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Ebola - the deadly filamentous virus which continues to plague Africa
Emily Maghen1, Dyjhana Ali1, Kotryna Lucinskaité1, Tom Galazkowski1
Although relatively rare, the Ebola virus disease (EVD), is an extremely deadly filamentous virus, with an average mortality rate of 50%, responsible for thousands of deaths in Africa . Since the discovery of EVD in 1976, with the outbreaks occurring in southern Sudan and Zaire, six species of Ebola virus have been identified, although the Zaire species has been responsible for the most human mortality and infection (Figure 1). Hereinafter when referring to the Ebola virus, we will be referring to the Zaire species. In 2014, the Ebola virus re-appeared in West Africa, resulting in an epidemic in Liberia, Guinea, and Sierra Leone that would last two years and kill 11,325 people . The fear that this deadly virus could potentially spread across borders and continents, drew huge local and international efforts to contain the virus, but not before the virus had left lasting impacts. Between 2014-2016, the Ebola virus epidemic claimed the lives of 8% of healthcare workers in Liberia, 7% in Sierra Leone, and 1% in Guinea, leaving a lasting impact on healthcare systems in those countries . Many factors contributed to the rapid spread of EVD during the 2014-2016 epidemic, including poverty and conflict, poor initial domestic and international government response, and cultural and individual risk behaviours.
Figure 1. Transmission electron micrograph of Zaire ebolavirus viron. Credit: “Ebola virus” by Centers for Disease Control (CDC) Global Health, marked under CC 2.0. To view terms, visit: https://creativecommons.org/licenses/by/2.0/
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Classification of ebolaviruses
Along with marburgviruses, the genus Ebolavirus belongs to the family Filoviridae, in the order Mononegavirales. Also pathogenic to humans, marbugviruses are a close relative of ebolaviruses, which likely diverged from each other several thousand years ago. Six species of ebolaviruses have been identified so far, likely diverging from each other within the last 1000 years. Although, only four species of ebolavirus:
Figure 2. Figure 2. Classification of the order Mononegavirales including the genus Ebolavirus.
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Filoviruses such as EBOV are enveloped and contain one molecule of single-stranded, non-segmented, negative-sense RNA, approximately 19 kilobases in length. The EBOV genome codes for seven structural proteins in the order: NP, VP35, VP40, GP, VP30, VP24, and L (RNA-dependent RNA polymerase) . NP oligomerizes into a helical nucleocapsid to encapsidate the viral genome, which then protects it from nucleases and the cellular innate immune response [5, 6]. Some other structural proteins implicated in this protective function include VP35, VP30, VP24, and L. VP35 plays a critical role in viral RNA synthesis and immune evasion by suppressing innate immune signalling [7-9]. VP35 also acts as a polymerase cofactor in RNA polymerase transcription and replication complexes . VP40 is a major matrix protein that plays a leading role in regulating viral morphogenesis, transcription, packaging, and budding at the plasma membrane of infected cells, as well as preparing the host cell for final encapsulation . GP is a surface glycoprotein, fundamental in the EBOV life cycle, as the principal driver of attachment, fusion, and entry into target cells . GP downregulates the expression of multiple host cell surface molecules important for immune surveillance and cell adhesion . GP also functions as a decoy for anti-GP1,2 antibodies thereby contributing to viral immune evasion . RNA binding of VP30 is crucial due to the transcriptional support provided as well as the stabilization of the VP35/L polymerase complexes . VP24, while considered a minor matrix protein, has been proven to display inhibition of transcription and replication of the EBOV genome . This suggests that VP24 and VP40 are especially relevant for the conversion of the EBOV genome into a helical nucleocapsid primed for viral assembly .
Knowledge of the pathogenesis of EBOV is finite as Biosafety level 4 (BSL-4) laboratories are required to conduct experimental studies, as well as the inaccessibility of the geographic regions where the vast majority of infections materialize.
EBOV is known to enter the human body through mucosal surfaces, parenterally, and via injuries or abrasions to the skin . EBOV exhibits extensive cell tropism, though macrophages, dendritic cells, and monocytes appear to be the early and preferred replication sites in non-human primate models . Lymphocytes are spared from infection, however, their destruction by apoptosis cannot be understated as a hallmark feature of EBOV infection . An analysis of human peripheral blood samples from the 2000 EBOV outbreak in Sudan revealed a substantial decrease in T lymphocytes in those with the fatal disease while an unremarkable change in cell count was observed in survivors . This may suggest a correlation between mortality and reduced T lymphocyte count. It has been shown that filovirus pathogenicity at the cellular level is reliant on functional lipid rafts, through receptor-mediated endocytosis and macropinocytosis, which have been proposed mechanisms of virus entry into target cells [20-23]. Entry into the host cell is orchestrated by viral spike GP which facilitates the docking of viral particles onto the cell surface . Infected monocytes, macrophages, and dendritic cells disseminate to regional lymph nodes, the liver, and spleen via blood, and then to other tissues .
Reservoir and transmission
Although the exact reservoir remains unknown, bats have long been suspected as the most likely natural reservoir of the Ebola virus [25, 26]. In 2005, the wild reservoir for the Ebola virus was discovered in Gabon and the Republic of Congo. After testing 1,030 animals near carcasses of infected gorillas and chimpanzees in the region, three fruit bat species tested positive for IgG specific for the Zaire ebolavirus and ZEBOV RNA:
Infected bats can transmit the Ebola virus to other species including antelopes and non-human primates, which can then go on to infect humans. Great apes and fruit bats share fruit resources, and when the fruit is scarce (i.e. during dry seasons), animals are more likely to compete and come in close contact with each other [18, 20]. Zoonotic transmission from bats to humans may be the result of close contact in living spaces, and the consumption of bushmeat (i.e. E. helvum - the most popular hunted species in West and Central Africa) [26, 28] (Figure 3).
