Ebola virus (EBOV), an enveloped, negative-stranded RNA virus of the family Filoviridae, is the causative agent of Ebola virus disease (EVD), formerly known as Ebola hemorrhagic fever. Since it was first reported in 1976 in two subsequent outbreaks in southern Sudan and northern Zaire, now the Democratic Republic of Congo, EVD has plagued equatorial Africa for decades with the number of outbreaks increasing since 2000 . To date, there are five EBOV species, of which four are pathogenic to humans: Sudan, Zaire (ZEBOV), Tai Forest, and Bundibugyo; Reston EBOV has not been implicated in human infection. EVD represents a classic zoonotic infection with persistence of EBOV in a host such as rodents, fruit bats, chimpanzees, or monkeys, which is then introduced into the human population through close contact with the blood, fluids or organs of these infected animals. Human-to-human transmission occurs through direct contact with blood or other fluids including urine, saliva, sweat, feces, vomit, breast milk, and semen of symptomatic individuals, contaminated objects, or deceased human victims. EVD clinically manifests with nonspecific symptoms such as fever, chills, malaise, and myalgias following a 2–21 day incubation period and progresses to a severe gastroenteritis/hepatitis phase with anorexia, nausea, vomiting, and diarrhea resulting in volume depletion, electrolyte loss, and metabolic acidosis . However, in some individuals, EVD progresses to multiorgan failure and death with a case fatality rate ranging from 21.2 to 60.8% depending on the outbreak .
THE 2014 WEST AFRICA EBOLA VIRUS OUTBREAK
The most recent EBOV outbreak in West Africa in 2014 has marked the deadliest occurrence of the disease, killing five times more than all other known EBOV outbreaks combined. Since the first reported case on 23 March 2014, the Centers for Disease Control and Prevention and the World Health Organization (WHO) have reported 27,748 suspected, probable, and confirmed cases of EVD as of 29 July 2015 with an approximate overall case fatality rate of 40% in those countries with widespread transmission including Liberia, Sierra Leone, and Guinea [3,4][3,4]. Additional reported cases in Africa occurred in Nigeria, Senegal, and Mali, and this epidemic also resulted in the treatment of multiple individuals with EVD in the United States and Europe who were either medically evacuated or acquired EVD outside of West Africa.
TREATMENT OF PATIENTS WITH EBOLA VIRUS DISEASE
Without a licensed vaccine or other treatment, management of EVD has been limited to supportive care including fluid and electrolyte replacement and management of secondary symptoms, in addition to barrier methods to prevent transmission. Given the magnitude of the current epidemic and EVD cases being treated outside of West Africa, there has been an opportunity to investigate experimental agents both for compassionate use and now in clinical trials. An overview of the investigational therapies available for the treatment of EVD is summarized in Table 1[5–14,15 ▪ ,16,17][5–14,15 ▪ ,16,17][5–14,15 ▪ ,16,17][5–14,15 ▪ ,16,17][5–14,15 ▪ ,16,17][5–14,15 ▪ ,16,17][5–14,15 ▪ ,16,17][5–14,15 ▪ ,16,17][5–14,15 ▪ ,16,17][5–14,15 ▪ ,16,17][5–14,15 ▪ ,16,17][5–14,15 ▪ ,16,17][5–14,15 ▪ ,16,17].
One of the first experimental agents used to treat EVD patients in the United States and Europe was ZMapp (Mapp Biopharmaceutical, Inc., San Diego, California, USA), a drug cocktail comprised of individual monoclonal antibodies targeted against EBOV; however, until the current outbreak, ZMapp had never been tested in humans and only proven effective in animal models [15▪]. A limited supply of ZMapp was used to treat several individuals infected with EVD including the first two patients to be treated with EVD in the United States; however, shortly after the beginning of the epidemic, this limited supply of ZMapp was exhausted [18▪▪].
