Ebola and Marburg Virus: A Brief Review

C H A P T E R

11 Ebola and Marburg Virus: A Brief Review A. Ndjoyi-Mbiguino1, S. Zoa-Assoumou1, G. Mourembou1 and Moulay Mustapha Ennaji2 1

STD/Aids National Reference Laboratory, Measles, Rubella, Yellow fever, WHO Reference Laboratory, Department of Bacteriology, Virology, Immunology and Basic Hematology, Faculty of Medicine and Health Sciences, University of Health Sciences, Libreville, Gabon 2Laboratory of Virology, Microbiology, Quality, Biotechnologies/Eco-Toxicology and Biodiversity, Faculty of Sciences and Techniques, Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco

INTRODUCTION The Ebola and Marburg filoviruses are among the most pathogenic viruses in the world. They are responsible for outbreaks of hemorrhagic fevers in human and nonhuman primates, as well as other vertebrates, causing many deaths (Feldmann et al., 2003; Leroy and Gonzalez, 2012). Some parts of Africa are particularly affected by outbreaks. The frequency, the rapid spread of epidemics, the mobilization of human, health and socioeconomic resources, the implementation of security measures, an effective management, and the search for treatment, and especially an effective vaccine against these viruses and their variants, militate in favor of the preparation and the response (GasquetBlanchard, 2014).

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HISTORY Marburg Virus The first cases of filovirus hemorrhagic fever were reported in Germany (Marburg and Frankfurt) and in Belgrade, Serbia (formerly Yugoslavia), in laboratory technicians from the Behring laboratory in Marburg, who were handling monkey (Cercopithecus aethiops) kidney cells imported from Uganda for vaccine production in 1967 (de La vega et al., 2015; Georges et al., 1999; Kiley et al., 1982; Martini et al., 1968; Slenczka and Klenk, 2007; Stille et al., 1968; WHO, 1992). The isolated virus was then called Marburg. It was responsible for 25 primary human infections, including 7 deaths in people who directly manipulated the infected tissues and 6 secondary cases (Georges et al., 1999). The virus is also responsible for epizootics in African monkeys. Indeed, a number of studies have reported that the Ebola virus causes epizootics in gorillas and chimpanzees in Gabon and Congo, with hundreds of deaths recorded (Formenty et al., 2003; Georges et al., 1999). After the first epidemic in Europe, three human cases were reported in South Africa in 1975, three in Kenya, two in 1980, and one in 1987 (Centers for Disease Control and Prevention, 2012). The disease cases in Kenya were consecutive to cave visits colonized by bats (Amman et al., 2012; Centers for Disease Control and Prevention, 2005; Centers for Disease Control and Prevention, 2010; Gentilini et al., 2012; Georges et al., 1999; Negredo et al., 2011; Timen et al., 2009). In 1998 the epidemic Durba, in the northeast of the Democratic Republic of Congo (DRC), the largest epidemic, caused 80% of the deaths (WHO, 1998). In 2000 few cases were reported in South Africa, Kenya, and Zimbabwe. In 2004, 400 cases of Marburg virus disease, including one death, were reported in Angola by WHO. In 2005 an epidemic occurred in Angola, in which 387 cases were reported including 329 deaths (Roddy et al., 2007; Roddy et al., 2010). The last case of Marburg virus infection was reported in 2008 in a Dutch tourist after cave visits in Uganda (Timen et al., 2009). In 1987 and 1990 two laboratory accidents, in which one was fatal, were recorded in Russia. In 1999 a number of clinical cases of hemorrhagic fevers were reported in the northeast of the DRC, with 18 suspected cases and the death of the doctor reporting the cases. In 2014 the Government of Uganda announced a case of illness (Polonsky et al., 2014; Towner et al., 2008). In 2017 an epidemic of Marburg hemorrhagic fever was declared by the WHO, which caused three deaths. This virus is similar to Ebola but less lethal (23% 90%) than the latter (Georges et al., 1999; Leroy et al., 2011a; WHO, 2012c).