Figure 3. African fruit bats have long been suspected as the most likely natural reservoir of Ebola. E. helvum is especially popular among hunters in West African countries where Ebola is present. Credit: "Eidolon helvum" by Martin Grimm, marked by CC BY-NC-SA 2.0. To view terms visit: https://creativecommons.org/licenses/by-nc-sa/2.0/
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Decreased fish catch due to overfishing by international fishing fleets, and reduced soil fertility may have left West-African communities turning to hunting and consuming bushmeat, increasing the risk of zoonotic transmission . Meanwhile, in Democratic Republic of the Congo (DRC), exploitation of forests, illegal military assembly, and displacement of people due to war may have also increased the risk of zoonotic transmission, by forcing communities to live closer to wildlife . Although consumption of bushmeat greatly increases the risk of zoonotic transmission of the Ebola virus, once zoonotic spillover has occurred, epidemics of the Ebola virus are driven largely by human to human transmission. Healthcare workers, friends, and family members in close contact with infected individuals are at the greatest risk of contracting the Ebola virus .
In humans, a high risk of transmission is associated with contact with bodily fluids, including mucosal exposure to bodily fluids, laboratory specimens or tissue, and percutaneous injury (i.e. needles). Ebola virus is also known to survive on dry surfaces for several hours, and body fluids for several days .
There has been no evidence of airborne transmission of the Ebola virus between humans and animals, or communication by mosquitoes or other insects [32, 33]. Unlike humans and non-human primates, evidence of airborne transmission from pigs to primates has been observed [32, 33].
The persistence of Ebola virus RNA in the semen of male survivors has been well documented by both anecdotal evidence as well as several studies [34-36]. Between 2015-2016, the semen samples of 220 male survivors of EBOV in Sierra Leone were tested for EBOV RNA using quantitative reverse transcription PCR (qRT-PCR) . Testing was performed every two weeks, with two consecutive qRT-PCR tests negative for EBOV RNA indicating the endpoint . The EBOV RNA semen positive rate was 75.4% six months after the men were discharged from the Ebola treatment unit, and 50% after 204 days . Older age (>35 years) and severity of the illness, both increased the likelihood of semen positive for EBOV RNA after 1 year . The risk of transmission through semen is a significant risk of recurrent outbreaks of EVD, as seen in the 2018-2020 outbreak in the DRC (see Current outbreaks section) .
On average, the incubation period of the Ebola virus is between 8-10 days, during which individuals are asymptomatic and unable to transmit the virus [38, 39]. Initial symptoms are non-specific, mimicking many other tropical illnesses prevalent in the region, including influenza, malaria, typhoid fever, yellow fever, and other hemorrhagic fevers . After the incubation period, “dry symptoms” (i.e. fever, headache, fatigue, myalgia, and joint pain) present, followed by “wet symptoms” (i.e. vomiting, and diarrhoea) [38, 40, 41]. In the acute phase, patients may present with a fever unresponsive to anti-malarial drugs or antibiotics . Hemorrhagic symptoms are seen in approximately half of the patients in the late stage of EVD and can include epistaxis, gingival bleeding, melena, and haematemesis . Other late-stage symptoms include skin manifestations (i.e. petechiae and purpura), dyspnoea, cough and hiccups, conjunctivitis, dysphagia, jaundice, and hypovolaemic shock [40, 41]. Critically ill patients typically die 7-10 days after illness onset and present with multi-system organ failure and altered mental status [39, 42].
Management of the illness commonly involves the administration of intravenous fluids to combat dehydration and hypovolaemia as well as oxygen support. A blood transfusion using the blood of an Ebola survivor may also be implemented in some instances .
History of Ebola virus, cultural responses and viral deviations
The exact date that Ebola emerged is subject to debate, based on the classification of presented symptoms. However, it is commonly accepted that the idiopathic hemorrhagic fever-based disease first presented itself in emerging cases at the Yambuku Mission Hospital , Democratic Republic of Congo, in August 1976 . The name Ebola was taken from the Ebola river near the village in which this initial outbreak occurred. Its rapid and uncontrollable spread led to the infection of over 300 people with an 88% mortality rate and the requirement of international aid . First responders, who had been unable to identify the virus, were able to exclude other known and common diseases such as typhoid, malaria, and yellow fever . The unknown cause led to the virus being spread through shared hospital equipment and further by cultural differences which would later prohibit the correct removal and disposal of the infected dead.
It became apparent that cultural traditions play a significant role in the understanding, treatment, and recovery from Ebola outbreaks. The West African countries plagued by Ebola are also deeply entrenched in spirituality and mysticism. This led to a mistrust of modern medicine and treatments and hindered the creation of biohazardous burial sectors. Some of the afflicted cultures were ruled by the mystic belief of Yat end Gemo. Spirits that would either prevent or cause illness in individuals . Due to these kinds of beliefs, many of the afflicted individuals believed that Gemo, which can be passed by proximity, was affected due to disrespect for the Jak of Tura. A disrespect that was encouraged and exacerbated by foreigners and their western medicines.
Despite this known distrust of the medics who were sent to deal with the growing epidemic, the WHO failed to correctly address the situation. Memos put out on the dealing of Ebola across different countries lacked the cultural awareness and conscientiousness to effectively convince older, traditional tribes and people to accept international aid.
The emergence of different Ebola strains throughout recent decades with varying degrees of fatality and transmission was deeply considered by the WHO when developing aid and containment strategies. The first such strain was the Zaire ebolavirus (ZEBOV) that appeared in 1976, in the Democratic Republic of Congo (formerly the Republic of Zaire) . The ZEBOV has continued to be the most prevalent and deadly of all the known Ebola virus strains, responsible for the 2014-2016 epidemic, and a fatality rate as high as 90% (Table 1) .