THE USE OF CONVALESCENT PLASMA FOR INFECTIOUS DISEASES: THE PAST AS PROLOGUE
The protective and therapeutic benefits of transfusing plasma or serum obtained from immune survivors of an infectious disease was formally studied in animal models at the beginning of the 20th century . This knowledge was translated into human use in 1916, when 26 patients with acute poliomyelitis were treated with convalescent serum from polio survivors with some favorable outcomes . Subsequently, convalescent serum was used to treat many infectious diseases including influenza, as well as prophylaxis against measles [21,22][21,22].
As newer antibiotics, antivirals, and vaccines emerged, the use of convalescent serum or plasma as a frontline therapy decreased. However, with infections wherein there are no specific therapies available, modern medicine still turns to immune therapies derived from the immune survivors such as in recent preparation for pandemic influenza or severe acute respiratory syndrome (SARS) [23,24][23,24]. Moreover, transfusion of convalescent plasma has been shown to reduce viral load in patients with H1N1 influenza . In addition, a recently published systematic review and exploratory meta-analysis performed to evaluate the clinical effectiveness of convalescent plasma, serum, or hyperimmune immunoglobulin for the treatment of severe viral acute respiratory infections including those due to SARS coronavirus, Spanish influenza A (H1N1), avian influenza A (H5N1), and 2009 pandemic influenza A (H1N1), was able to demonstrate a statistically significant reduction in the odds of mortality among those who were treated with convalescent plasma or serum .
CONVALESCENT WHOLE BLOOD AND PLASMA TRANSFUSIONS FOR THE TREATMENT OF EBOLA VIRUS DISEASE
The earliest use of convalescent plasma for the treatment of EVD has been documented in the Zaire Ebola outbreak of 1976, with a single recipient, a laboratory worker accidentally infected with EBOV, making a full recovery following transfusion of two units of convalescent plasma, each 200–300 ml [27,28][27,28]. Moreover, during this epidemic 201 plasma units were collected from 26 convalescent donors, which had EBOV antibody titers of 1 : 64 or higher and all donations contained microfiliaria demonstrating the feasibility to collect and characterize convalescent plasma in the developing world . The plasma remaining from that outbreak was stored, but the limiting factor at the time was the ability to make a rapid diagnosis of EBOV infection; however, it was a recommendation from the International Commission to ‘keep plasma from immune donors in readiness’ . In addition, the use of convalescent whole blood transfusion during an outbreak of ZEBOV in Kikwit, Democratic Republic of Congo, in 1995 has also been published . During this outbreak, eight patients were transfused with EBOV convalescent whole blood and seven recipients survived accounting for a 12.5% case fatality rate compared with the overall case fatality rate of 80% for the epidemic; however, the authors could not conclude that better supportive care could have accounted for the survival benefit. Moreover, a controlled study in nonhuman primates was unable to replicate the benefit of passive immunization using convalescent whole blood transfusion . Despite these reports, a study of passive transfusion of polyclonal immune serum in EBOV infected severe combined immunodeficiency mice resulted in 100% survival following a lethal challenge with ZEBOV; nonetheless, the authors could not confirm the mechanism by which adaptive immunity provides protection . More recently, Dye et al. treated filovirus infected nonhuman primates with multiple doses of EBOV concentrated, species-matched, polyclonal immunoglobulin G obtained from vaccinated rhesus macaques that subsequently survived challenge with a lethal dose of filovirus. In all EBOV-challenged nonhuman primates, passively transferred, species-matched, polyclonal immunoglobulin G provided complete protection offering support that antibody therapeutic agents may be an effective means of treating filovirus infections.
USE OF EBOLA CONVALESCENT PLASMA DURING THE 2014 WEST AFRICA EBOLA VIRUS EPIDEMIC IN THE UNITED STATES AND EUROPE
As a result of the anecdotal success of ZMapp, support of the use of polyclonal anti-EBOV antibodies from animal studies, and the observation from previous outbreaks that fatal infection was characterized by impaired humoral responses, physicians at the University of Nebraska Medical Center (UNMC) and Emory University, two of the three dedicated biocontainment units who treated patients with EVD in the United States, sought other immune therapies for the treatment of additional EVD patients in the United States . In September 2014, plasma was collected from a survivor and transfused to a patient with EVD being treated at the UNMC; this was the first account of the use of Ebola convalescent plasma (ECP) for treatment of EVD in the United States. ECP was subsequently used to treat multiple patients with EVD in the United States and Europe and is currently in clinical trials in West Africa. The WHO has also issued an interim guidance to national health authorities and transfusion services to outline the necessary steps required to collect convalescent whole blood or ECP from EVD recovered patients for transfusion to patients with early EVD as an empirical treatment modality .