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Ebola Virus The Ebola disease was first observed in 1976 with two outbreaks: one in Nzara, Sudan, and the other in Yambuku, Zaire (now DRC), in Central Africa (WHO, 1978a; WHO, 1978b). It is the deadliest among all the filoviruses. A percentage of 53 and 88 deaths was reported respectively in those cities. The two viruses isolated from these two regions have been named Ebola, after the name of the river that flows near Yambuku. These two closely related viruses are serologically and genetically distinct. There is no evidence of a link between the two epidemics that have spread rapidly. The epidemic in Sudan resulted in 284 cases, out of which 151 deaths were reported, among which 76 hospital infections and 41 reported from medical staff (WHO, 1978b; WHO, 1992). Zaire recorded 318 cases, including 280 deaths (Gentilini et al., 2012; Georges et al., 1999). Since then, epidemics have been reported in many parts of the globe. First in Nzara in 1979 followed by in the United States in 1989 and 1990 (in Virginia), in Siena (Italia) in 1992, in the United States in 1996, in Taı¨ (Ivory Coast) in 1994, in Kikwitt (Zaire) in 1995, and in Gabon, three epidemics occurred, one at the end of 1994 and two in 1996 (Georges et al., 1999; Jahrling et al., 1990). In addition to outbreaks, there were laboratory contamination cases in England and Russia in the years 1976 and 1997, respectively. A fatal secondary infection, following Gabon outbreak, was reported in South Africa in 1996. Nosocomial extensions and secondary outbreaks were reported in Uganda in 2000 01, and a new variant (Bundibugyo) was isolated (Roddy et al., 2012). It is now recognized that the reservoir of the virus is the fruit bat and that those affected might have become contaminated when came in contact with these animals, their excrements and fruits contaminated by them, or while handling the corpses of the infected monkeys (Gene et al., 2009; Gonzalez et al., 2007; Kuhn et al., 2010a; Leroy et al., 2005; Leroy et al., 2009a; Pourrut et al., 2007; Pourrut et al., 2009; Towner et al., 2007). The first victims are hunter gatherers living in primary and secondary forests (Monath, 1999; Muehlenbein, 2005; Mwavu and Witkowski, 2008). Interhuman contamination occurs through close contact with patients, their blood, excreta, and corpses, and by the reuse of contaminated injectable materials. Sexual transmission was mentioned because the virus was isolated from the sperm of patients and convalescents. Apart from these, airborne transmission is also possible. The causes of emergence and reemergence of the virus are not known (Leroy and Gonzalez, 2012; Wittmann et al., 2007). Nevertheless, it was anticipated that ecological disturbances might be one of the reasons for contamination because of climatic variations,

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displacements of the populations, and forceful immigration for intraor intercountry conflicts (Kuhn, 2008). Besides, the migration of fruit bats remained the other reason.

VIRUSES The Marburg and Ebola viruses belong to the Filoviridae family, the Ebolavirus, Marburgvirus, and Cuevavirus genera. The genus Ebolavirus has five species: Zaire ebolavirus (EBOV), Sudan ebolavirus (SUDV), Reston ebolavirus (RESV), Bundibugyo ebolavirus (BDV), Taı¨ Forest ebolavirus (TAV). The genus Marburgvirus comprises one species: Marburg marburgvirus (formerly Lake Victoria marburgvirus); the third genus Cuevavirus has a single species, Llovirus. They are long filamentous particles, U and 6 shaped, enveloped with a single-stranded RNA of 19-kb having a negative polarity (Adjemian et al., 2011; Anthony and Bradfute, 2015; Baron et al., 1983; Barrette et al., 2009; Geisbert and Jahrling, 1995; Hayes et al., 1992; Kuhn et al., 2010a; Kuhn et al., 2010b; Kuhn et al., 2011; Le Guenno et al., 1995; MacNeil and Rollin, 2012; MacNeil et al., 2011; Miranda et al., 1991; Miranda et al., 1999; Okware et al., 2002; WHO, 2005).