Table 1. Cases and outbreaks of Ebolavirus outside of Africa. Based on data from the CDC .
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The Sudan ebolavirus (SUDV) emerged at approximately the same time, possibly earlier than ZEBOV, however, less deadly and less common . Although the SUDV was responsible for many deaths in the years following its discovery, the prevalence of SUBV has significantly declined between 1976—2004 (Table 1) . The SUDV has been proven to have both human-to-human and non-human infective properties. Despite this fact and SUDV being classed as a risk group 5 level pathogen, outbreaks of this species have remained relatively well contained in the Northeastern African region . These two strains of Ebola set the course of treatment and understanding of the virus for the following decades .
The Reston ebolavirus (RESTV), the first Ebola strain to have originated outside Africa, emerged in Reston, Virginia USA, in 1989 . RESTV is considered a more zoonotic version of the virus and has been studied since its emergence. Outbreaks of RESTV in animals have been widespread, with cases documented in Pennsylvania, Texas, Siena (Italy), and the Philippines (Table 1) . The RESTV was first documented in cynomolgus monkeys which had been transported to the United States from the Philippines in 1989 (Table 1). During this period RESTV was also linked to another hemorrhagic fever, Simian hemorrhagic fever, that only affected non-human primates . Although humans are asymptomatic when infected with RESTV, the immune response is enough to elicit immunoglobulins and natural immunity to the virus. The RESTV ability to be contained only to animals has yet to be fully explained but continues to have low pathogenicity in humans.
Some 18 years after the initial emergency of ZEBOV, another deadly strain of ebolavirus was documented in two chimpanzees in the Tai forest of Cote d'Ivoire in 1994. The species was named Tai forest ebolavirus (TAFV) based on the place of origin . The infected presented with no changes to the shapes of the organs or any noticeable physical changes. The TAFV also presented with stagnant deoxygenated blood in the heart as well as blood-filled lungs. This strain has primarily been recorded in western chimpanzees and has not been linked to any major outbreaks. The zoonotic transmission was noted after post-mortem studies of the chimpanzees when a scientist presented with dengue fever-like symptoms. It should be noted that although this strain has been identified, there is little information available on the reservoir, thus the suspicion remains linked to fruit bats native to the Taï forest .
The Bundibugyo ebolavirus (BDBV), first emerged in 2007 with a 34% mortality rate . The BDBV named after the Bundibugyo District of Uganda is considered the third most deadly strain of Ebola after ZEBOV and SUDV, however, BDBV has not been linked to any current outbreaks (Table 1). Outbreaks of BDBV have remained localized to different African provinces and countries including, the Democratic Republic of Congo . Research into BDBVs emergence and pathological differences is ongoing.
The final and most recent discovery of Ebola species is the Bombali ebolavirus (BOMV). First identified in 2018, in the samples of free-tailed bats (M. condylurus and C. pumilus) in Sierra Leone, BOMV has recently also been identified in the free-tailed bats of Kenya and Guinea [55-57]. Although there is no indication the BOMV causes illness in humans, monitoring to ensure spillover events onto humans do not occur continues .
International responses to the 2014-2016 epidemic
The outbreak of the Ebola Virus Disease has had disastrous consequences which can be attributed to a lack of competence and insufficient leadership . After the outbreak began in Guinea in late 2013, 1 711 cases and 932 deaths had been confirmed when the World Health Organization claimed that "This is currently the largest EVD outbreak ever recorded" and that the conditions for a Public Health Emergency of International Concern (PHEIC) have been met . It took 17 months after the PHEIC declaration to lift the designation, after 28 616 cases and 11 310 deaths were registered in Guinea, Sierra Leone, and Liberia. The WHO has acknowledged the criticism that their initial response to the Ebola outbreak was slow and did not provide a sufficient warning to the world on the severity of the virus. The WHO also admitted that there was confusion in the roles and responsibilities between the levels of the Organization . Similarly, other organizations have also failed to cooperate adequately to combat the epidemic, including organizations such as the Africa Centres for Disease Control and Prevention (Africa CDC), Coalition for Epidemic Preparedness Innovations (CEPI), and the European Medical Corps (EMC) .
Other factors which may have slowed the response to the 2014-2016 Ebola epidemic, as well as increased transmission include:
Poverty and conflict
Before the 2014 epidemic, years of civil war had left Guinea, Liberia, and Sierra Leone with large populations of displaced people uneducated and without work. Transportation, telecommunication networks, and public health infrastructure declined to levels that were already some of the lowest in the world. An important consequence of conflict and political instability is the low trust by communities in government and public health authorities, making it increasingly difficult to track and contain outbreaks. In addition, poverty has led to nomadic populations due to people constantly seeking food and work abroad, contributing to the spread of the virus [62, 63].
Disparity existing within countries has also had an impact on the infection rates in affected West African countries. Poorer counties of Liberia were found to have higher rates of infection and spread compared to less-poor counties in the country. The spread of infection may be attributed to dense housing conditions and increased distances to health care centres. Both these factors increase the chance infected individuals will come in contact with others and spread the virus. Conversely, densely packed communities may help prevent future outbreaks, due to close social networks which can aid health authorities in contact tracing .
