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Ebola outbreak in Western Africa 2014: what is going on with Ebola virus?

Ebola outbreak in Western Africa 2014: what is going on with Ebola virus? Review article CLINICAL Ebola outbreak in Western Africa EXPERIMENTAL 2014: what is going on with Ebola VACCINE RESEARCH virus? Clin Exp Vaccine Res 2015;4:17-22 http://dx.doi.org/10.7774/cevr.2015.4.1.17 pISSN 2287-3651 • eISSN 2287-366X 1,2 1,2 Woonsung Na *, Nanuri Park *, The 2014 outbreak of Ebola virus disease (EVD) in West Africa, caused by Ebola virus (Zaire 1,2 1,2 Minju Yeom , Daesub Song Ebola virus species), is the largest outbreak of EVD in history. It cause hemorrhagic fever in Viral Infectious Disease Research Center, human and nonhuman primates with high mortality rate up to 90% and can be transmitted Korea Research Institute of Bioscience and Biotechnology, Daejeon; University of Science by direct contact with blood, body fluids, skin of EVD patients or persons who have died of and Technology, Daejeon, Korea EVD. As of December 17, 2014, 450 healthcare personnel are known to have been infected *These authors contributed equally to this work. with Ebola, of whom 244 died. For development of Ebola vaccine and treatment are highly dif- ficult due to its dangerous and accessibility that requires biosafety level 4 (BSL-4) to conduct Received: December 26, 2014 Revised: December 28, 2014 experiment. Also there is no specific vaccine and treatment for Ebola virus; however, many Accepted: December 30, 2014 candidate vaccines and antiviral-drugs such as ZMapp and TKM-Ebola are being developed Corresponding author: Daesub Song, DVM, PhD for Ebola virus disease. In this review, we focus on the epidemiology of 2014 outbreak of Ebola Viral Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnol- virus and candidate agent for preventing and curing from Ebola virus. ogy, 125 Gwahak-ro, Yuseong-gu, Daejeon 305-806, Korea Tel: +82-42-879-8273, Fax: +82-42-879-8498 Keywords: Ebolavirus, Vaccines, Epidemiology, Therapy E-mail: sds1@kribb.re.kr No potential conflict of interest relevant to this article was reported. Introduction This work was supported by BioNano Health- Guard Research Center funded by the Ministry of Ebola viruses are the causative agents of Ebola hemorrhagic fever (EHF), which are Science, ICT & Future Planning (MSIP) of Korea as Global Frontier Project” (grant number H-GUARD_ highly virulent zoonosis that affect both human and nonhuman primates. Since then ERND 2013M3A6B2078954). Ebola outbreaks have been reported on average every 1.5 years, with a total of 7 prior outbreaks generated over 100 reported cases. A recent study has estimated 22 million people distributed in areas of Central and West Africa to be at risk of Ebola. Ebola virus contains single-stranded negative RNA linear genome, about 18-19 kb in size and en- code seven genes (NP, VP35, VP40, VP30, VP24, L, and GP) [1]. Five genetically distinct Ebola virus species within the genus Ebola virus are known (Zaire Ebola virus [ZEBOV], Sudan Ebola virus [SEBOV], Côte d’Ivoire Ebola virus, Bundibugyo Ebola virus [BE- BOV], and Reston Ebola virus [REBOV]). The genomes of the five different Ebola vi- ruses (BEBOV, ZEBOV, REBOV, SEBOV, and Taï Forest ebolavirus) are different in se- K O R E A N quence and the number and location of gene overlaps. However, REBOV species is re- V A C C I N E S O C I E T Y ported to cause disease only in nonhuman primates, ZEBOV, SEBOV, and BEBOV are responsible for most of the EHF outbreaks [2,3] but ZEBOV constitutes a particularly © Korean Vaccine Society. serious threat to both human and animals in sub-Saharan Africa with case fatality rates This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Com- as high as 90%. The 2014 outbreak of EHF in West Africa, caused by ZEBOV is the larg- mercial License (http://creativecommons.org/licenses/ by-nc/3.0) which permits unrestricted non-commercial est outbreak of EHF in history. Fruit bats are believed to be the normal carrier in na- use, distribution, and reproduction in any medium, pro- K O R E A N ture, although the means of local enzootic maintenance and transmission of the virus vided the original work is properly cited. V A C C I N E S O C I E T Y http://www.ecevr.org/ K O R E A N V A C C I N E S O C I E T Y Woonsung Na et al • Ebola outbreak in Western Africa 2014: what is going on with Ebola virus? within bat populations remain unknown. The virus is trans- animal reservoir in the Philippines, which has not been found mitted from wildlife to people through contact with infected in Africa. Therefore it differs from the others [8]. Ebola Reston fruit bats, and through intermediate hosts, such as monkeys, virus was recognized first when it caused an outbreak of le- apes, or pigs that have themselves become infected through thal infection in macaques imported into the United States in contact with bat saliva or faeces. So far there are no approved 1989 [9]. Nothing further was heard of the Reston virus until antiviral drugs or vaccines against Ebola viruses. The preven- 2008, when the investigation of an outbreak of disease in pigs tion of EHF requires improving our understanding of the epi- in the Philippines unexpectedly revealed that some of the sick demiology of the disease. In this review, we report important animals were infected both by an arterivirus, porcine repro- epidemiologic features related to Ebola outbreaks in Africa ductive and respiratory disease virus, and by Ebola Reston virus. based on previous findings during major outbreaks that oc- However, most previous Ebola outbreak occurred in Cen- curred on the continent. Also we elucidate a current status of tral Africa, Ebola outbreak has started in the West African na- promising Ebola vaccine and drug that is being developed. tion of Guinea which is confirmed by the World Health Orga- nization (WHO) in late 2013. This outbreak was spread to Li- beria, Sierra Leone, Nigeria, Senegal, and Mali [10]. Viral se- Epidemiology quence of Ebola patients in Sierra Leone showed that the epi- Contacting with the