Convalescent plasma for COVID-19: planning for the next pandemic using the worldwide experience.

Recruitment Strategy for Potential COVID-19 Convalescent Plasma Donors

Convalescent plasma to treat COVID-19: Following the Argentinian lead

See article on page 1471–1478, in this issue

Decision letter: Convalescent plasma use in the USA was inversely correlated with COVID-19 mortality

Response

HLA Antibody Rates Are Not Increased in a Regional Group of Male COVID-19 Convalescent Plasma Donors

Introduction When the COVID-19 pandemic struck no specific therapies were available and many turned to COVID-19 convalescent plasma (CCP), a form of antibody therapy. The literature provides mixed evidence for CCP efficacy. Areas covered PubMed was searched using the words COVID-19 and convalescent plasma and individual study designs were evaluated for adherence to the three principles of antibody therapy, i.e. that plasma 1) contain specific antibody; 2) have enough specific antibody to mediate a biological effect; and 3) be administered early in the course of disease. Using this approach, a diverse and seemingly contradictory collection of clinical findings was distilled into a consistent picture whereby CCP was effective when used according to the above principles of antibody therapy. In addition, CCP therapy in immunocompromised patients is useful at any time in the course of disease. Expert opinion CCP is safe and effective when used appropriately. Today, most of humanity has some immunity to SARS-CoV-2 from vaccines and infection, which has lessened the need for CCP in the general population. However, COVID-19 in immunocompromised patients is a major therapeutic challenge, and with the deauthorization of all SARS-CoV-2-spike protein-directed monoclonal antibodies, CCP is the only antibody therapy available for this population.

Convalescent plasma in the management of COVID-19 pneumonia

Convalescent plasma for COVID-19 - encouraging signals of efficacy.

