key: cord-280221-s6oxq772
authors: Montelongo-Jauregui, Daniel; Vila, Taissa; Sultan, Ahmed S.; Jabra-Rizk, Mary Ann
title: Convalescent serum therapy for COVID-19: A 19th century remedy for a 21st century disease
date: 2020-08-12
journal: PLoS Pathog
DOI: 10.1371/journal.ppat.1008735
sha: 
doc_id: 280221
cord_uid: s6oxq772

nan

global recognition and revolutionized the way infectious diseases were treated, and in 1901, Emil von Behring was awarded the Nobel Prize for Medicine for his work, which served as a basis for treatment of multiple diseases in the 1900s as well as the development of vaccines [15] . In fact, there are numerous examples throughout history in which convalescent serum was used with some degree of success to treat an array of diseases, including rheumatic fever [16] , scarlet fever [17] , mumps [18] , measles [18, 19] , chickenpox [18] , and pneumococcal and meningococcal infections [20] (Fig 1) . Most notable use was during the Spanish Flu pandemic (1918 to 1920) , where meta-analysis studies showed a significantly reduced mortality risk in patients treated with convalescent serum [8, 12] . However, with the advent of antimicrobials, by the middle of the 20th century, the use of serum therapy had declined. Nevertheless, the interest in passive antibody therapy has been renewed periodically when new epidemics or pandemics have emerged. One example is during the Ebola virus (EBOV) outbreak in 1976 in the Democratic Republic of Congo, where an infected laboratory worker recovered after transfusion with convalescent plasma containing anti-EBOV antibodies. Similarly, in 1979, patients with Argentine hemorrhagic fever virus treated with convalescent plasma had a lower mortality rate compared with subjects treated with normal plasma, and similar results were reported for subsequent epidemics of the disease [21] . Over the following decades, convalescent plasma therapy was successfully employed during the H1N1 swine influenza pandemic (2009), the H5N1 avian flu epidemic (2003), as well as during the EBOV outbreak in West Africa in 2013. 

Most relevant and encouraging is the use of convalescent plasma during 2 previous coronavirus epidemics: severe acute respiratory syndrome (SARS) in 2003, and Middle East respiratory syndrome (MERS) in 2012 [21] . The high degree of success in achieving favorable clinical outcomes during these coronaviruses outbreaks establishes a strong precedent and supports the notion that convalescent plasma could be a viable option for treatment of COVID-19 patients, particularly upon early administration [6, 9, 12, [21] [22] [23] .

The convalescent plasma therapeutic approach is based on the principle of passive antibody therapy, a short-term strategy whereby antibodies from the blood of someone who recovered from an infection can be administered to protect or treat another person [6, 21] . Effectively, the end goal is the same as vaccines, making antibodies against a specific infectious agent readily available. For instance, a vaccine relies on the host immune cells (B lymphocytes specifically) to produce antibodies after antigen recognition and signal amplification by the immune system, a process that may take weeks [24] ; on the other hand, in the case of passive antibody therapy, the process is expedited by providing a patient with immediate immunity when the premade antibodies are given. Therefore, for COVID-19 patients, the expedited approach could prove lifesaving. Nevertheless, this advantage does not come without caveats, as immunization with passive antibody therapy is typically of shorter-term protection, in part because of the half-life of antibodies in circulation [25] and lack of new production by B lymphocytes. Today, passive antibody therapy relies primarily on pooled immunoglobulin preparations that contain high concentrations of antibodies. In contrast, plasma has been used emergently in epidemics in which there is insufficient time or resources to generate immunoglobulin preparations [21] .