MOLECULAR EPIDEMIOLOGY EBOV, a member of the Ebolavirus genus, was first identified in Zaire, DRC (Central Africa), in 1976, resulting in 15 consecutive epidemics and 79% mortality rate. In the same period an epidemic occurred in Sudan in northeast Africa, with a recorded mortality rate of 63% (WHO, 1978b; WHO, 1992). The viral species responsible, SUDV, caused six additional outbreaks (Shoemaker et al., 2012). In 1994 another Ebola species, the TAV, was identified in West Africa. It infected a Swiss scientist who performed an autopsy on an infected chimpanzee. After treatment the patient has recovered, and this is the only known case in humans so far. In 2007 Uganda is affected by an episode of Ebolavirus hemorrhagic fever, where the BDV species caused 37 deaths out of 149 cases (25%) (Roddy et al., 2012; Towner et al., 2008; Wamala et al., 2010). The first four species described are pathogenic for humans. The fifth species, RESV, has a pathogenicity known till date in nonhuman primates and pork only (Center for Disease Control, 1990; Marsh et al., 2011; Pan et al., 2014; WHO, 1998; WHO, 2009a; WHO, 2009b). Although it is recognized that the first Ebola outbreaks have their origin in Central Africa, the relationship between the localization of these viruses and that of the 2014 epidemic was only due to phylogenetic analyzes, which showed that the virus would have left Central Africa and spread slowly,

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during the last decades (Gire et al., 2014). The 2014 outbreak would be a single transmission from a natural reservoir, followed by human-tohuman transmission during the outbreak (de La Vega et al., 2014). The temporal evolution of Ebola epidemics, all interrelated, begins with the wave of 1975, with three epidemics in the DRC (1975 77), which gives birth to that of 1988, including an epidemic in the DRC, two in Gabon (1994 96), and another in Congo and Gabon (2001 03); then the wave of 1999, with an epidemic in Congo and Gabon (2001 05), and an epidemic in the DRC (2007 08), that of Uganda in 2007 and 2008, and finally that of 2014 in Guinea and Sierra Leone (Adjemian et al., 2011; Baize et al., 2014; Borchert et al., 2011; Heymann et al., 1980; Khan et al., 1999; MakwKaput, 2007; WHO, 2003; WHO, 2004; WHO, 2005; WHO, 2009a; WHO, 2009b; WHO, 2012a; WHO, 2012b; WHO, 2014). Since the beginning of the epidemics, we have witnessed the emergence of multiple variants of Ebola and Marburg viruses, originating from the DRC or Gabon and having evolved in parallel from a common ancestor, which would have been around 1257 years ago (Slenczka, 1999). This evolution seems complex (Li and Chen, 2014; Pourrut et al., 2007). Several factors play a role in the selection or elimination of variants (Leroy et al., 2004). The first phylogenetic tree is constructed in 1990, using the nextgeneration sequencing data. The difference in the clinical expression of the disease between Ebola strains, especially between Zaire and Reston, is unclear. Nevertheless, it is attributed to the existence of mutations in the genes of the Ebola virus. Studies on the EBOV species have revealed that fruit bats may be the reservoir of the virus, but it would not be the primary reservoir (Becquart et al., 2010; Leroy et al., 2005; Olival et al., 2013; Pourrut et al., 2007). Indeed, the genome of the virus would have been detected by polymerase chain reaction (PCR), as well as the presence of anti-EBOV antibodies, in these bats, although no living virus has been isolated from these animals (Suzuki and Gojobori, 1997; Towner et al., 2009).

PATHOLOGY Filoviruses are highly pathogenic and highly contagious viruses. They grow in chiroptera as well as in human and nonhuman primates. The pathology is similar in Ebolaviruses as in Marburgviruses, but with very different severities, due to the variation of 30 40 nucleotide sequences between the two genera and environmental factors (Centers for Disease Control and Prevention, 2005). Reston virus was isolated in the Philippines in 1989 from macaques (Barrette et al., 2009). It is present in China and affects nonhuman primates (Hayes et al., 1992; Jahrling et al., 1990). Although of almost zero lethality in humans, its