unknown reservoir host, Ebola virus has demic was originated from sustained person-to-person trans- been circulated among wild nonhuman primates. Subsequent mission without additional introductions from animal reser- to outbreak of Ebola virus in wild environment, chimpanzee voirs. Its case-fatality rate has been estimated approximately and gorilla population were remarkably reduced [4]. Also this 70% [11]. In Liberia and Sierra Leone, the magnitude of the have negatively affected to animal, source of food, which re- outbreak was not clearly underestimated because of individ- sulted in human epidemics. uals with Ebola virus disease being cared for outside the hos- Ebola virus is divided into five different species (the Zaire, pital setting. Accumulative number of presumable, suspect- Sudan, Ivory Coast, Bundibugyo, and Reston agents) and they ed, and laboratory-confirmed case of Ebola virus is 19,065 in- are different in virulence to humans [5,6]. Zaire species, first cluding 7,388 deaths as of December 17, 2014 (Table 1). These recognized appearance in 1976, has overspread in a variety of comprise 564 healthcare workers died approximately 50% [12]. regions with high mortality rate up to 88%. Sudan virus is re- WHO informed that Senegal and Nigeria became free from lated to approximate 50% case-fatality rate in four known epi- Ebola outbreaks by October 17 and 19, respectively due to the demic cases [6]: two in Sudan in the 1970s, one in Uganda in fact that no more case report of Ebola virus in both Senegal 2000, and another in Sudan in 2004. Ivory Coast virus case for and Nigeria from September 5, 2014 and August 29, respec- human has only been known in ethologist who conduct nec- tively. ropsy on a chimpanzee found dead in the Tai Forest where There were reports of Ebola virus diseases case outside of population of ape were remarkably decreased [3]. The Bun- West Africa [12]. Ebola virus diseases associated with Ebola dibugyo virus causing an outbreak of hemorrhagic fever with outbreak occurred to healthcare workers who caring for pa- lower case-fatality rate (approximately 30%) than Zaire and tients suffered from Ebola virus disease, as well as a returning Sudan viruses, are emerged in Uganda in 2007. Sequence traveler. The index case of Ebola virus diseases associated analysis has revealed that the agent is most closely related to with outbreak were reported in the Democratic Republic of the Ivory Coast agent [7,8]. Reston virus is maintained in an Congo in August of 2014, which a pregnant woman is infect- Table 1. Case count of Ebola outbreak 2014 (December 17, 2014) Total cases Lab-confirmed cases Total deaths Country Countries with widespread transmission 2,453 2,164 1,550 Guinea 7,819 3,021 3,346 Liberia 8,759 6,856 2,477 Sierra Leone Initial case or cases and/or localized transmission 4 4 2 United States 8 7 6 Mali Previously affected countries 20 19 8 Nigeria http://dx.doi.org/10.7774/cevr.2015.4.1.17 http://www.ecevr.org/ Woonsung Na et al • Ebola outbreak in Western Africa 2014: what is going on with Ebola virus? ed from bushmeat which was killed by her family in wild. A failure, and disseminated intravenous coagulation. For now, total of 66 cases of Ebola virus diseases (confirmed and sus- whole blood transfusions from convalescent patients are high- pected), including 49 deaths are associated with Ebola out- ly recommended for treatment of EHF. Although live attenu- break as of November 9, 2014. Although there is no relation ated vaccine and recombinant protein have been actively stud- with the current epidemic in West Africa, sequence of Zaire ied for Ebola virus based on murine model by 1990s, immu- strain of Ebola virus causing this outbreak is most closely re- nogenicity and the biosafety of those ways were not clearly lated to the case that occurred in 1995 outbreak in Kikwit [13]. described. DNA vaccine synthesizing immune-related genes in host cell or haring viral genes such as nucleoprotein (NP), glycoprotein (GP) in plasmid vector showed high efficacy to Diagnosis guinea pig and mouse model against various infectious dis- It is difficult to diagnosing Ebola virus in advance from infect- eases. While it was successful to induce immunization with ed person owing to nonspecific symptoms which are often DNA vaccine for Ebola virus in mouse model, DNA vaccine seen in patients who is suffering from more common diseases showed less effect on nonhuman primate and human mod- such as malaria and typhoid fever. After symptoms with high els. Replacement of plasmid DNA vector to poxivirus, a viral levels of circulating virus within the patient’s body appear, se- vector carrying the genes of viral protein, lead out greatly in- roconversion of Ebola virus diseases can be detected in blood. creased antibody titer and cellular immunity. Also adenovi- This require three days to reach for viral detectable levels. rus which is impaired in replication for enhancing safety have Laboratory test conducted in diagnosis such as antigen-cap- been used as a priming agents, which show high cellular im- ture enzyme-linked immunosorbent assay (ELISA) testing, mune response and humoral immunity in cynomolgus ma- IgM ELISA, and polymerase chain reaction (PCR) using spe- caques. The animal which is challenged by lethal viral dose, cific primers are used within a few days after symptoms begin. however, it showed complete protection, showing the way to Immunohistochemistry testing, PCR, and virus isolation for prevent Ebola virus on primates against infection. In recent patients who is expired could be tested (Table 2). days, vesicular stomatitis virus (VSVΔG-ZEB OV) and chim- panzee adenovirus (cAd3-EBO Z) are being actively studied as a promising vaccine for Ebola virus diseases. VSVΔG-ZEBOV, Vaccines and Therapeutics a candidate vaccine for the Ebola filovirus, is a DNA vaccine Many national departments of drug including WHO have re- that is developed by NewLink Genetics and Public Health searched useful treatments and vaccines, though there are no Agency of Canada [14]. The vaccine consists genes for the effective and target