It is not hard to see why some people would be wary of trusting government officials. Foreign aid sent to Liberia during the 2014 epidemic was used to strengthen military forces, and the rebuilding of healthcare infrastructure was largely overlooked. Unsurprisingly, this weakened Liberia's response to combat the EVD epidemic outbreak. As an example, The United States sent 3,000 people to construct 17 Emergency Trauma Centres (ETCs) in Liberia, but the facilities could not be fully utilized due to healthcare labour shortages, decreasing the healthcare worker to patient ratio, leading to the overcrowding of Ebola Treatment Centres (ETCs). Mistrust in government efforts to combat the outbreak resulted in people hiding themselves and their ill family members at home, believing that they could provide better care than the public facilities .
Another big consequence of governmental mistrust in Liberia was the looting of a clinic in 2014. Believing that Ebola was made up by the government, the looters forcefully made infected patients flee, stole infected bed sheets, and rioted the clinic . Several other attacks have taken place in West Africa, including the killing of a WHO Ebola responders, due to the fear and ignorance of the Ebola virus . Some believe that Ebola was being used as propaganda for the government to steal money, control the population or collect human organs [62, 63].
Cultural and behavioral factors
Traditional burial practices have been implicated as one of the most significant factors leading to the high rates of EVD transmission. As of August 2014, 60% and 80% of new infections were linked to unsafe funeral practices, in Guinea and Sierra Leone respectively. The virus can survive in a deceased person and infected sheets for several days. Aside from preparations of the body, during which people come in close contact with the infected person through washing and clothing the body, high rates of transmission can also be attributed to the gathering of friends of family members of the deceased and travelling to the funeral .
The need for traditional burials has led to numerous highly infectious and unregulated zones, which increased the number of under-recorded EVD cases . Traditional burials have strong cultural, religious, and spiritual importance to many affected communities, which was recognized by the WHO when implementing burial teams to ensure safe burials (Figure 4) . It is worth mentioning that alerting a burial team, after the death of a community member can only be useful if the call is answered urgently. If deceased persons are left out in the community waiting several days for safe burial, loved ones would be more inclined to perform a dignified burial themselves, with an increased risk of infection .
Treatment / novel therapies
As of May 2021, Inmazeb (REGN-EB3) is the only FDA-approved treatment for ZEBOV. Inmazeb can be effective in the treatment of both adults and children and is administered by a single IV injection consisting of 50 mg of each IgG1 monoclonal antibodies: atoltivimab (REGN3470), maftivimab (REGN3489), and odesivimab (REGN3471). This antibody cocktail neutralizes the Ebola virus by binding to surface glycoproteins and inhibiting attachment and entry into host cells.
These cells then induce other immune cells to target infected cells to clear them from the body . Results of a 2018, randomized controlled trial conducted in the DRC testing the efficacy of four different EVD therapies, found Inmazeb to have the most significant effect on patient mortality during 28 days .
The Ervebo (rVSV-ZEBOV) vaccine is the first and only Ebola vaccine that has been approved by the FDA. The Ervebo vaccine, which protects against the ZEBOV, is a live attenuated vesicular stomatitis virus (VSV) that has been genetically altered to express ZEBOV glycoproteins .
In the United States, the vaccine is recommended to individuals above 18 years, at the highest risk of exposure to the ZEBOV, including those responding to EVD outbreaks, healthcare workers in Ebola treatment centres in the US, and staff working in level 4 laboratory facilities in the United States .
In regions affected by ZEBOV outbreaks, the Ervebo vaccine has been implemented using the "ring vaccination" approach. Aside from healthcare workers, ring vaccination focuses on the vaccination of individuals who have been in contact with EVD patients, as well as individuals who have been in contact with them (i.e. contacts of contacts). Once all contacts are offered a vaccine the ring is closed. Even though approximately 16,000 individuals in Guinea and 300,000 in eastern DRC have been vaccinated using this method, other vaccination strategies may prove more efficient. For example, in the recent outbreak in the DRC, many new cases were not identified as contacts, which may have led to the spread of the virus. Bausch argues other strategies may be worth implementing including vaccinating the sex partners of male survivors, and vaccination campaigns during outbreaks . Additionally, vaccination of populations after an outbreak is over may prevent subsequent zoonotic transmission of the virus which persists in the local animal reservoir [71, 72].
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Figure 4. Members of a burial team in Margibi County Liberia are sprayed with disinfectant (chlorine) after a safe burial. Many international organizations provided safe burials for Ebola victims during the 2014-2016 epidemic in West Africa. Credit: "Chlorine spraying" by USAID_IMAGES, marked by CC BY-NC 2.0. To view terms visit: https://creativecommons.org/licenses/by-nc/2.0/
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At the start of 2021, UNICEF, the WHO, IFRC, and MSF announced the establishment of a global Ebola vaccine stockpile, to ensure populations in regions at risk of outbreaks have access to vaccines .
Response to Ebola virus vs. other epidemics
The Ebola epidemic, unlike many epidemics before it, changed and shaped international responses to medical emergencies. By forcing changes in reaction times, the way Ebola has been dealt with through its multiple re-emergences can be attributed to how the world health bodies have dealt with the novel SAR-CoronaVirus-2. Continents and countries that had previously been segregated by health standards, created and adhere to centralized health organizations such as Africa Centres for Disease Control and Prevention. This body’s quicker response times and creation of standardized guidelines have helped lesser developed towns and villages with the current SARS-CoV-2 pandemic, however, it has also further highlighted the aberrant standards to which healthcare is administered [74, 75].