Convalescent plasma (CP) has been used to treat emerging infectious diseases for over a century. It was notably deployed during the 1918 flu pandemic and has been explored during numerous disease outbreaks, including those caused by other coronaviruses—such as in severe acute respiratory syndrome (SARS)1 and Middle East respiratory syndrome (MERS)2—influenza,3 and Ebola.4 The potential efficacy of CP in COVID-19 was first suggested by several observational studies that associated reduced mortality with CP administration.5 Following results of the PLACID randomized controlled trial (RCT) from India that failed to show a benefit of low-titer CP in moderate COVID-19,6 a prospective RCT from Argentina demonstrated that the administration of CP with a high titer of anti-SARS-CoV-2 immunoglobulins within 3 days after the onset of mild COVID-19 symptoms in older patients could significantly reduce the progression of the disease.7 Further, a retrospective analysis of data from the Expanded Access Program implemented in the United States highlighted not only the safety but also provided signs of efficacy (i.e., dose-dependent effect) of high-titer CP in nonventilated patients,8 again supporting early use. Similarly, a large retrospective, health-record-based analysis showed that administration of CP was associated with lower in-hospital mortality as compared with matched controls.9 Multiple studies showed significant benefits of CP in immunocompromised and oncology patients with COVID-19.10-12 On the other hand, there have been a large number of well-executed clinical trials, such as RECOVERY, REMAP-CAP, or CONCOR-1 that did not find CP to be beneficial, albeit in advanced COVID-19. A summary of some of these findings is maintained in the living systematic Cochrane Review, which reports a "high certainty in the evidence that CP for the treatment of individuals with moderate to severe disease does not reduce mortality and has little to no impact on measures of clinical improvement."13-18 While not known at the time of their inception, studies of CP have focused, disproportionately, on populations (i.e., late-stage COVID-19) and interventions (low-titer CP) that are now known to be suboptimal or ineffective for passive antibody-based therapy, whereby early administration of high-titer plasma is critical.19 As an example, a subgroup analysis of the RECOVERY data for patients without use of corticosteroids (indicative of earlier disease stage) showed a trend toward fewer deaths at 28 days in the CP versus the control groups (19% vs. 24%, respectively). There was a similar observation in patients that did not receive respiratory support.15 Trials of outpatients afford insight into the efficacy of CP in early COVID-19. In addition to the seminal trial by Libster et al.,7 two large clinical trials have evaluated the use of CP in the outpatient setting. Korley et al. (SIREN-C3PO) conducted a multicenter RCT of 511 patients (50 years of age or older, or one or more risk factors for disease progression) to receive centrally sourced high-titer CP (intervention) or saline infusion (control) within 7 days after symptom onset.14 The study was unable to find a significant difference with respect to its primary endpoint (i.e., a 50% relative risk reduction for a composite measure of hospital admission for any reason, seeking emergency or urgent care, or death without hospitalization). However, a post-hoc analysis by the authors showed that if excluding 25 patients that were hospitalized during their initial visit (it is questionable that the intervention could have been effective in that timeframe), the rates were 22.5% for CP versus 29.5% for the control arm (93% posterior probability of superiority of CP).14 Patients in the CP arm showed significant improvement in two secondary endpoints of the study (dyspnea, symptom worsening), offering signals of benefit of CP in this setting.14 Sullivan et al. conducted the largest (1181 treated patients) multicenter RCT in the outpatient setting to date.20 The trial, which enrolled adult patients 18 years or older, independent of risk factors or vaccination status, showed a significant reduction in the primary outcome of COVID-19-related hospitalization within 28 days of plasma transfusion. The primary endpoint occurred in 37 of 589 (6.3%) patients who received placebo control plasma and in 17 of 592 (2.9%) patients who received CP (relative risk, 0.46; one-sided 95% upper bound confidence interval 0.733; p = .004) corresponding to a 54% risk reduction in those who received CP within 9 days of symptom onset.20 On December 7, 2021, the World Health Organization (WHO) revised its living guideline on treatments for COVID-19, stating that "current evidence shows that CP does not improve survival or reduce the need for mechanical ventilation, while it has significant costs," citing evidence that CP confers no benefit in patients with nonsevere COVID-19 (WHO website, retrieved on January 8, 2022: https://www.who.int/news/item/07-12-2021-who-recommends-against-the-use-of-convalescent-plasma-to-treat-covid-19). Of note, the statement from WHO preceded the announcement of the findings from Sullivan et al.20 On December 28, 2021, "The U.S. Food and Drug Administration (FDA) has issued an Emergency Use Authorization to permit the emergency use of the unapproved product, COVID-19 CP with high titers of anti-SARS-CoV-2 antibodies, for the treatment of COVID-19 in patients with immunosuppressive disease or receiving immunosuppressive treatment, in either the outpatient or inpatient setting." (FDA website, retrieved on January 8, 2022: https://www.fda.gov/media/141478/download). This broadened its use to the outpatient setting yet restricted its use to immunocompromised patients. Further guidance on investigational COVID-19 CP to the industry was provided by FDA on January 7, 2022, including direction for the collection of CP (FDA website, retrieved on January 8, 2022: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/investigational-covid-19-convalescent-plasma). CP is a readily scalable intervention given extant blood collection infrastructure. Importantly, it can be deployed rapidly, well before direct-acting antivirals, vaccines, and immunotherapies (e.g., monoclonal antibodies) becoming available. Time is CP's major advantage where availability is measured in days or weeks rather than months or even years for more refined therapies (e.g., vaccines and antiviral therapies). The other major advantage is versatility, the potential ability to use CP to respond to emerging variants (such as omicron). By their nature, outbreaks of highly contagious infectious diseases are characterized by rapid onset, placing intense strain on health care systems. This impedes the ability to establish the safety and efficacy of CP, given the challenges of high-quality data collection in times of crisis. Prospective RCTs of CP are inherently challenging, requiring careful preparation, funding support, and ultimately an infrastructure to execute the study successfully, from product procurement (i.e., donor qualification and collection) to transfusion and posttransfusion evaluation and follow-up. These challenges are universal but are amplified in low- and middle-income countries.21, 22 This explains, in part, the dearth of rigorous data on CP prior to COVID-19, despite its repeated deployment. Before COVID-19, well-designed RCTs of CP were the exception and showed mixed results, from highly effective in the setting of Argentine hemorrhagic fever23 to nonsignificant in the case of severe flu.24 Instead, empirical data supporting use was primarily confined to observational studies, which were potentially flawed by bias, as well as insufficient characterization of the transfused CP and its clinical use, and, thus, confounding. Thanks to the implementation of multiple RCTs, the COVID-19 pandemic has now helped to delineate the clinical utility of CP. This has been achieved despite the myriad of organizational challenges that plagued researchers at the onset of the COVID-19 pandemic. There was insufficient testing capacity to ensure that units of CP were sufficiently characterized to confer the intended effect (i.e., potent passive immunization). As the epidemic shifted to new areas, patients also found themselves in health care facilities with limited access to clinical trials. As experience with CP use grew, it became apparent that CP efficacy was greatest when locally collected from donors with high-titers of neutralizing antibodies and administration proximal to symptom onset or early during hospitalization. So, it took a pandemic of epic proportions, the focus of the global research community, and unprecedented funding to forge an environment in which CP could be tested rigorously, garnering insight into its optimal clinical use. Looking back and drawing on the accumulated experience, CP could have potentially had a more dominant role during the respective SARS (2003), MERS (2012), and most notably the West African Ebola (2013–2016) outbreaks if applied differently. Blood transfusion services might have adapted rapidly to focus on transitioning recovered patients with high-titer antibodies, to become donors early in the disease course. However, this approach requires advanced preparation by the local collection services to respond in a manner that is sufficiently timely to contend with the epidemic surge of clinical cases. This remains an enduring challenge in resource-limited settings. So, where does CP go next? Undoubtedly, the experience from this pandemic will need to be applied for the good of patients globally. Specifically, the high-quality evidence gleaned from rigorous clinical trials can be applied broadly in a way that previous underpowered, small-scale research efforts could not. Looking ahead, another pandemic or more variants of COVID-19 are certain to occur. When that happens, we now are better positioned to apply passive immunotherapy using CP transfusion to confer favorable outcomes. The hard-won knowledge from this pandemic should serve to expedite clinical trials, ethical approval, reliable testing infrastructure to identify safe and efficacious CP, and donation pipelines during similar future crises.25 Recently, the Association for the Advancement of Blood & Biotherapies (AABB) has formed the Passive Antibody Therapies Forum Advisory Group with that goal in mind. The lessons learned from long ago—that plasma with high antibody titers should be safely administered as early as possible for maximum benefit— should be heeded as a guiding principle in the design of clinical trials and associated practices for emergent CP use against future pandemics. All authors are inaugural members of the AABB Passive Antibody Therapies Forum Advisory Group. JH is an employee of Haemonetics Corporation, a manufacturer of plasma collection devices; EMB reports personal fees and nonfinancial support from Terumo BCT, Grifols Diagnostics Solutions, and Abbott Laboratories outside of the submitted work; EMB is a member of the FDA Blood Products Advisory Committee. Any views or opinions that are expressed in this manuscript are that of the author's, based on his own scientific expertise and professional judgment; they do not necessarily represent the views of either the Blood Products Advisory Committee or the formal position of FDA and also do not bind or otherwise obligate or commit either Advisory Committee or the Agency to the views expressed. TB's laboratory at Taipei Medical University has received research grants from plasma industry suppliers (Asahi-Kasei Medical; Merck-Millipore), and TB has served on the scientific advisory board of Haemonetics Corporation.