vaccine or treatment which are approved surface protein of ZEBOV in attenuated vesicular stomatitis by Food and Drug Administration (FDA) applicable for hu- virus (VSV), which interfere DNA recombination. Since VSV man use. It is strongly required to focus on clinical manage- is not critical to human, its biosafety and immune response ment of additive care for complication such as hypovolemia, are being estimated in clinical human trials (phase I). electrolyte abnormalities, hematologic abnormalities, refrac- In addition, ChAd3-EBOV, a candidate of Ebola virus vac- tory shock, hypoxia, hemorrhage, septic shock, multi-organ cine, is a modified and attenuated chimpanzee adenovirus composed by GP of the Ebola virus [15]. It is developed by Table 2. Current diagnosis of Ebola virus GlaxoSmithKline (GSK) and National Institute of Allergy and Timeline of infection Diagnostic tests available Infectious Diseases (NIAID). Although rescued virus could not easily replicate in humans, it stimulated a protective im- Within a few days after symptoms begins ELISA IgM ELISA mune response in humans. NIAID and Oxford University have PCR studied its effectiveness on clinical trials (phage I) for volun- Virus isolation teer. Above this, MVA-BN, developed by Bavarian Nordic com- Later in diseases course or after recovery IgM and IgG antibodies pany, is a vaccine of attenuated vaccinia virus and AdVac, a Retrospectively in deceased patients Immunohistochemistry testing DNA vaccine based on adenovirus, is being developed. And PCR clinical trial will be conducted in 2015 years (Table 3). Virus isolation Furthermore, as monoclonal antibodies, RNA-based drugs, ELISA, antigen-capture enzyme-linked immunosorbent assay; PCR, polymerase and small antiviral molecules novel therapeutic drugs are ac- chain reaction. http://dx.doi.org/10.7774/cevr.2015.4.1.17 http://www.ecevr.org/ Woonsung Na et al • Ebola outbreak in Western Africa 2014: what is going on with Ebola virus? Table 3. List of Ebola virus vaccine that is actively being developed for Table 4. List of Ebola virus drug that is actively being developed for clinical use clinical use Vaccine Status Feature Company Drug Status Feature Company cAd3-ZEBOV Phage I Attenuated adenovirus GSK and NIAID ZMapp Phage I Three chimeric monoclonal LeafBio, Inc. antibodies VSVΔG-ZEBOV Phage I Attenuated VSV NewLink Genetics and PHAC Favipiravir Approved for IAV Inhibition of viral RNA- Fujifilm a) dependent RNA MVA-BN 2015 Attenuated vaccinia virus Bavarian Nordic a) TKM-Ebola Phage I siRNA Tekmira AdVac 2015 Attenuated adenovirus Crucell Brincidofovir Phage III Oral nucleotide analog Chimerix SynCon Pre-clinical Polyvalent vaccine Inovio BCX4430 pre-clinical Inhibition of viral RNA BioCryst VesiculoVax Pre-clinical Attenuated VSV Profectus BioSciences polymerase NIAID, National Institute of Allergy and Infectious Diseases; PHAC, Public Health AVI-7537 Phage I Binding Ebola RNA Sarepta Agency of Canada; VSV, vesicular stomatitis virus. a) Scheduled for 2015 clinical trial. IAV, influenza A virus. tively being studied to be useful treatment. ZMapp, one of the ple. The FDA put the trial on clinical hold in July 2014 to as- powerful anti therapeutics, is an experimental biopharmaceu- sess results, after some subjects had flu-like responses. In Au- tical drug with three chimeric monoclonal antibodies under gust, the FDA changed the status to “partial hold,” allowing development as a treatment for Ebola virus diseases [16]. The the drug to be used under expanded access in people infected drug was first tested in humans during the 2014 West Africa with Ebola but with the phase I trial still suspended (Table 4). Ebola virus outbreak, but has not been subjected to a rando- mized controlled trial to determine whether it works, and whe- Research Facility for Ebola ther it is safe enough to allow on the market. It was first used experimentally to treat some people with Ebola virus disease Ebola virus is dangerous and exotic agent that poses high in- during the 2014 West African Ebola outbreak, but as of August dividual risk of laboratory infections and hospital settings, 2014 it had not yet been tested in a clinical trial to support which are frequently fatal because there are no vaccines or widespread usage in humans. Although ZMapp use plant as treatments. For these reasons, experiments with Ebola virus a production unit, considering an innovative ways to produce have to be performed in biosafety level 4 (BSL-4) laborato- antiviral drug, its productivity is too low to provide in time. ries. Currently, there are 21 BSL-4 facilities worldwide, how- Therefore, more study for producing ZMapp is needed. ever almost are operated in United States and Europe (Fig. 1). Favipiravir, also known as T-705 or Avigan, is an experimen- In East Asia, China and Japan are running the BSL-4 centers tal anti-viral drug being developed with activity against many and developed Ebola treatments and detection technologies, RNA viruses: influenza viruses, West Nile virus, yellow fever while South Korea still has not only been equipped the facility virus, and foot-and-mouth disease virus. It is a pyrazinecar- yet but also scientists who are trained to work in BSL-4. It boxamide derivative as like some other experimental antivi- evokes urgent investment on facilities and training research- ral drugs (T-1105 and T-1106), The mechanism of its actions ers for utilizing BSL-4 to keep up advanced defense for Ebola is related to the selective inhibition of viral RNA-dependent outbreak. RNA polymerase while it does not inhibit RNA or DNA syn- thesis in mammalian cells [17]. In 2014, favipiravir was ap- Conclusion proved in Japan for stockpiling against influenza pandemics. The drug appears to be effective in a mouse model of Ebola As the natural history and reservoir of Ebola viruses are not virus disease, leading for clinical use of favipiravir as a Ebola perfectly elucidated, there have been no specific methods for treatment. TKM-Ebola, as known as Ebola-SNALP, which is a avoiding infection from the natural exposure. However, in combination of Small