hyperimmune plasma donation must be in good health without current or pre-existing diseases, according to Italian laws on selection of voluntary unpaid blood donors. 18 Information about the course of COVID-19 disease for the patient (e.g., severity, treatment, dates of onset and resolution of clinical symptoms) is usually requested prior to plasma collection. In our experience, approximately 30 to 40% of recovered patients initially screened are finally eligible for convalescent plasma donation, with comorbidities (i.e., cardiovascular, neoplastic, or autoimmune disorders), age (> 70 years) and sex (pluriparous females) the main causes for exclusion from plasma donation.…”