The first two US EVD patients who received ECP, in addition to another experimental agent TKM-100802 (Tekmira Pharmaceuticals Corp, Vancouver, Canada), were recently reported by Kraft et al.[36▪▪]. The first patient, a 51-year-old male healthcare worker medically evacuated from Liberia, received 1 liter of ECP divided into two 500 ml doses on days 9 and 10 of illness and six daily infusions of TKM-100802, which began on day 8 of illness. Following treatment, the patient's plasma tested negative for EBOV RNA on days 22, 24, and 25 of illness, and he was discharged on day 28. The other patient, a 43-year-old male physician who contracted EVD in Sierra Leone while treating patients in an Ebola treatment unit (ETU), received ECP in six doses of 500 ml on days 8, 9, 11, 12, 14, and 15 of illness, together with TKM-100802 on days 3–8 of illness, which was prematurely discontinued due to development of acute kidney injury and progressive multiorgan failure. Despite being critically ill and the first EVD patient treated with mechanical ventilation and dialysis, the patient's whole blood tested negative for EBOV RNA on days 37 and 38 of illness and he was discharged on day 44. Notwithstanding the anecdotal success of ECP and TKM-100802, the authors of the case reports could not conclude that the uncontrolled use of this specific experimental intervention modality altered the clinical course of these two EVD survivors and instead the intensity of the supportive care provided to these patients was critical to their recovery.
Two additional reports of three US EVD patients successfully treated with brincidofovir (Chimerix, Durham, North Carolina, USA) and ECP have been published [37,38][37,38]. Similar to the cases reported by Kraft et al. the authors could not conclude whether ECP and/or brincidofovir treatment provided additional clinical benefit to aggressive supportive clinical management. As a result, the authors suggested that randomized controlled clinical trials are needed to further evaluate these new therapies against EVD.
Limited data have emerged from Europe on the management of multiple patients treated in the United Kingdom, Spain, France, Germany, and others. In a case report of a women nurse assistant who was infected with EBOV while caring for a Spanish missionary with EVD, she developed acute respiratory distress, approximately, 3 h after the infusion of a third unit of ECP and there was clinical concern for transfusion-related acute lung injury; however, the authors did not detect any human leukocyte antigen or human neutrophil antibodies in the donor . Nonetheless, there was no other plausible cause for the patient's hypoxia and acute lung injury has not been commonly described in EVD. Therefore, additional studies investigating the pulmonary complications of EVD including those possibly related to transfusion are necessary.
ONGOING STUDIES ON THE USE OF EBOLA CONVALESCENT PLASMA
Currently in the United States, there are two ongoing efforts to create an inventory of ECP. The first, Prospective, Open Label, Phase 1 Safety Study of Passive Immune Therapy During Acute Ebola Virus Infection Using Transfusion of INTERCEPT Plasma Prepared From Volunteer Donors Who Have Recovered From Ebola Virus Infection, is being conducted at the UNMC and Emory University . The goal of the study is to collect, pathogen inactivate, characterize, and store plasma from survivors of EVD to create a national inventory of an unlicensed biologic product. The study includes an investigational device exemption sponsored by the Cerus Corporation (Concord, California, USA) and includes collection of plasma using apheresis, pathogen inactivation using the INTERCEPT Blood System (Cerus Corporation), characterization of the plasma for both infectious diseases and anti-EBOV total and neutralizing antibodies, storage, and transfusion of ECP to US patients with EVD. An additional effort is underway at the National Institutes of Health to collect men who have been infected with or vaccinated for an emerging infectious disease such as EBOV to create a similar inventory .