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effect on humans was reported in 2009 following its transmission from pork to humans (WHO, 2009a). Ebola and Marburg hemorrhagic fever occurs after an incubation period of 2 21 days (5 10 days, for Marburg virus), with a sudden onset of flu-like symptoms, that is, fever, myalgia, headache, weakness, red eyes, and pharyngitis. Petechiae, coagulopathy, thrombocytopenia, and internal and external hemorrhage are observed later. The patients very often suffer from nausea, vomiting, diarrhea, anorexia, sore throat, abdominal pain, chest pain, cough, and edema (Friedrich et al., 2012; Gasquet-Blanchard, 2014; Gentilini et al., 2012). The patient appears prostrate (Friedrich et al., 2012). A nonpruriginous maculopapular or papulovessicular rash appears 5 7 days later. It is followed by a thin desquamation. Sometimes you can see an enanthem of the soft palate. The simple hemorrhagic signs, present in half of the cases, are conjunctival, digestive, petechiae, and bleeding at the point of bites (for severe forms). The fever remains high in plateau. The severe forms are mental clouding, coma, acute renal failure, cytolytic hepatitis with jaundice, pancreatitis, hemorrhagic syndrome characterized by disseminated intravascular coagulation, and hepatic insufficiency (Kortepeter et al., 2011). These last clinical forms are scarce and always fatal. The pathological abnormalities reported in the case of Ebola and Marburg are identical to those observed in the case of other viral hemorrhagic fevers (Lassa fever, Rift Valley, Crimea Congo). Necrosis is noted in the liver and lymphoid tissues. Hemorrhages are noted in the skin, mucous membranes, and organs. Microscopic observation of biopsy or other products showed the presence of viral particles and intracytoplasmic inclusions in all tissues, particularly hepatocytes, macrophages, endothelial cells, causing damage to the vascular endothelium, and increased vascular permeability causing shock and hemorrhage (Escudero-Pe´rez et al., 2014). The infection of macrophages and endothelial cells plays a role in pathology via the exaggerated secretion of cytokines and mediators of inflammation (Baize et al., 2001; Leroy et al., 2000; Leroy et al., 2001). The glycoprotein of the viral envelope, which in its form attached to the virus allows its attachment and entry into the host cell, has also, in its soluble form, another harmful role, by attaching itself to the membranes of polymorphonuclear neutrophils, inhibiting their activation, which contributes to the inhibition of the host response. This soluble protein can also have a superantigen activity required in the apoptosis of T cells (Baize et al., 1999; Baize et al., 2000; Garcı´a-Dorival et al., 2014; Leroy et al., 2011b; Liang et al., 2014; Luthra et al., 2013). The search for immunological phenomena related to the Ebola virus disease showed that the occurrence of infections with fatal prognosis was due to an aberrant action innate immunity and complete suppression of adaptive immunity (Chan et al., 2000; Morikawa et al., 2007; Takada et al., 2000; Wauquier et al., 2010a; Xu et al., 2014;

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Yang et al., 2006; Yen et al., 2014). All of these factors contribute to the rapid progression of the disease (Anthony and Bradfute, 2015; Baize et al., 1999). Death occurs 5 8 days after the onset of the disease. In asymptomatic patients, the strong and early inflammatory response inhibits viral replication from the beginning. In survivors, convalescence is long and accompanied by arthralgia, orchitis, uveitis, hepatitis, parotitis, and myelitis. Cases of secondary infections occur in the family environment (parents caring for the patient), during funeral ceremonies, or in healthcare settings (health centers, hospitals, traditional therapists, pastors/caregivers, etc.) (Gasquet-Blanchard, 2014; Georges et al., 1999).