Despite the high rate of SARS-CoV-2 infection, the relatively low mortality rate provides a rich pool of donors [26] . However, potential COVID-19 donors must meet several eligibility criteria that ensure the donor has antibodies against SARS-CoV-2 and lacks the presence of other types of infections [21, 27] . Additionally, only plasma with high anti-SARS-CoV-2 titers of immunoglobulins G and M (IgG and IgM) are used. Once collected, plasma can be tested and administered within hours, following conventional donor-patient blood compatibility typing [27] . In addition to rapid mobilization, this therapeutic approach is also versatile in applicability as it can be used for prophylaxis or treatment, as illustrated in Fig 2. In the case of prophylaxis, a subject considered at high risk for infection (because of age or underlying medical conditions or who is likely to be in contact with people with COVID-19) could be administered convalescent plasma or neutralizing antibodies for protection against infection. Alternatively, plasma can be administered to treat subjects who have contracted the infection but have not made sufficient antibodies against the virus yet in order to augment their immune response, improve disease course, and enhance recovery [21] . However, it is important to note that passive antibody therapy is most effective when administered prophylactically or implemented early after the onset of symptoms [21] .

Convalescent plasma with neutralizing antibodies is currently being used for investigational purposes in the COVID-19 pandemic, and preliminary results from 2 small studies performed in China are encouraging. A pilot study exploring the feasibility of convalescent plasma transfusion to rescue a group of 10 patients with severe disease showed that 1 dose (200 mL) of convalescent plasma with high neutralizing antibody titers was well tolerated, resulted in disappearance of viremia, and improved clinical symptoms in all patients within days of administration [8] . Similar results were reported from another study with 5 critically ill patients on mechanical ventilation [7] . Although these small, nonrandomized studies had limitations, these findings indicate that convalescent plasma could be a promising rescue option for severe COVID-19 [21] .

Although convalescent plasma therapy is considered a relatively safe therapeutic modality, there are some potential risks [12] . One theoretical complication that may arise is an antibodymediated proinflammatory disease enhancement known as antibody-dependent enhancement (ADE), whereby antibodies that developed during a prior infection exacerbate severity of the disease [12, 28] . The transfer of these antibodies may aberrantly activate fragment crystallizable (Fc) or complement receptors, increasing recruitment of proinflammatory cytokines and chemokines to the site of infection and causing severe tissue damage [29] [30] [31] . Additionally, the presence of non-neutralizing antibodies may exacerbate viral endocytosis or phagocytosis into host cells via Fc receptors, potentializing viral replication [29, 32] . However, although this phenomenon is well known with Dengue and other viral diseases, there have not been any reported ADE cases with the use of convalescent plasma for SARS, MERS, or COVID-19 [12, 29, [32] [33] [34] [35] . Nevertheless, it is crucial to have a clear understanding of the role of the recipients' immune response [12] . Transmission of the virus through transfusion is another concern; however, the risk is relatively low because of strict transfusion protocols, and when used for treatment purposes, the recipient is already infected [12, 36] .

The success of convalescent plasma therapy hinges on the availability of plasma with high concentrations of antibodies, which may not be a major limitation for COVID-19 because SARS-CoV-2 has been shown to elicit high neutralizing antibody titers in recently convalesced individuals [7] [8] [9] . Apheresis is an automated technology that allows for selective collection of a blood fraction while other components can be transfused back to the donor. Therefore, for donation of convalescent plasma, plasmapheresis is recommended because it is highly efficient and approximately 400-800 mL of plasma can be collected in a single donation, providing 2-4 units of convalescent plasma for transfusion [21] . There are some practical and logistical limitations for the implementation of a large-scale convalescent plasma transfusion program such as training of study personnel, recruitment of donors, and transport of plasma to hospitals, as well considerations for plasma shelf-life and half-life of antibodies in the plasma [21, 36] .