In West Africa, there are at least three ongoing clinical trials evaluating the efficacy of ECP. In Liberia, ELWA-2 ETU together with Clinical Research Management, Inc (Hinckley, Ohio, USA) and funded by the Gates Foundation are enrolling for the Clinical Trial to Evaluate the Efficacy and Safety of Convalescent Plasma for Ebola Treatment study . In this study, ECP is being provided as two units of 90–110 ml from two donors, and transfusion of up to three doses of ECP not less than 48 h apart is permitted. The primary outcome of the study is determination of EBOV viral load in the recipient blood and no data have been published to date.
In Guinea, a clinical trial, Emergency Evaluation of Convalescent Plasma for Ebola Viral Disease, conducted by the Institute of Tropical Medicine (Antwerp, Belgium) in collaboration with an Ebola Treatment center in Conakry managed by Médecins Sans Frontières has completed enrollment; however, results are not yet available . The study was expected to enroll 200 individuals with EVD who were to receive two doses of ECP (200–250 ml) from two donors, and the primary outcome was the effect of ECP in improving survival at day 14.
Last, there is an ongoing study of ECP in Sierra Leone, Convalescent plasma for early EVD in Sierra Leone, being conducted by the University of Liverpool with an ETU in Freetown . The planned enrollment is 200 individuals in the intervention group, a single transfusion of ECP, and 100 control individuals to receive the same amount of Ringer's Lactate solution. The primary outcome of the study is all-cause mortality at day 14 after treatment and no data are available at this time.
TREATMENT OF OTHER EMERGING INFECTIOUS DISEASES WITH CONVALESCENT PLASMA
Since first reported in 2012, Middle East respiratory syndrome (MERS) has emerged as a highly lethal respiratory disease with an overall case fatality rate of 40%, but is higher in patients with at least one comorbid illness (60%) . Similar to SARS, MERS is caused by a novel single-stranded, positive-sense RNA betacoronavirus (MERS-CoV). Similar to EVD, no specific treatment is available for MERS and supportive therapy is critical; however, recently treatment with convalescent plasma has been suggested as a potential therapy and is currently under investigation in clinical trials with at least one study sponsored by King Abdullah International Medical Research Center in Saudi Arabia .
During the 2014 West Africa Ebola virus outbreak, ECP was utilized in the treatment of multiple patients in the United States, and studies evaluating the role of ECP have been initiated in the United States and West Africa. However, as the EBOV response was delayed and the current outbreak wanes, it is unlikely these clinical trials especially those with mortality endpoints will reach enrollment and knowledge of the efficacy of ECP will still likely not be known. Nonetheless, it will be critical to be more prepared when this virus emerges again, in addition to investigating the efficacy of convalescent plasma for the treatment of new emerging infectious diseases.
The authors would like to thank Shannon Bonds and Jessica Ingersoll for their commitment to the Ebola convalescent plasma bank at Emory University. In addition, the authors would like to thank Dr Nisha Jain, former Chief of the Clinical Review Branch of the Division of Hematology Clinical Review of the Office of Blood Research and Review at the Food and Drug Administration for her assistance. The authors would also like to thank Dr Laurence Corash, Dr Adonis Stassinopoulos, Dr Salvador Rico, Dr Kent Carter, Dr Jessica Hanover, Elan Weiner, Samantha Shiraishi, Nia Sengupta, Tina Landess, and Bonnie Mills from the Cerus Corporation and Dr John Dye and Dr Jay Hooper at the United States Army Medical Research Institute of Infectious Diseases for their ongoing support. The authors would also like to thank Axel Stover and Fresenius Kabi for their generous donation of laboratory equipment. Finally, the authors would like to thank all of the members of the Emory University Hospital Serious Communicable Diseases Unit and Nebraska Biocontainment Unit teams for their dedication and outstanding clinical care.
Financial support and sponsorship
Emory's participation was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000454 (Atlanta Clinical and Translational Science Institute).
Conflicts of interest
A.W. has received honoraria from the Cerus Corporation. S.K. has no conflicts of interest to declare.
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