PHASES OF PREPARATION AND RESPONSE TO THE EPIDEMIC The frequency and magnitude of Ebolavirus outbreaks have increased in recent times, but preparedness and response measures are limited and need to be reviewed for improvement (Bausch et al., 2007; Hewlett and Amola, 2003; Larkin, 2003; Raabe et al., 2010; Roddy, 2014a). The reasons for the increase in frequencies, according to Uganda’s experience, are variations in the surveillance system, which should be reinforced by the integration of international assistance with the establishment of isolation cells by Me´decins Sans Frontie`res (MSF) in collaboration with the Ministry of Health and the Centers for Disease Control and Prevention (CDC), Atlanta, the communities education that should in case of suspected illness, address first to the hospital rather than to traditional healers; changes in patterns of interaction between humans and natural reservoirs, due to tourism; seasonal variations in seroprevalence in natural reservoirs that may lead to increases in the frequency of zoonoses (Hewlett et al., 2005; Jeffs et al., 2007; Kuhn, 2008; Monath, 1999; Muehlenbein, 2005; Mwavu and Witkowski, 2008). Proposals have been made to overcome these limitations, including the call for rapidly acting teams; the Ministries of Health of the affected countries; WHO; MSF; the CDC, Atlanta; etc. The outbreak response team is made up of frontline health professionals, reinforced by the Ministry of Health of the affected country, WHO, MSF, CDC, and others (Roddy, 2014b; Singhi et al., 2007). Preparedness and response to the epidemic require confirmation of the suspected cases by an accredited laboratory that then reports cases to WHO, which is responsible for reporting the outbreak. In addition, there is a need for laboratories capable of performing the differential diagnosis that would eliminate the suspicion of an Ebola or Marburg hemorrhagic fever, the introduction of rapid tests for the detection of infection and surveillance, seroprevalence in the whole population. The objectives of the response and the

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components include prevention and control of the spread of the disease; ensuring optimal follow-up and treatment for those infected; epidemiological surveillance of new cases; burial and disinfection; risk reduction in families; support for access to healthcare at peripheral level; psychological support; public information and health education campaigns; studies to understand the ecology of fruit bats, the mechanisms of natural infection, and the effects of virus excretion, in order to understand the transmission pathways; comparative studies of the ecology and serology between the zones having known several epidemics and those having known only one episode, in order to know the factors of sensitivity and transmission; the construction of care pavilions for filovirus cases; access to care; case management; psychological care; and control of the infection.

SUPPORT AND SECURITY MEASURES To be able to assess the epidemic risks, the reemergences and even the risks of a pandemic, one must know the history of the viruses (Ebola and Marburg), as well as their evolutionary, mutational, and adaptive capacity in the environment and in the host. For this, studies are needed to understand the ecology of fruit bats, the mechanisms of natural infection, and the effects of virus excretion, in order to understand the transmission pathways. In addition, comparative ecology and serology studies need to be conducted between areas with multiple epidemics and those with only one episode, to determine susceptibility and transmission factors. That should help to understand the role of reservoirs, as well as the mechanisms of emergence and evolution of the disease. It is also important to understand the concepts of carrying wild, farmed, and domestic animals, and how they can become potential vectors of viruses. The security measures in the event of an epidemic are at several levels. Some of these are at laboratory level, at care units level, and family level. At the laboratory level, a safety laboratory 4 (BSL-4 or P4) is required, having the necessary arsenal for handling high-risk pathogens (Caron et al., 2012; Grard et al., 2010; Grard et al., 2011; Polonsky et al., 2014). There are two countries in Africa having such laboratories, including the International Center for Medical Research, located in Franceville, Gabon, in Central Africa (Leroy and Gonzalez, 2012). During an epidemic, with Ebolavirus and in the absence of vaccines and effective treatments, personal protective equipment (PPE) plays an important role in the response (Falzarano et al., 2011). This equipment, consisting of head and face covering masks, body protective clothing, must be accompanied by other measures such as training in good safety practices in the laboratory or in the environment of the

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Ebola treatment units. In addition, one must make sure of the absence of undesirable effects of these equipment on the skin. On the other hand, PPE must be tested under tropical conditions. Patients should be isolated and treated by one person, equipped with protective equipment (Sprecher et al., 2015). Transferring the patient is not advisable unless there is a highly specialized care unit that can effectively care for the patient, as it could be a source of spread of the infection. In most cases, it is advisable to keep the patient on the spot and transfer an isolation cell and a specialized team to the scene. In this case the risk prevention will be focused on transporting the samples to the specialized laboratory. In addition the personal belongings of the patients, the biological products as well as the corpses must be confined and not given to the parents.