A deeper understanding from a cultural perspective is still greatly required to successfully stem viral disease transmissions as well as encourage local compliance. Although this was seen and is still seen, in recent Ebola outbreaks, very little is being done to encourage the inclusion of elder leaders and locals in decisions that directly impact communities. This lack of inclusion has continued to encourage the widespread mismanagement of the disease. Studies performed on the outbreaks before the SARS-CoV-2 Pandemic have used a unique classification method to further explain how and why Ebola has continued to thrive [74, 75]:
Lesser developed countries have depended heavily on the international support for COVID19, which had been previously lacking in the Ebola epidemic. However, international organizational bodies such as the Africa Centre of disease control were absent during 2014, which made dealing with the EVD epidemic less efficient . The large distrust of foreign aid continues to plague certain groups and tribes making it an impossibility to combine cultural considerations with medically sound preventive guidelines. Paired with the socio-economic divide, which has been seen correlating between the effectiveness of aid and outbreaks, has left much to be desired in terms of rectifying the way Ebola is dealt with [74,75].
However, it should be noted that Ebola prepared African countries to promote better sanitary conditions but also highlighted the flaw in this treatment method when considering the lower developed areas and the access to clean and safe water. Countries continued to drown under the weight of lacking resources while fighting multiple epidemics on a home front. This has led to gross mistrust, miscommunication, and ultimately an extremely high mortality rate.
Outbreaks since 2014-2016 epidemic
Democratic Republic of the Congo outbreaks
In the spring of 2017, a hunter in the Likati health zone of Bas Uélé province of the DRC brought the carcass of a wild boar and a live non-human primate back to his town after hunting. An outbreak was declared in May of 2017, likely due to a single spillover event, speculated to have arisen from this incident. Limited human-to-human contact occurred although the outbreak resulted in 8 probable cases (5 laboratory-confirmed), and deaths. The WHO declared the outbreak over in July of the same year [76, 77].
In May 2018 the WHO reported an outbreak in the Équateur province of the DRC, resulting in 54 cases (38 laboratory-confirmed), and 33 deaths. The outbreak was suspected to have started the month before after the unsafe burial of a man suspected of having EVD, with seven of the funeral attendants dying shortly after. The response to contain the outbreak was rapid, with contact-tracing individuals through three mobile laboratories to each affected area (Bikoro, Iboko, and Wangata health zones), and the administration of the, then, experimental rVSV-ZEBOV vaccine, which was administered to 3,481 people for the first time. The outbreak was declared over in July of the same year [78, 79].
Not one month after the EVD outbreak was declared over in July 2018, a new outbreak in the North Kivu province of the DRC arrived. Between August 2018 and June 2020, this outbreak became the largest since the 2014-2016 epidemic, and the second-largest outbreak recorded in history.
The first cases at the beginning of August are speculated to have arisen after the burial of a 65-year-old woman in the town of Mangina on July 25, followed by the death of seven close family members. There were 3,313 confirmed cases with 2,266 deaths in the DRC and 4 recorded cases with 4 deaths in neighbouring Uganda. Containing cases in this part of the country proved much more challenging with approximately 100 armed militias operating the area, and over one million internally displaced people and refugees living along the border with Uganda. Contact tracing was very difficult in conflict zones. Violent attacks by armed groups on Ebola treatment centres resulted in the deaths of both healthcare workers and civilians. Poverty and conflict may have severely undermined government attempts at containing the EVD outbreak, with 25% of individuals in the towns of Beni and Butembo believing that EVD is a hoax. Ring-vaccination programs with the rVSV-ZEBOV vaccine continued, reaching over 300,000 people by the time the outbreak was over [80-82].
Since the end of the North Kivu province epidemic, there have been smaller outbreaks in the Equateur province of the DRC, resulting in 130 cases with 55 deaths, and the ring-vaccination of 2,500 more people from June to November 2020. The outbreak was likely caused by a persistent infection in a survivor of the 2018-2020 epidemic, that either relapsed or spread by sexual transmission .
Another outbreak in North Kivu province from February to May 2021, resulted in an additional 11 confirmed cases and 6 deaths, and the vaccination of 2,000 people, including 500 health care workers .
2021 Guinea, N'Zérékoré outbreak
The current outbreak in Guinea has likely spread from a persistent infection from the 2014-2016 epidemic in the region. On February 14, 2021, a group of cases in the town of Gouécké, in the Nzérékoré Region of Guinea were reported to the WHO by the ministry of health of Guinea. A 51-year-old nurse presented to a health care center with symptoms of EVD but was diagnosed with Typhoid, a few days later she went to a second health practitioner and was diagnosed with malaria. She died five days after her second visit to a health centre. The cases occurred in family members after the unsafe burial of the nurse, after which several attendants showed symptoms of EVD. As of June 1st, 2021, there have been 16 confirmed EVD cases in Guinea, including 5 deaths. Since February 2021, 10,873 people have been vaccinated, including 2,889 healthcare workers, and as of June 7th, 2021, Guinea is 19 days from declaring the end of the EVD outbreak [83, 85, 86].
Please observe Figure 5 for the number of deaths due to Ebolavirus since the discovery of the pathogen.
Figure 5. Deaths from outbreaks of Ebolavirus worldwide since the discovery of the virus in 1976. Zaire ebolavirus—red, Sudan ebolavirus—orange, Bundibugyo ebolavirus—green. Based on data from the CDC .
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The history of outbreaks since the 2014-2016 epidemic suggests that EVD is still a significant threat to people living in Africa, especially central and west regions. The persistence of the virus in survivors, such as the semen in male survivors, can be a significant factor leading to new outbreaks in these communities. Outbreaks due to unsafe burials and scepticism around the legitimacy of EVD due to years of government mistrust, suggests public health measures to educate community members may need improvement.
Although several measures, such as contact tracing and ring-vaccination have proved to contain recent outbreaks to a certain extent, different strategies may need to be implemented to reduce outbreaks, to begin with. Although Ebola is relatively rare and individual risk is low, in comparison to other illnesses (i.e. COVID-19), mortality is much greater and risk management strategies should continue to evaluate what vaccine implementation is best to prevent future infections.