interfering RNAs is being studied. It these days, extensive studies performed to determine the nat- targets three proteins of Ebola virus: Zaire Ebola L polymerase, ural reservoir of Ebola viruses have identified in common Zaire Ebola membrane-associated protein (VP24), and Zaire species of fruit bat (Rousettus aegyptiacus) as a potential and Ebola polymerase complex protein (VP35). Phase I clinical promising candidate. Since there have been no officially li- trial of TKM-Ebola was assessed for its safety in healthy peo- censed vaccines or antiviral drugs for the treatment of Ebola http://dx.doi.org/10.7774/cevr.2015.4.1.17 http://www.ecevr.org/ Woonsung Na et al • Ebola outbreak in Western Africa 2014: what is going on with Ebola virus? Europe: 12 - England (7) - Switzerland (2) - Netherlands (1) - Sweden (1) Artic Ocean - France (1) - Belarus (1) - Russia (1) - Romania (2) - Czech (1) - Italy (2) - Germany (4) America: 2 Atlantic Pacific - Australia (4) - USA (15) Ocean Ocean - Canada (2) Asia: 5 a) Pacific Ocean - Korea (1) Indian - Japan (2) Ocean - China (1) - India (3) - Taiwan (1) Africa: 2 - Gabon (1) - Republic of South Africa (1) Fig. 1. Biosafety level 4 (BSL-4) facilities in the world. There are totally 54 BSL-4 facilities in the world: 15 in USA; 2 in Canada; 1 in Gabon; 1 in Republic of South Africa; 7 in England; 2 in Switzerland; 1 in Netherlands; 1 in Sweden; 1 in France; 1 in Belarus; 1 in Russia; 2 in Romania; 1 in a) Czech; 2 in Italy; 4 in Germany; 4 in Australia; 1 in Korea; 2 in Japan; 1 in China; 3 in India; 1 in Taiwan. Under construction. virus infections although there are effort to develop vaccine Nichol ST. Inhibition of IRF-3 activation by VP35 is critical and treatment such as ZMapp and cAd-ZEBOV, early detec- for the high level of virulence of ebola virus. J Virol 2008; tion and diagnosis of infection from animals and human are 82:2699-704. very crucial for now. And for the prevention of transmission 2. Feldmann H, Jones SM, Schnittler HJ, Geisbert T. Therapy of the diseases, strict isolation of patient with fever and rigor- and prophylaxis of Ebola virus infections. Curr Opin In- ous use of barrier and quarantine precautions are very im- vestig Drugs 2005;6:823-30. portant. Also, many experts and institution consider the Ebo- 3. Towner JS, Sealy TK, Khristova ML, et al. Newly discov- la virus as potential biological weapons [18]. Therefore, for ered ebola virus associated with hemorrhagic fever out- the research of public health and biodefense against Ebola break in Uganda. PLoS Pathog 2008;4:e1000212. viruses, extensive studies of basic research including patho- 4. Frieden TR, Damon I, Bell BP, Kenyon T, Nichol S. Ebola biology, immune responses after infection should be inten- 2014: new challenges, new global response and responsi- sively studied. In addition, additional BSL-4 containments bility. N Engl J Med 2014;371:1177-80. which are only a few facilities exist worldwide are strongly re- 5. Georges-Courbot MC, Lu CY, Lansoud-Soukate J, Leroy E, quired to study for preventing and treating Ebola virus dis- Baize S. Isolation and partial molecular characterisation eases. of a strain of Ebola virus during a recent epidemic of viral haemorrhagic fever in Gabon. Lancet 1997;349:181. 6. Onyango CO, Opoka ML, Ksiazek TG, et al. Laboratory di- ORCID agnosis of Ebola hemorrhagic fever during an outbreak in Woonsung Na http://orcid.org/0000-0002-7254-5240 Yambio, Sudan, 2004. J Infect Dis 2007;196 Suppl 2:S193-8. Nanuri Park http://orcid.org/0000-0002-7951-0956 7. Jahrling PB, Geisbert TW, Dalgard DW, et al. Preliminary Minju Yeom http://orcid.org/0000-0001-8949-6361 report: isolation of Ebola virus from monkeys imported to Daesub Song http://orcid.org/0000-0002-2759-1061 USA. Lancet 1990;335:502-5. 8. Miranda ME, Ksiazek TG, Retuya TJ, et al. Epidemiology of Ebola (subtype Reston) virus in the Philippines, 1996. J References Infect Dis 1999;179 Suppl 1:S115-9. 1. Hartman AL, Bird BH, Towner JS, Antoniadou ZA, Zaki SR, 9. Barrette RW, Metwally SA, Rowland JM, et al. Discovery of http://dx.doi.org/10.7774/cevr.2015.4.1.17 http://www.ecevr.org/ Woonsung Na et al • Ebola outbreak in Western Africa 2014: what is going on with Ebola virus? swine as a host for the Reston ebolavirus. Science 2009; tion of cynomolgus macaques with the VSVDeltaG/ZE- 325:204-6. BOVGP vaccine stimulates strong ebola GP-specific im- 10. Gire SK, Goba A, Andersen KG, et al. Genomic surveil- mune responses. PLoS One 2009;4:e5547. lance elucidates Ebola virus origin and transmission dur- 15. Stanley DA, Honko AN, Asiedu C, et al. Chimpanzee ade- ing the 2014 outbreak. Science 2014;345:1369-72. novirus vaccine generates acute and durable protective 11. WHO Ebola Response Team. Ebola virus disease in West immunity against ebolavirus challenge. Nat Med 2014;20: Africa: the first 9 months of the epidemic and forward pro- 1126-9. jections. N Engl J Med 2014;371:1481-95. 16. Zhang Y, Li D, Jin X, Huang Z. Fighting Ebola with ZMapp: 12. Bausch DG, Towner JS, Dowell SF, et al. Assessment of the spotlight on plant-made antibody. Sci China Life Sci 2014; risk of Ebola virus transmission from bodily fluids and 57:987-8. fomites. J Infect Dis 2007;196 Suppl 2:S142-7. 17. Furuta Y, Gowen BB, Takahashi K, Shiraki K, Smee DF, Bar- 13. World Health Organization. Global Alert Response (GAR). nard DL. Favipiravir (T-705), a novel viral RNA polymerase Ebola virus disease: Democratic Republic of Congo [In- inhibitor. Antiviral Res 2013;100:446-54. ternet]. Geneva: World Health Organization; 2014 [cited 18. Borio L, Inglesby T, Peters CJ, et al. Hemorrhagic fever vi- 2014 Dec 1]. Available from: http://www.who.int/csr/don/ ruses as biological weapons: medical and public health 2014_08_27_ebola/en/. management. JAMA 2002;287:2391-405. 14. Qiu X, Fernando L, Alimonti JB, et al. Mucosal immuniza- http://dx.doi.org/10.7774/cevr.2015.4.1.17 http://www.ecevr.org/ http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical and Experimental Vaccine Research Pubmed Central

Ebola outbreak in Western Africa 2014: what is going on with Ebola virus?

