The Ongoing Evolution of Antibody-Based Treatments for Ebola virus Infection
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Abstract:
The 2014-2016 Ebola virus outbreak in West Africa was the deadliest in history, prompting the evaluation of various drug candidates, including antibody-based therapeutics for the treatment of Ebola hemorrhagic fever (EHF). Prior to 2014, only convalescent blood products from EHF survivors had been administered to newly infected individuals as a form of treatment. However, during the recent outbreak, monoclonal antibody cocktails such as ZMapp, ZMAb and MB-003 were either tested in a human clinical safety and efficacy trial or provided to some based on compassionate grounds. This review aims to discuss the evolution of antibody-based treatments for EHF, their clinical trial efficacy and the development of new antibody-based therapies currently advancing in preclinical testing.Keywords:
Ebola Hemorrhagic Fever
Antibody therapy
Ebola virus disease is one of the most deadly ailments known to mankind due to its high mortality rate (up to 90%) accompanying with the disease. Ebola haemorrhagic fever (EHF) is an infectious disease of animal that can be transmitted to both human and non-human primates. The first epidemic of EHF occurred in 1976 in the Democratic Republic of the Congo. The incubation period of ebola is less than 21 days. Ebola virus infections are depicted by immune suppression and a systemic inflammatory response that leads to damage of the vascular, coagulation and immune systems, causing multi-organ failure and shock. Five genetically distinct members of the Filoviridae family responsible for EHF are as follows: Zaire ebolavirus, Sudan ebolavirus, Côte d'Ivoire ebolavirus, Bundibugyo ebolavirus and Reston ebolavirus. The ongoing 2014 West Africa ebola epidemic has been considered as the most serious panic in the medical field with respect to both the number of human cases and death toll. The natural host for ebola virus is unknown, thus it is not possible to carry out programs to regulate or abolish virus from transmission to people. The ebola virus infection provides little chance to develop acquired immunity causing rapid progression of the disease. It is pertinent to mention that at present, there is no antiviral therapy or vaccine that is helpful against ebola virus infection in humans. The impediment of EHF necessitates much better understanding of the epidemiology of the disease, particularly the role of wildlife, as well as bats, in the spread of ebola virus to humans.
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Ebola virus disease is a rare but severe, often fatal illness in humans. Fruit bats are the natural reservoirs of Ebola virus, and it is transmitted to humans from wild animals and spreads between humans. Ebola virus is a class A bioterrorism agent, known to cause highly lethal haemorrhagic fever. Clinical symptoms include fever, myalgia, headache followed by vomiting, diarrhea, hemorrhagic rash, bleeding, and multi-organ failure. Vaccines to protect against Ebola have been developed and used to control the spread of Ebola virus disease. Treatment is mainly early supportive care with rehydration and symptomatic treatment. Ebola virus is a neglected pathogen and the knowledge and scientific information on Ebola virus disease is relatively limited and received little attention. Better understanding of ebolavirus disease mechanisms is needed to guide development of drugs, vaccines, and treatment strategies. Hence this comprehensive review on Ebola virus is undertaken to provide an overview of its transmission, pathogenesis, clinical symptoms, differential diagnosis, laboratory diagnosis, treatment, vaccines and preventive aspects and to highlight its importance, and impact on public health and further research.
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The Ebola virus is a single-stranded negative sense RNA virus belonging to the filovirus family. The Ebo- ]a virus causes Ebola virus disease (EVD). EVD is characterized by fever and malaise, muscle pain, and abnormal blood clotting. The mortality rate associated with EVD is very high, at 88%. In the worldwide outbreak in 2014, the epidemic of EVD started in Guinea and expanded to western Africa. Thereafter, cases of infection with the Ebola virus spread around the world, especially Europe and America. EVD is a zoono- sis. It is considered that the natural host of Ebola virus is a bat, and it causes a fatal clinical condition in go- rillas and chimpanzees as well as humans. People were infected by touching body fluids of blood, secretions, vomit, and other discharges from patients with EVD. Since the numbers of Japanese who work overseas and foreigners who visit Japan are increasing, it is necessary to establish the diagnosis of and medical treatment system for EVD in Japan. In this paper, we mainly describe the laboratory-based testing and risk manage- ment of Ebola hemorrhagic fever in Japanese hospitals. [Review].
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Ebola hemorrhagic fever (EBHF), or Ebola virus disease, is an acute hemorrhagic infectious disease with severe symptoms and high mortality caused by Ebola virus (EBOV). Several Ebola outbreaks have been reported in Africa since the initial discovery of Ebola.One of outbreak origins is a village nearby the river of Ebola to the north of Zaire region in West Africa, hence comes the name of Ebola.In April 2014, there was an Ebola outbreak again, and epidemic situation spread at an alarming rate.According to the announcement of WHO, the global number of Ebola virus infection was 14098, in which 5160 people died.Latest Ebola outbreak is more severe and more wide-spread than any previous Ebola events.EBHF is highly contagious and fatal, moreover, little is known of Ebola virus and there have not been effective drugs against Ebola virus.