Additionally, these methods are incredibly labour-intensive and are increasingly hard to implement in conflict zones, where security is very low, and people are constantly becoming displaced. Food insecurity and poverty are additional factors that are bringing people into the habitats of species harbouring the illness, making zoonotic transmission a large threat. Monitoring programs of these species should continue to predict and prevent future outbreaks of Ebola.
Despite this, strides have been made in the scientific field to minimize the impact of the virus. Additional steps by the WHO and other health-related governing bodies have continued to attempt to bridge the gap between culture and medicine in the hopes of creating a better understanding of EBV. The creation and distribution of the vaccine must continue to be stressed in Western Africa, or other high-risk countries, to lower the mortality rates. Furthermore, it is up to the international community to promote safety standards that can further prevent future outbreaks and stem the spread of current ones.
 World Health Organization. Ebola virus disease, 23 February 2021. Access valid on 25 March 2021: https://www.who.int/news-room/fact-sheets/detail/ebola-virus-disease
 Centers for Disease Control and Prevention. Cost of the Ebola Epidemic, 8 March 2019. Access valid on 16 March 2021: https://www.cdc.gov/vhf/ebola/history/2014-2016-outbreak/cost-of-ebola.html
 Kaner J, Schaack S. Understanding Ebola: the 2014 epidemic. Global Health 2016; 12:53.
 Ncbi.nlm.nih.gov, 14 December 2014. Zaire ebolavirus isolate H.sapiens-wt/GIN/2014/Makona-Kissidougou-C15, - Nucleotide - NCBI. Access valid on 27 March 2021.
 Kirchdoerfer RN, Abelson DM, Li S, Wood MR, Saphire EO. Assembly of the Ebola virus nucleoprotein from a chaperoned VP35 complex. Cell reports 2015; 12:140-9.
 Sugita Y, Matsunami H, Kawaoka Y, Noda T, Wolf M. Cryo-EM structure of the Ebola virus nucleoprotein–RNA complex at 3.6 Å resolution. Nature 2018; 563:137-40.
 Becker S, Rinne C, Hofsäss U, Klenk HD, Mühlberger E. Interactions of Marburg virus nucleocapsid proteins. Virology 1998; 249:406-17.
 Muhlberger E, Weik M, Volchkov VE, Klenk HD, Becker S. Comparison of the transcription and replication strategies of Marburg virus and Ebola virus by using artificial replication systems. J Virol 1999; 73:2333-42.
 Basler CF, Wang X, Mühlberger E, Volchkov V, Paragas J, Klenk HD, García-Sastre A, Palese P. The Ebola virus VP35 protein functions as a type I IFN antagonist. Proc Nat Acad Sciences 2000; 97:12289-94.
 Johnson RF, Bell P, Harty RN. Effect of Ebola virus proteins GP, NP and VP35 on VP40 VLP morphology. Virol J 2006; 3:1-7.
 Lee JE, Saphire EO. Ebolavirus glycoprotein structure and mechanism of entry. Future virology 2009; 4:621-35.
 Simmons G, Wool-Lewis RJ, Baribaud F, Netter RC, Bates P. Ebola virus glycoproteins induce global surface protein down-modulation and loss of cell adherence. J Virol 2002; 76:2518-28.
 Audet J, Kobinger GP. Immune evasion in ebolavirus infections. Viral immunology 2015; 28:10-8.
 Biedenkopf N, Schlereth J, Grünweller A, Becker S, Hartmann RK. RNA binding of Ebola virus VP30 is essential for activating viral transcription. J Virol 2016; 90:7481-96.
 Watanabe S, Noda T, Halfmann P, Jasenosky L, Kawaoka Y. Ebola virus (EBOV) VP24 inhibits transcription and replication of the EBOV genome. J Infect Dis 2007;196: S284-90.
 Hoenen T, Biedenkopf N, Zielecki F, Jung S, Groseth A, Feldmann H, Becker S. Oligomerization of Ebola virus VP40 is essential for particle morphogenesis and regulation of viral transcription. J Virol 2010; 84:7053-63.
 Feldmann H, Geisbert TW. Ebola haemorrhagic fever. The Lancet 2011; 377:849-62.
 Geisbert TW, Young HA, Jahrling PB, Davis KJ, Larsen T, Kagan E, Hensley LE. Pathogenesis of Ebola hemorrhagic fever in primate models: evidence that hemorrhage is not a direct effect of virus-induced cytolysis of endothelial cells. Amer J Pathol 2003; 163:2371-82.
 Sanchez A, Lukwiya M, Bausch D, Mahanty S, Sanchez AJ, Wagoner KD, Rollin PE. Analysis of human peripheral blood samples from fatal and nonfatal cases of Ebola (Sudan) hemorrhagic fever: cellular responses, virus load, and nitric oxide levels. J Virol 2004; 78:10370-7.
 Bavari S, Bosio CM, Wiegand E, Ruthel G, Will AB, Geisbert TW, Hevey M, Schmaljohn C, Schmaljohn A, Aman MJ. Lipid raft microdomains: a gateway for compartmentalized trafficking of Ebola and Marburg viruses. J Exp Med 2002; 195:593-602.
 Sanchez A. Analysis of filovirus entry into vero e6 cells, using inhibitors of endocytosis, endosomal acidification, structural integrity, and cathepsin (B and L) activity. J Infect Dis 2007;196: S251-8.
  Nanbo A, Imai M, Watanabe S, Noda T, Takahashi K, Neumann G, Halfmann P, Kawaoka Y. Ebolavirus is internalized into host cells via macropinocytosis in a viral glycoprotein-dependent manner. PLoS Pathog 2010; 23;6:e1001121.