Clinical and Experimental Vaccine Research , Volume 4 (1) – Jan 30, 2015

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Review article CLINICAL Ebola outbreak in Western Africa EXPERIMENTAL 2014: what is going on with Ebola VACCINE RESEARCH virus? Clin Exp Vaccine Res 2015;4:17-22 http://dx.doi.org/10.7774/cevr.2015.4.1.17 pISSN 2287-3651 • eISSN 2287-366X 1,2 1,2 Woonsung Na *, Nanuri Park *, The 2014 outbreak of Ebola virus disease (EVD) in West Africa, caused by Ebola virus (Zaire 1,2 1,2 Minju Yeom , Daesub Song Ebola virus species), is the largest outbreak of EVD in history. It cause hemorrhagic fever in Viral Infectious Disease Research Center, human and nonhuman primates with high mortality rate up to 90% and can be transmitted Korea Research Institute of Bioscience and Biotechnology, Daejeon; University of Science by direct contact with blood, body fluids, skin of EVD patients or persons who have died of and Technology, Daejeon, Korea EVD. As of December 17, 2014, 450 healthcare personnel are known to have been infected *These authors contributed equally to this work. with Ebola, of whom 244 died. For development of Ebola vaccine and treatment are highly dif- ficult due to its dangerous and accessibility that requires biosafety level 4 (BSL-4) to conduct Received: December 26, 2014 Revised: December 28, 2014 experiment. Also there is no specific vaccine and treatment for Ebola virus; however, many Accepted: December 30, 2014 candidate vaccines and antiviral-drugs such as ZMapp and TKM-Ebola are being developed Corresponding author: Daesub Song, DVM, PhD for Ebola virus disease. In this review, we focus on the epidemiology of 2014 outbreak of Ebola Viral Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnol- virus and candidate agent for preventing and curing from Ebola virus. ogy, 125 Gwahak-ro, Yuseong-gu, Daejeon 305-806, Korea Tel: +82-42-879-8273, Fax: +82-42-879-8498 Keywords: Ebolavirus, Vaccines, Epidemiology, Therapy E-mail: sds1@kribb.re.kr No potential conflict of interest relevant to this article was reported. Introduction This work was supported by BioNano Health- Guard Research Center funded by the Ministry of Ebola viruses are the causative agents of Ebola hemorrhagic fever (EHF), which are Science, ICT & Future Planning (MSIP) of Korea as Global Frontier Project” (grant number H-GUARD_ highly virulent zoonosis that affect both human and nonhuman primates. Since then ERND 2013M3A6B2078954). Ebola outbreaks have been reported on average every 1.5 years, with a total of 7 prior outbreaks generated over 100 reported cases. A recent study has estimated 22 million people distributed in areas of Central and West Africa to be at risk of Ebola. Ebola virus contains single-stranded negative RNA linear genome, about 18-19 kb in size and en- code seven genes (NP, VP35, VP40, VP30, VP24, L, and GP) [1]. Five genetically distinct Ebola virus species within the genus Ebola virus are known (Zaire Ebola virus [ZEBOV], Sudan Ebola virus [SEBOV], Côte d’Ivoire Ebola virus, Bundibugyo Ebola virus [BE- BOV], and Reston Ebola virus [REBOV]). The genomes of the five different Ebola vi- ruses (BEBOV, ZEBOV, REBOV, SEBOV, and Taï Forest ebolavirus) are different in se- K O R E A N quence and the number and location of gene overlaps. However, REBOV species is re- V A C C I N E S O C I E T Y ported to cause disease only in nonhuman primates, ZEBOV, SEBOV, and BEBOV are responsible for most of the EHF outbreaks [2,3] but ZEBOV constitutes a particularly © Korean Vaccine Society. serious threat to both human and animals in sub-Saharan Africa with case fatality rates This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Com- as high as 90%. The 2014 outbreak of EHF in West Africa, caused by ZEBOV is the larg- mercial License (http://creativecommons.org/licenses/ by-nc/3.0) which permits unrestricted non-commercial est outbreak of EHF in history. Fruit bats are believed to be the normal carrier in na- use, distribution, and reproduction in any medium, pro- K O R E A N ture, although the means of local enzootic maintenance and transmission of the virus vided the original work is properly cited. V A C C I N E S O C I E T Y http://www.ecevr.org/ K O R E A N V A C C I N E S O C I E T Y Woonsung Na et al • Ebola outbreak in Western Africa 2014: what is going on with Ebola virus? within bat populations remain unknown. The virus is trans- animal reservoir in the Philippines, which has not been found mitted from wildlife to people through contact with infected in Africa. Therefore it differs from the others [8]. Ebola Reston fruit bats, and through intermediate hosts, such as monkeys, virus was recognized first when it caused an outbreak of le- apes, or pigs that have themselves become infected through thal infection in macaques imported into the United States in contact with bat saliva or faeces. So far there are no approved 1989 [9]. Nothing further was heard of the Reston virus until antiviral drugs or vaccines against Ebola viruses. The preven- 2008, when the investigation of an outbreak of disease in pigs tion of EHF requires improving our understanding of the epi- in the Philippines unexpectedly revealed that some of the sick demiology of the disease. In this review, we report important animals were infected both by an arterivirus, porcine repro- epidemiologic features related to Ebola outbreaks in Africa ductive and respiratory disease virus, and by Ebola Reston virus. based on previous findings during major outbreaks that oc- However, most previous Ebola outbreak occurred in Cen- curred on the continent. Also we elucidate a current