Although large-scale randomized clinical trials will ultimately confirm the safety and efficacy of convalescent plasma therapy for COVID-19, a recent safety study by Joyner and colleagues [12] provided encouraging data. By analyzing key safety metrics following transfusion of convalescent plasma in 5,000 hospitalized adults with severe or life-threatening COVID-19, the incidence of serious adverse events was found to be <1%, and the 7-day mortality incidence was 14.9%. These early indicators are encouraging and highly supportive of the use of convalescent plasma as a rescue therapy in hospitalized patients, given that the reported fatality rate of COVID-19 among patients admitted to the intensive care units (ICUs) is 57% [37] . In fact, the low risk indicated by the study support expanding the use of convalescent plasma therapy in less ill individuals [6] .

The global reach of the COVID-19 pandemic and the desperate need for effective treatments have provided an impetus to develop convalescent plasma therapy into a viable (albeit shortterm) treatment option particularly for the critically ill. Although its efficacy and safety have not yet been fully proven, convalescent plasma therapy for COVID-19 patients is projected to be a safe and potentially effective therapy for prophylaxis and treatment. However, it is critically important to perform rigorous randomized controlled trials to confirm efficacy and safety and to provide evidence for improved meaningful clinical outcomes. Nevertheless, despite the nuanced challenges, the substantial evidence of benefit with use for prior viral infections offers strong precedent for convalescent plasma as a therapeutic approach. Importantly, efforts should be focused not only on evaluation of the feasibility of plasma treatment for infectious diseases but also ensure that use of convalescent plasma therapy takes place according to ethical and controlled conditions.

Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding

The SARS, MERS and novel coronavirus (COVID-19) epidemics, the newest and biggest global health threats: what lessons have we learned?

Origin and evolution of pathogenic coronaviruses

Bat Coronaviruses in China

Remdesivir for the Treatment of Covid-19-Preliminary Report

The convalescent sera option for containing COVID-19

Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma

Effectiveness of convalescent plasma therapy in severe COVID-19 patients

Anti-SARS-CoV-2 virus antibody levels in convalescent plasma of six donors who have recovered from COVID-19

Treatment with convalescent plasma for COVID-19 patients in Wuhan

Convalescent serum lines up as first-choice treatment for coronavirus

Early Safety Indicators of COVID-19 Convalescent Plasma in 5,000 Patients

Ueber das Zustandekommen der Diphtherie-Immunitä t und der Tetanus-Immunitä t bei Thieren

Untersuchungen über das Zustandekommen der Diphtherie-Immunitä t bei Thiere. Philipps-Universitä t Marburg

Remembering Emil von Behring: from Tetanus Treatment to Antibody Cooperation with Phagocytes

The Action of Vaccines and of Concentrated Antistreptococcus Serum in Experimental Streptococcal Arthritis

Serum treatment of scarlet fever

University of Nebraska

The use of convalescent serum in the treatment of measles, chickenpox, mumps and whooping cough, including the prophylactic value of parental blood

Treatment of preeruptive measles with convalescent serum

Serum therapy revisited: animal models of infection and development of passive antibody therapy

Deployment of convalescent plasma for the prevention and treatment of COVID-19

Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection

Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A (H1N1) infection

Principles of Vaccination

Public Health Foundation. 13th

Therapeutic antibodies: successes, limitations and hopes for the future

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges

Points to consider in the preparation and transfusion of COVID-19 convalescent plasma

COVID-19: immunopathology and its implications for therapy

Impact of immune enhancement on Covid-19 polyclonal hyperimmune globulin therapy and vaccine development

How immune complexes from certain IgG NAbs and any F(ab')(2) can mediate excessive complement activation

Immune complex-mediated tissue injury: a multistep paradigm

Antibody-dependent enhancement of SARS coronavirus infection and its role in the pathogenesis of SARS

Participants in the Summit on Dengue Immune Correlates of P. Immune correlates of protection for dengue: State of the art and research agenda

Is COVID-19 receiving ADE from other coronaviruses? Microbes Infect

Dengue viruses and mononuclear phagocytes. I. Infection enhancement by non-neutralizing antibody

Convalescent plasma: new evidence for an old therapeutic tool?

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet

We would like to thank Dr. Arturo Casadevall for critical review of the manuscript.