 Saeed MF, Kolokoltsov AA, Albrecht T, Davey RA. Cellular entry of ebola virus involves uptake by a macropinocytosis-like mechanism and subsequent trafficking through early and late endosomes. PLoS Pathol 2010; 6:e1001110.
 Miller EH, Obernosterer G, Raaben M, Herbert AS, Deffieu MS, Krishnan A, Ndungo E, Sandesara RG, Carette JE, Kuehne AI, Ruthel G. Ebola virus entry requires the host‐programmed recognition of an intracellular receptor. EMBO J 2012; 3:1947-60.
 Monath TP. Ecology of Marburg and Ebola Viruses: Speculations and Directions for Future Research. J Infect Dis 1999; 179: S127–38.
 Leroy EM, Kumulungui B, Pourrut X, Rouquet P, Hassanin A, Yaba P, Délicat A, Paweska JT, Gonzalez JP, Swanepoel R. Fruit bats as reservoirs of Ebola virus. Nature 2005; 438:575-6.
 Koch LK, Cunze S, Kochmann J, Klimpel S. Bats as putative Zaire ebolavirus reservoir hosts and their habitat suitability in Africa. Scientific reports 2020; 10:1-9.
 Olival KJ, Hayman DT. Filoviruses in bats: current knowledge and future directions. Viruses 2014; 6:1759-88.
 Omoleke SA, Mohammed I, Saidu Y. Ebola viral disease in West Africa: a threat to global health, economy and political stability. J Pub Health Africa 2016; 7.
 Ditekemena J. COVID-19 amidst Ebola's retreat. Science 2020; 6490:445.
 Centers for Disease Control and Prevention. Ebola (Ebola Virus Diseases): Transmission, 14 January 2021. Access valid on 16 March 2021: https://www.cdc.gov/vhf/ebola/transmission/index.html
 Gebretadik FA, Seifu MF, Gelaw BK. Review on Ebola virus disease: its outbreak and current status. Epidemiology (sunnyvale) 2015; 5:1-8.
 Thippeswamy NB. Ebola Virus Disease. In: New Horizons in Biotechnology 2015; 007-014.
 Thorson AE, Deen GF, Bernstein KT, Liu WJ, Yamba F, Habib N, Sesay FR, Gaillard P, Massaquoi TA, McDonald SL, Zhang Y. Persistence of Ebola virus in semen among Ebola virus disease survivors in Sierra Leone: A cohort study of frequency, duration, and risk factors. PLoS Medicine 2021;18: e1003273.
 Uyeki TM, Erickson BR, Brown S, McElroy AK, Cannon D, Gibbons A, Sealy T, Kainulainen MH, Schuh AJ, Kraft CS, Mehta AK. Ebola virus persistence in semen of male survivors. Clin Infect Dis 2016; 62:1552-5.
 Bausch DG, Towner JS, Dowell SF, Kaducu F, Lukwiya M, Sanchez A, Nichol ST, Ksiazek TG, Rollin PE. Assessment of the risk of Ebola virus transmission from bodily fluids and fomites. J Infect Dis 2007;196: S142-7.
 Centers for Disease Control and Prevention. Democratic Republic of the Congo, North Kivu Province, 3 May 2021. Access valid on 5 June 2021: https://www.cdc.gov/vhf/ebola/outbreaks/drc/2021-february.html
 Centers for Disease Control and Prevention. Ebola (Ebola Virus Diseases): Signs and Symptoms, 4 May 2021. Access valid on 16 March 2021: https://www.cdc.gov/vhf/ebola/symptoms/index.html
 Choi MJ, Cossaboom CM, Whitesell AN, Dyal JW, Joyce A, Morgan RL, Campos-Outcalt D, Person M, Ervin E, Yu YC, Rollin PE. Use of Ebola Vaccine: Recommendations of the Advisory Committee on Immunization Practices, United States, 2020. MMWR Recommendations and Reports 2021; 70:1
 Jain V, Charlett A, Brown CS. Meta-analysis of predictive symptoms for Ebola virus disease. PLoS Negl Tropic Dis 2020;14.
 Rewar S, Mirdha D. Transmission of Ebola virus disease: an overview. Annals of global health 2014; 80:444-51.
 Kiiza P, Mullin S, Teo K, Adhikari NK, Fowler RA. Treatment of Ebola-related critical illness. Intensive Care Med 2020; 46:285-97.
 Augusto BF, Teboh-Ewungkem M, Gumel AB. Mathematical assessment of the effect of traditional beliefs and customs on the transmission dynamics of the 2014 Ebola outbreaks. BMC Med 2015; 13:1-7.
 Publichealthintelligence.org, 2014. Chronology of Ebola Virus Disease outbreaks, 1976-2014 | Health Intelligence. Access valid on 6 April 2021: http://publichealthintelligence.org/content/chronology-ebola-virus-disease-outbreaks-1976-2014
 Martiner, 2014. Chronology of Ebola Virus Disease outbreaks, 1976-2014. Health Intelligence. Publichealthintelligence.org. Access valid on 6 April 2021: http://publichealthintelligence.org/content/chronology-ebola-virus-disease-outbreaks-1976-2014
 Breman JG, Heymann DL, Lloyd G, McCormick JB, Miatudila M, Murphy FA, Muyembé-Tamfun JJ, Piot P, Ruppol JF, Sureau P, van der Groen G. Discovery and description of Ebola Zaire virus in 1976 and relevance to the West African epidemic during 2013–2016. J Infect Dis 2016; 214:S93-101.
 Hewlett BS, Amola RP. Cultural contexts of Ebola in northern Uganda. Emerging infectious diseases 2003;9:1242.