status of tral Africa, Ebola outbreak has started in the West African na- promising Ebola vaccine and drug that is being developed. tion of Guinea which is confirmed by the World Health Orga- nization (WHO) in late 2013. This outbreak was spread to Li- beria, Sierra Leone, Nigeria, Senegal, and Mali [10]. Viral se- Epidemiology quence of Ebola patients in Sierra Leone showed that the epi- Contacting with the unknown reservoir host, Ebola virus has demic was originated from sustained person-to-person trans- been circulated among wild nonhuman primates. Subsequent mission without additional introductions from animal reser- to outbreak of Ebola virus in wild environment, chimpanzee voirs. Its case-fatality rate has been estimated approximately and gorilla population were remarkably reduced [4]. Also this 70% [11]. In Liberia and Sierra Leone, the magnitude of the have negatively affected to animal, source of food, which re- outbreak was not clearly underestimated because of individ- sulted in human epidemics. uals with Ebola virus disease being cared for outside the hos- Ebola virus is divided into five different species (the Zaire, pital setting. Accumulative number of presumable, suspect- Sudan, Ivory Coast, Bundibugyo, and Reston agents) and they ed, and laboratory-confirmed case of Ebola virus is 19,065 in- are different in virulence to humans [5,6]. Zaire species, first cluding 7,388 deaths as of December 17, 2014 (Table 1). These recognized appearance in 1976, has overspread in a variety of comprise 564 healthcare workers died approximately 50% [12]. regions with high mortality rate up to 88%. Sudan virus is re- WHO informed that Senegal and Nigeria became free from lated to approximate 50% case-fatality rate in four known epi- Ebola outbreaks by October 17 and 19, respectively due to the demic cases [6]: two in Sudan in the 1970s, one in Uganda in fact that no more case report of Ebola virus in both Senegal 2000, and another in Sudan in 2004. Ivory Coast virus case for and Nigeria from September 5, 2014 and August 29, respec- human has only been known in ethologist who conduct nec- tively. ropsy on a chimpanzee found dead in the Tai Forest where There were reports of Ebola virus diseases case outside of population of ape were remarkably decreased [3]. The Bun- West Africa [12]. Ebola virus diseases associated with Ebola dibugyo virus causing an outbreak of hemorrhagic fever with outbreak occurred to healthcare workers who caring for pa- lower case-fatality rate (approximately 30%) than Zaire and tients suffered from Ebola virus disease, as well as a returning Sudan viruses, are emerged in Uganda in 2007. Sequence traveler. The index case of Ebola virus diseases associated analysis has revealed that the agent is most closely related to with outbreak were reported in the Democratic Republic of the Ivory Coast agent [7,8]. Reston virus is maintained in an Congo in August of 2014, which a pregnant woman is infect- Table 1. Case count of Ebola outbreak 2014 (December 17, 2014) Total cases Lab-confirmed cases Total deaths Country Countries with widespread transmission 2,453 2,164 1,550 Guinea 7,819 3,021 3,346 Liberia 8,759 6,856 2,477 Sierra Leone Initial case or cases and/or localized transmission 4 4 2 United States 8 7 6 Mali Previously affected countries 20 19 8 Nigeria http://dx.doi.org/10.7774/cevr.2015.4.1.17 http://www.ecevr.org/ Woonsung Na et al • Ebola outbreak in Western Africa 2014: what is going on with Ebola virus? ed from bushmeat which was killed by her family in wild. A failure, and disseminated intravenous coagulation. For now, total of 66 cases of Ebola virus diseases (confirmed and sus- whole blood transfusions from convalescent patients are high- pected), including 49 deaths are associated with Ebola out- ly recommended for treatment of EHF. Although live attenu- break as of November 9, 2014. Although there is no relation ated vaccine and recombinant protein have been actively stud- with the current epidemic in West Africa, sequence of Zaire ied for Ebola virus based on murine model by 1990s, immu- strain of Ebola virus causing this outbreak is most closely re- nogenicity and the biosafety of those ways were not clearly lated to the case that occurred in 1995 outbreak in Kikwit [13]. described. DNA vaccine synthesizing immune-related genes in host cell or haring viral genes such as nucleoprotein (NP), glycoprotein (GP) in plasmid vector showed high efficacy to Diagnosis guinea pig and mouse model against various infectious dis- It is difficult to diagnosing Ebola virus in advance from infect- eases. While it was successful to induce immunization with ed person owing to nonspecific symptoms which are often DNA vaccine for Ebola virus in mouse model, DNA vaccine seen in patients who is suffering from more common diseases showed less effect on nonhuman primate and human mod- such as malaria and typhoid fever. After symptoms with high els. Replacement of plasmid DNA vector to poxivirus, a viral levels of circulating virus within the patient’s body appear, se- vector carrying the genes of viral protein, lead out greatly in- roconversion of Ebola virus diseases can be detected in blood. creased antibody titer and cellular immunity. Also adenovi- This require three days to reach for viral detectable levels. rus which is impaired in replication for enhancing safety have Laboratory test conducted in diagnosis such as antigen-cap- been used as a priming agents, which show high cellular im- ture enzyme-linked immunosorbent assay (ELISA) testing, mune response and humoral immunity in cynomolgus ma- IgM ELISA, and polymerase chain