TREATMENT AND VACCINE DEVELOPMENTS Even if progress has been done in the field of filoviruses, there is still no approved treatment or vaccine for prevention and management in humans until the recent outbreak of 2014 15, occurred in West Africa where experimental treatments were developed and used to treat health professionals who cared for the sick (Roddy et al., 2011; Stroher and Feldmann, 2006). The treatments of the time were symptomatic and aimed at improving the quality of life of patients (Baize and Deubel, 2003; Sullivan et al., 2000). Rehydration was done in severe cases to fight the infection, to avoid renal dysfunction and shock (Roddy et al., 2011). There have been therapeutic models (Bradfute et al., 2011). The first therapeutic model used was ZMapp, which is a mixture of monoclonal antibodies by the Public Health Agency of Canada, in collaboration with the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) at Defyrus and BioProcessing, and Mapp Biopharmaceutical in Kentucky (Baize and Deubel, 2003; de La vega et al., 2015; Qiu et al., 2014). The second model was the use of a compound MIL-77, includes Favipirir (an inhibitor of the action of RNA-dependent RNA polymerase) and a cocktail of antibiotics similar to those used in ZMapp. The third therapeutic model was the treatment of patients with whole blood or plasma convalescents (Hirschberg et al., 2014; Mupapa et al., 1999; Wong and Kobinger, 2015). The emergence of different Ebola variants taking place due to the pressure of selection that the virus is experiencing causing epidemics and reemergencies and the fact that Ebola virus can be used for bioterrorism purposes has pleaded for the need for an effective vaccine against this virus. Thus, in 1980, a vaccine, made using inactivated virus, produced and tested in guinea pigs and nonhuman primates, demonstrated efficacy in guinea

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pigs and not in nonhuman primates (Fernandez et al., 2010; Geevarghese and Simoes, 2012; Jones et al., 2005; Lupton et al., 1980; Qiu et al., 2014). In 1997 a DNA vaccine, produced by a group of Howard Hughes Medical Institute researchers, from genes encoding Ebola virus surface proteins, inserted into a bacterial plasmid, was intramuscularly injected into guinea pigs and provided protection in these animals 2 4 months after administration. In 2000 two teams from the Vaccine Research Center, the National Institute of Health and the CDC’s Special Pathogens Branch, developed a vaccine made by the combination of DNA and an adenovirus vector in which genes coding for Ebola viral proteins was inserted (Ann Arbor). This vaccine induced cellular and humoral immunity in cynomolgus macaques. In fact, these animals remained asymptomatic for more than 6 months after receiving a high dose of the 1976 Ebola Zaire virus (ZEBOV). This study proved that infection could be prevented in nonhuman primates. In 2003 the same team associated with a laboratory of the USAMRIID of Fort Detrick, Maryland, United States, and improved the vaccination process done in a single dose, which led to produce antibodies and ensure immunization of macaques only 4 weeks later, without detectable viremia. In 2005 results were obtained in nonhuman primates, with both Ebola and Marburg, using a recombinant vaccine (Marzi et al., 2015). In 2007 with the emergence of a new Ebola strain in Bundibugyo, Uganda (BEBOV), came the idea of verifying the crossprotection between strains of virus, whether the vaccine against ZEBOV and Ebola Sudan (SEBOV) strains could protect against infection with the BEBOV strain (Hensley et al., 2010). For this, a team from the National Institute of Allergy and Infectious Diseases has tried the prime-boost strategy that stimulates a cellular and humoral immune response at the same time, thanks to the first place (prime) of DNA vectors containing the genes encoding the envelope proteins of the ZEBOV and SEBOV strains and then proceed to a second immunization (booster or boost dose), using recombinant adenovirus vectors (rAd5), attenuated, expressing the surface proteins of the Ebola virus (de Wit et al., 2015). This process made that cynomolgus macaques, immunized with ZEBOV and SEBOV strains, survived to infection with the BEBOV strain. The prime-boost strategy used in a small group of humans stimulated an immune response, but it remained conditional on confirming full protection against Ebola. Clinical trials were conducted on two candidate vaccines, the Chimpanzee-adenovirus-ZEBOV (ChAd3-ZEBOV) and the recombinant vesicular stomatitis virus-ZEBOV (rVSV-ZEBOV) vaccine, supported by WHO and international partners in United Kingdom, United States, Mali, and Switzerland in 2014 (Henao-Restrepo et al., 2017). The clinical trials of rVSV-ZEBOV vaccine were conducted in the United States, Gabon, Germany, Switzerland, Kenya, and in