Background and objectivesUse of convalescent plasma for coronavirus disease 2019 (COVID‐19) treatment has gained interest worldwide. However, there is lack of evidence on its dosing, safety and effectiveness. Until data from clinical studies are available to provide solid evidence for worldwide applicable guidelines, there is a need to provide guidance to the transfusion community and researchers on this emergent therapeutic option. This paper aims to identify existing key gaps in current knowledge in the clinical application of COVID‐19 convalescent plasma (CCP).Materials and methodsThe International Society of Blood Transfusion (ISBT) initiated a multidisciplinary working group with worldwide representation from all six continents with the aim of reviewing existing practices on CCP use from donor, product and patient perspectives. A subgroup of clinical transfusion professionals was formed to draft a document for CCP clinical application to identify the gaps in knowledge in existing literature.ResultsGaps in knowledge were identified in the following main domains: study design, patient eligibility, CCP dose, frequency and timing of CCP administration, parameters to assess response to CCP treatment and long‐term outcome, adverse events and CCP application in less‐resourced countries as well as in paediatrics and neonates.ConclusionThis paper outlines a framework of gaps in the knowledge of clinical deployment of CPP that were identified as being most relevant. Studies to address the identified gaps are required to provide better evidence on the effectiveness and safety of CCP use.

In Reply—How Safe Is COVID-19 Convalescent Plasma?

Published data on coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) use in children and obstetric patients are limited. We describe a single-center experience of hospitalized patients who received CCP for acute COVID-19. A retrospective review of children 0-18-years-old and pregnant patients hospitalized with laboratory-confirmed acute COVID-19 who received CCP from March 1, 2020 to March 1, 2021 was performed. Clinical and laboratory data were collected to assess the safety of CCP administration. Antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were measured in the CCP products and in patients before transfusion and at various time points post-transfusion. Correlation between the administered SARS-CoV-2 administered versus the SARS-CoV-2 anti-spike immunoglobulin response in patient serum was assessed. Twenty-two children and ten obstetric patients were eligible. Twelve pediatric and eight obstetric patients had moderate disease and ten pediatric and two obstetric patients had severe disease. Five pediatric patients died. Eighteen of 37 (48.6%) CCP titers that were measured met US Food and Drug Administration (FDA) criteria for high immunoglobulin G (IgG) antibody titer. There were no complications with transfusion. High-titer CCP showed a positive correlation with rise in patient total immunoglobulin levels only in obstetric patients but not in pediatric patients. Among pediatric patients, the median serum antibody level increased over time after transfusion. Coronavirus 2019 convalescent plasma was administered safely to our patients. Our study suggested that CCP did not interfere with endogenous antibody production. The antibody titer of CCP correlated with post-transfusion response only in obstetric patients. Randomized trials in pediatric and obstetric patients are needed to further understand how to dose CCP and evaluate efficacy.

Controlled trials needed to prove efficacy and safety of convalescent plasma therapy in coronavirus disease 2019

Convalescent plasma treatment of persistent severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in patients with lymphoma with impaired humoral immunity and lack of neutralising antibodies.