reaction (PCR) using spe- caques. The animal which is challenged by lethal viral dose, cific primers are used within a few days after symptoms begin. however, it showed complete protection, showing the way to Immunohistochemistry testing, PCR, and virus isolation for prevent Ebola virus on primates against infection. In recent patients who is expired could be tested (Table 2). days, vesicular stomatitis virus (VSVΔG-ZEB OV) and chim- panzee adenovirus (cAd3-EBO Z) are being actively studied as a promising vaccine for Ebola virus diseases. VSVΔG-ZEBOV, Vaccines and Therapeutics a candidate vaccine for the Ebola filovirus, is a DNA vaccine Many national departments of drug including WHO have re- that is developed by NewLink Genetics and Public Health searched useful treatments and vaccines, though there are no Agency of Canada [14]. The vaccine consists genes for the effective and target vaccine or treatment which are approved surface protein of ZEBOV in attenuated vesicular stomatitis by Food and Drug Administration (FDA) applicable for hu- virus (VSV), which interfere DNA recombination. Since VSV man use. It is strongly required to focus on clinical manage- is not critical to human, its biosafety and immune response ment of additive care for complication such as hypovolemia, are being estimated in clinical human trials (phase I). electrolyte abnormalities, hematologic abnormalities, refrac- In addition, ChAd3-EBOV, a candidate of Ebola virus vac- tory shock, hypoxia, hemorrhage, septic shock, multi-organ cine, is a modified and attenuated chimpanzee adenovirus composed by GP of the Ebola virus [15]. It is developed by Table 2. Current diagnosis of Ebola virus GlaxoSmithKline (GSK) and National Institute of Allergy and Timeline of infection Diagnostic tests available Infectious Diseases (NIAID). Although rescued virus could not easily replicate in humans, it stimulated a protective im- Within a few days after symptoms begins ELISA IgM ELISA mune response in humans. NIAID and Oxford University have PCR studied its effectiveness on clinical trials (phage I) for volun- Virus isolation teer. Above this, MVA-BN, developed by Bavarian Nordic com- Later in diseases course or after recovery IgM and IgG antibodies pany, is a vaccine of attenuated vaccinia virus and AdVac, a Retrospectively in deceased patients Immunohistochemistry testing DNA vaccine based on adenovirus, is being developed. And PCR clinical trial will be conducted in 2015 years (Table 3). Virus isolation Furthermore, as monoclonal antibodies, RNA-based drugs, ELISA, antigen-capture enzyme-linked immunosorbent assay; PCR, polymerase and small antiviral molecules novel therapeutic drugs are ac- chain reaction. http://dx.doi.org/10.7774/cevr.2015.4.1.17 http://www.ecevr.org/ Woonsung Na et al • Ebola outbreak in Western Africa 2014: what is going on with Ebola virus? Table 3. List of Ebola virus vaccine that is actively being developed for Table 4. List of Ebola virus drug that is actively being developed for clinical use clinical use Vaccine Status Feature Company Drug Status Feature Company cAd3-ZEBOV Phage I Attenuated adenovirus GSK and NIAID ZMapp Phage I Three chimeric monoclonal LeafBio, Inc. antibodies VSVΔG-ZEBOV Phage I Attenuated VSV NewLink Genetics and PHAC Favipiravir Approved for IAV Inhibition of viral RNA- Fujifilm a) dependent RNA MVA-BN 2015 Attenuated vaccinia virus Bavarian Nordic a) TKM-Ebola Phage I siRNA Tekmira AdVac 2015 Attenuated adenovirus Crucell Brincidofovir Phage III Oral nucleotide analog Chimerix SynCon Pre-clinical Polyvalent vaccine Inovio BCX4430 pre-clinical Inhibition of viral RNA BioCryst VesiculoVax Pre-clinical Attenuated VSV Profectus BioSciences polymerase NIAID, National Institute of Allergy and Infectious Diseases; PHAC, Public Health AVI-7537 Phage I Binding Ebola RNA Sarepta Agency of Canada; VSV, vesicular stomatitis virus. a) Scheduled for 2015 clinical trial. IAV, influenza A virus. tively being studied to be useful treatment. ZMapp, one of the ple. The FDA put the trial on clinical hold in July 2014 to as- powerful anti therapeutics, is an experimental biopharmaceu- sess results, after some subjects had flu-like responses. In Au- tical drug with three chimeric monoclonal antibodies under gust, the FDA changed the status to “partial hold,” allowing development as a treatment for Ebola virus diseases [16]. The the drug to be used under expanded access in people infected drug was first tested in humans during the 2014 West Africa with Ebola but with the phase I trial still suspended (Table 4). Ebola virus outbreak, but has not been subjected to a rando- mized controlled trial to determine whether it works, and whe- Research Facility for Ebola ther it is safe enough to allow on the market. It was first used experimentally to treat some people with Ebola virus disease Ebola virus is dangerous and exotic agent that poses high in- during the 2014 West African Ebola outbreak, but as of August dividual risk of laboratory infections and hospital settings, 2014 it had not yet been tested in a clinical trial to support which are frequently fatal because there are no vaccines or widespread usage in humans. Although ZMapp use plant as treatments. For these reasons, experiments with Ebola virus a production unit, considering an innovative ways to produce have to be performed in biosafety level 4 (BSL-4) laborato- antiviral drug, its productivity is too low to provide in time. ries. Currently, there are 21 BSL-4 facilities worldwide, how- Therefore, more study for producing ZMapp is needed. ever almost are operated in United States and Europe (Fig. 