Key words:
Ebola virus; Type; Viral structures; Laboratory techniques and procedures; Diagnosis; Combined modality therapy
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For almost 50 years, ebolaviruses and related filoviruses have been repeatedly reemerging across the vast equatorial belt of the African continent to cause epidemics of highly fatal hemorrhagic fever. The 2013-2015 West African epidemic, by far the most geographically extensive, most fatal, and longest lasting epidemic in Ebola's history, presented an enormous international public health challenge, but it also provided insights into Ebola's pathogenesis and natural history, clinical expression, treatment, prevention, and control. Growing understanding of ebolavirus pathogenetic mechanisms and important new clinical observations of the disease course provide fresh clues about prevention and treatment approaches. Although viral cytopathology and immune-mediated cell damage in ebolavirus disease often result in severe compromise of multiple organs, tissue repair and organ function recovery can be expected if patients receive supportive care with fluids and electrolytes; maintenance of oxygenation and tissue perfusion; and respiratory, renal, and cardiovascular support. Major challenges for managing future Ebola epidemics include establishment of early and aggressive epidemic control and earlier and better patient care and treatment in remote, resource-poor areas where Ebola typically reemerges. In addition, it will be important to further develop Ebola vaccines and to adopt policies for their use in epidemic and pre-epidemic situations.
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The recent large outbreaks of Ebola virus disease (EVD) in West Africa and the Democratic Republic of the Congo (DRC) have highlighted the need for rapid diagnostic tests to control this disease. In this study, we clinically evaluated a previously developed immunochromatography-based kit, QuickNaviTM-Ebola. During the 2018 outbreaks in DRC, 928 blood samples from EVD-suspected cases were tested with QuickNaviTM-Ebola and the WHO-approved GeneXpert. The sensitivity and specificity of QuickNaviTM-Ebola, estimated by comparing it to GeneXpert-confirmed cases, were 85% (68/80) and 99.8% (846/848), respectively. These results indicate the practical reliability of QuickNaviTM-Ebola for point-of-care diagnosis of EVD.
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The average time required to detect an Ebola virus disease (EVD) outbreak following spillover of Ebola virus (EBOV) to a primary human case has remained essentially unchanged for over 40 years, with some of the longest delays in detection occurring in recent decades. In this review, our aim was to examine the relationship between delays in detection of EVD and the duration and size of outbreaks, and we report that longer delays are associated with longer and larger EVD outbreaks. Historically, EVD outbreaks have typically been comprised of less than 100 cases (median = 60) and have lasted less than 4 months (median = 118 days). The ongoing outbreak in Democratic Republic of the Congo, together with the 2013–2016 west Africa outbreak, are stark outliers amidst these trends and had two of the longest delays in detection on record. While significant progress has been made in the development of EVD countermeasures, implementation during EVD outbreaks is problematic. Thus, EVD surveillance must be improved by the broad deployment of modern diagnostic tools, as prompt recognition of EVD has the potential to stem early transmission and ultimately limit the duration and size of outbreaks.
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Abstract Background Ebola virus (EBOV) is one of four ebolaviruses known to cause Ebola virus disease (EVD). It is widely thought that EVD outbreaks originate from spillover of ebolaviruses from wildlife into humans. However, phylogenetic analysis of EBOV sequences from recent EVD cases reveal genetic similarity to EBOV from prior outbreaks. Therefore, it is likely that these recent EVD outbreaks originated through human-to-human transmission instead of wildlife spillover. The aim of this study is to re-examine the origins and contexts of EVD outbreaks given this new knowledge. Methods All known EVD outbreaks and EBOV emergence events from 1976-2021 were analyzed via literature review. The primary and index cases for each outbreak were compared based on demographics and suspected sources of transmission. The diagnostic testing and treatment locations for each EVD index case were also investigated. Phylogenetic and epidemiologic relationships were examined to characterize whether outbreaks likely originated from separate spillover events or human-to-human transmission. Results Overall, 22 outbreaks caused by EBOV were identified from 1976-2021 (Table). 5/22 (22.7%) of outbreaks were possibly linked to previous EVD outbreaks, including the four most recent outbreaks. Possible sources for these outbreaks included relapse and delayed sexual transmission from survivors. 12/22 (54.5%) of outbreaks were linked to suspected spillover sources, which included contact with duikers, chimpanzees, gorillas, monkeys, and bats. The locations of these Ebola virus emergence events are shown in the Figure. Conclusion Recent EVD outbreaks have changed our understanding of the emergence of EBOV in humans. Most recent outbreaks have originated from human-to-human transmission rather than spillover from wildlife. Multiple large EVD outbreaks have created the potential for future resurgence among humans. Therefore, increased surveillance among humans as well as awareness among healthcare workers and traditional healers, who are often the first to encounter index cases, will be critical to preventing the next epidemic. Clinicians and researchers will need to carefully evaluate the origins of EVD outbreaks through epidemiological and phylogenetic analyses while also preventing stigma among survivors. Disclosures All Authors: No reported disclosures.
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Article history: Received 28 October 2015 Accepted 16 November 2015 Available online 27 November 2015 From the past several years West Africa is experiencing the largest, often calamitous, most severe, most complex outbreaks of Ebola virus disease (EVD) caused by the Ebola virus, a Filoviridae family virus. This virus was first recognized in the Democratic Republic of the Congo (formerly Zaire) in Africa. The Ebola virus outbreaks in 2014 are the most severe outbreak of Ebola in terms of the number of human deaths since the discovery of the virus in 1976. This disease has been classified among the highest priority for bioterrorism agents. The Ebola virus is introduced into the human population through close contact with the blood, secretions, organs or other bodily fluids of the infected non-human primate. Currently, there is no specific vaccine or antiviral agent available to treat Ebola virus infection. Considering the current situation of EVD, the World Health Organization (WHO) suggested its member countries to remain alert for the possible introduction of the virus, to raise the awareness of health care professional precautions for infection prevention. Due to the large number Ebola virus disease outbreaks, WHO implemented ethical guidelines for clinical use of some unregistered drugs that have not yet been evaluated for safety and efficacy in humans.
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