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Canada, also in 2014, but it was the rVSV-ZEBOV tested in Guinea that gave 100% efficiency (Henao-Restrepo et al., 2017). Indeed, in 2016 this vaccine was produced by the Canadian Government and tested in Guinea in West Africa in people who have been in contact with patients infected with the Ebola virus and proved effective because no contamination has been registered with these people. People who have been in close or distant contact have been vaccinated using the ring vaccination method used to eradicate smallpox. Children over 6 years have benefited, but the safety of pregnant women remains to be proven. In 2017 a freeze-dried Ebola vaccine produced by the Institute of Bioengineering of the Chinese Academy of Military Biomedical Sciences and CanSino Biotechnology Inc. is approved by the China Administration of Medicines and Food (Zhang, 2017; Marzi and Feldmann, 2014; Pavot, 2016).

CONCLUSION Despite advances in therapeutics and vaccines, there are still some problems. One of them is the viral target (vaccines and drugs directed against a single viral species, among the eight existing and variants), the other problem is the human target (vaccines to be administered to populations at risk, that is to say to those who were exposed to different viral strains, i.e., all health professionals without forgetting the researchers and the military). On the other hand, there is the lack of competent staff who can conduct vaccine research and highly secure laboratories (laboratory type P4). Ecologists are aiming to know the migratory movements of the reservoir, as well as the cycle of viral multiplication in these animals.

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Further Reading Adams, M.J., Lefkowitz, E.J., King, A.M., Carstens, E.B., 2014. Ratification vote on taxonomic proposals to the International Committee on Taxonomy of Viruses (2014). Arch. Virol. 159, 2831 2841. Albarin˜o, C.G., Shoemaker, T., Khristova, M.L., Wamala, J.F., Muyembe, J.J., et al., 2013. Genomic analysis of filoviruses associated with four viral hemorrhagic fever outbreaks in Uganda and the Democratic Republic of the Congo in 2012. Virology 442, 97 100. Arie, S., 2014. Trial of Ebola virus vaccine is due to start next week. BMJ 349, g5562. Ebihara, H., Takada, A., Kobasa, D., Jones, S., Neumann, G., et al., 2006. Molecular determinants of Ebola virus virulence in mice. PLoS Pathog. 2, 0705 0711. Klink, S., 2010. One Ebola Virus Vaccine Offers Protection for Three Viral Species. Promega Connections. Available from: ,promega.wordpress.com/2010/06/02/oneebola-virus-vaccine-for-three-species/.. Leroy, E.M., Nkoghe, D., Ollomo, B., Nze-Nkogue, C., Becquart, P., Grard, G., et al., 2009b. Concurrent chikungunya and dengue virus infections during simultaneous outbreaks, Gabon, 2007. Emerg. Infect. Dis. 15, 591 593. Wauquier, N., Padilla, C., Becquart, P., Leroy, E., Vieillard, V., 2010b. Association of KIR2DS1 and KIR2DS3 with fatal outcome in Ebola virus infection. Immunogenetics 62, 767 771. Wauquier, N., Becquart, P., Nkoghe, D., Padilla, C., Ndjoyi-Mbiguino, A., Leroy, E.M., 2011. The acute phase of chikungunya virus infection in humans is associated with strong innate immunity and T CD8 cell activation. J. Infect. Dis. 204, 115 123.

EMERGING AND REEMERGING VIRAL PATHOGENS