1). Favipiravir, also known as T-705 or Avigan, is an experimen- In East Asia, China and Japan are running the BSL-4 centers tal anti-viral drug being developed with activity against many and developed Ebola treatments and detection technologies, RNA viruses: influenza viruses, West Nile virus, yellow fever while South Korea still has not only been equipped the facility virus, and foot-and-mouth disease virus. It is a pyrazinecar- yet but also scientists who are trained to work in BSL-4. It boxamide derivative as like some other experimental antivi- evokes urgent investment on facilities and training research- ral drugs (T-1105 and T-1106), The mechanism of its actions ers for utilizing BSL-4 to keep up advanced defense for Ebola is related to the selective inhibition of viral RNA-dependent outbreak. RNA polymerase while it does not inhibit RNA or DNA syn- thesis in mammalian cells [17]. In 2014, favipiravir was ap- Conclusion proved in Japan for stockpiling against influenza pandemics. The drug appears to be effective in a mouse model of Ebola As the natural history and reservoir of Ebola viruses are not virus disease, leading for clinical use of favipiravir as a Ebola perfectly elucidated, there have been no specific methods for treatment. TKM-Ebola, as known as Ebola-SNALP, which is a avoiding infection from the natural exposure. However, in combination of Small interfering RNAs is being studied. It these days, extensive studies performed to determine the nat- targets three proteins of Ebola virus: Zaire Ebola L polymerase, ural reservoir of Ebola viruses have identified in common Zaire Ebola membrane-associated protein (VP24), and Zaire species of fruit bat (Rousettus aegyptiacus) as a potential and Ebola polymerase complex protein (VP35). Phase I clinical promising candidate. Since there have been no officially li- trial of TKM-Ebola was assessed for its safety in healthy peo- censed vaccines or antiviral drugs for the treatment of Ebola http://dx.doi.org/10.7774/cevr.2015.4.1.17 http://www.ecevr.org/ Woonsung Na et al • Ebola outbreak in Western Africa 2014: what is going on with Ebola virus? Europe: 12 - England (7) - Switzerland (2) - Netherlands (1) - Sweden (1) Artic Ocean - France (1) - Belarus (1) - Russia (1) - Romania (2) - Czech (1) - Italy (2) - Germany (4) America: 2 Atlantic Pacific - Australia (4) - USA (15) Ocean Ocean - Canada (2) Asia: 5 a) Pacific Ocean - Korea (1) Indian - Japan (2) Ocean - China (1) - India (3) - Taiwan (1) Africa: 2 - Gabon (1) - Republic of South Africa (1) Fig. 1. Biosafety level 4 (BSL-4) facilities in the world. There are totally 54 BSL-4 facilities in the world: 15 in USA; 2 in Canada; 1 in Gabon; 1 in Republic of South Africa; 7 in England; 2 in Switzerland; 1 in Netherlands; 1 in Sweden; 1 in France; 1 in Belarus; 1 in Russia; 2 in Romania; 1 in a) Czech; 2 in Italy; 4 in Germany; 4 in Australia; 1 in Korea; 2 in Japan; 1 in China; 3 in India; 1 in Taiwan. Under construction. virus infections although there are effort to develop vaccine Nichol ST. Inhibition of IRF-3 activation by VP35 is critical and treatment such as ZMapp and cAd-ZEBOV, early detec- for the high level of virulence of ebola virus. J Virol 2008; tion and diagnosis of infection from animals and human are 82:2699-704. very crucial for now. And for the prevention of transmission 2. Feldmann H, Jones SM, Schnittler HJ, Geisbert T. Therapy of the diseases, strict isolation of patient with fever and rigor- and prophylaxis of Ebola virus infections. Curr Opin In- ous use of barrier and quarantine precautions are very im- vestig Drugs 2005;6:823-30. portant. Also, many experts and institution consider the Ebo- 3. Towner JS, Sealy TK, Khristova ML, et al. Newly discov- la virus as potential biological weapons [18]. Therefore, for ered ebola virus associated with hemorrhagic fever out- the research of public health and biodefense against Ebola break in Uganda. PLoS Pathog 2008;4:e1000212. viruses, extensive studies of basic research including patho- 4. Frieden TR, Damon I, Bell BP, Kenyon T, Nichol S. Ebola biology, immune responses after infection should be inten- 2014: new challenges, new global response and responsi- sively studied. In addition, additional BSL-4 containments bility. N Engl J Med 2014;371:1177-80. which are only a few facilities exist worldwide are strongly re- 5. Georges-Courbot MC, Lu CY, Lansoud-Soukate J, Leroy E, quired to study for preventing and treating Ebola virus dis- Baize S. Isolation and partial molecular characterisation eases. of a strain of Ebola virus during a recent epidemic of viral haemorrhagic fever in Gabon. Lancet 1997;349:181. 6. Onyango CO, Opoka ML, Ksiazek TG, et al. Laboratory di- ORCID agnosis of Ebola hemorrhagic fever during an outbreak in Woonsung Na http://orcid.org/0000-0002-7254-5240 Yambio, Sudan, 2004. J Infect Dis 2007;196 Suppl 2:S193-8. Nanuri Park http://orcid.org/0000-0002-7951-0956 7. Jahrling PB, Geisbert TW, Dalgard DW, et al. Preliminary Minju Yeom http://orcid.org/0000-0001-8949-6361 report: isolation of Ebola virus from monkeys imported to Daesub Song http://orcid.org/0000-0002-2759-1061 USA. Lancet 1990;335:502-5. 8. Miranda ME, Ksiazek TG, Retuya TJ, et al. Epidemiology of Ebola (subtype Reston) virus in the Philippines, 1996. J References Infect Dis 1999;179 Suppl 1:S115-9. 1. Hartman AL, Bird BH, Towner JS, Antoniadou ZA, Zaki SR, 9. Barrette RW, Metwally SA, Rowland JM, et al. 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Clinical and Experimental Vaccine ResearchPubmed Central

Published: Jan 30, 2015

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