 Grard G, Biek R, Muyembe Tamfum JJ, Fair J, Wolfe N, Formenty P, Paweska J, Leroy E. Emergence of divergent Zaire ebola virus strains in Democratic Republic of the Congo in 2007 and 2008. The Journal of infectious diseases 2011; 204:S776-84.
 Rugarabamu S, Mboera L, Rweyemamu M, Mwanyika G, Lutwama J, Paweska J, Misinzo G. Forty-two years of responding to Ebola virus outbreaks in Sub-Saharan Africa: a review. BMJ Global Health 2020;5:e001955.
 Centers for Disease Control and Prevention. Ebola (Ebola Virus Diseases): History of Ebola Virus Disease (EVD) Outbreaks, 19 June 2021. Access valid on 25 June 2021: https://www.cdc.gov/vhf/ebola/history/chronology.html
 Kroeker A, He S, de La Vega M, Wong G, Embury-Hyatt C, Qiu X. Characterization of Sudan Ebolavirus infection in ferrets. Oncotarget 2017; 8:46262-72.
 Fogarty International Center, 2016. Analysis of 1976 Ebola outbreak holds lessons relevant today - Fogarty International Center @ NIH. Access valid on 13 April 2021: https://www.fic.nih.gov/News/Pages/2016-ebola-outbreak-1976-lessons-relevant.aspx
 Demetria C, Smith I, Tan T, Villarico D, Simon EM, Centeno R, Tachedjian M, Taniguchi S, Shimojima M, Miranda NL, Miranda ME. The reemergence of Reston ebolavirus in Cynomolgus monkeys, the Philippines, 2015. Emerg Infect Dis 2018; 24:1285.
 Formenty P, Boesch C, Wyers M, Steiner C, Donati F, Dind F, Walker F, Le Guenno B. Ebola virus outbreak among wild chimpanzees living in a rain forest of Cote d'Ivoire. J Infect Dis 1999;179: S120-6.
 Goldstein T, Anthony SJ, Gbakima A, Bird BH, Bangura J, Tremeau-Bravard A, Belaganahalli MN, Wells HL, Dhanota JK, Liang E, Grodus M, Jangra RK, DeJesus VA, Lasso G, Smith BR, Jambai A, Kamara BO, Kamara S, Bangura W, Monagin C, Shapira S, Johnson CK, Saylors K, Rubin EM, Chandran K, Lipkin WI, Mazet JAK. The discovery of Bombali virus adds further support for bats as hosts of ebolaviruses. Nat Microbiol 2018; 3:1084-9.
 Karan LS, Makenov MT, Korneev MG, Sacko N, Boumbaly S, Yakovlev SA, Kourouma K, Bayandin RB, Gladysheva AV, Shipovalov AV, Yurganova IA, Grigorieva YE, Fedorova MV, Scherbakova SA, Kutyrev VV, Agafonov AP, Maksyutov RA, Shipulin GA, Maleev VV, Boiro M, Akimkin VG, Popova AY. Bombali Virus in Mops condylurus Bats, Guinea. Emerg Infect Dis 2019; 25:1774-5.
 Forbes KM, Webala PW, Jääskeläinen AJ, Abdurahman S, Ogola J, Masika MM, Kivistö I, Alburkat H, Plyusnin I, Levanov L, Korhonen EM, Huhtamo E, Mwaengo D, Smura T, Mirazimi A, Anzala O, Vapalahti O, Sironen T. Bombali Virus in Mops condylurus Bat, Kenya. Emerg Infect Dis 2019; 25:955-957.  Agyeman AA, Laar A, Ofori-Asenso R. Will COVID-19 be a litmus test for post-Ebola -Saharan Africa? J Med Virol 2020; 92:1373-5.
 World Health Organization. Statement on the 1st meeting of the IHR Emergency Committee on the 2014 Ebola outbreak in West Africa: WHO statement, 8 August 2014. Access valid on 1 June 2021: https://www.who.int/mediacentre/news/statements/2014/ebola-20140808/en/
 United Nations. Joint statement on the Ebola response and WHO reforms. 5 October 2015. Access valid on 4 June 2021: https://un.org.au/2015/04/20/joint-statement-on-the-ebola-response-and-who-reforms/
 Ravi JS, Snyder RM, Rivers S. Review of international efforts to strengthen the global outbreak response system since the 2014–16 West Africa Ebola Epidemic: Health Policy and Planning 2019;1:47-54
 World Health Organization. Factors that contributed to undetected spread of the Ebola virus and impeded rapid containment, January 2015. Access valid on June 7 2021: https://www.who.int/news-room/spotlight/one-year-into-the-ebola-epidemic/factors-that-contributed-to-undetected-spread-of-the-ebola-virus-and-impeded-rapid-containment
 Coltart CEM, Lindsey B, Ghinai I, Johnson AM, Heymann DL. The Ebola outbreak, 2013– 2016: old lessons for new epidemics. Philosophical transactions B 2017;26;372:20160297.
 Fallah MP, Skrip LA, Gertler S, Yamin D, Galvani AP. Quantifying poverty as a driver of Ebola transmission. PLoS Negl Tropic Dis 2015; 9:e0004260.
 Southall HG, DeYoung SE. Lack of Cultural Competency in International Aid Responses: The Ebola Outbreak in Liberia. Frontiers in Public Health 2017;5:5.
 Aljazeera. Ebola patients flee as Liberia clinic looted. 18 Aug 2014. Access valid on 2 June 2021: https://www.aljazeera.com/news/2014/8/18/ebola-patients-flee-as-liberia-clinic-looted
 Maxmen, A. 2020. World’s second-deadliest Ebola outbreak ends in Democratic Republic of the Congo, 26 June 2020. Nature (news) 2020. Access valid on 6 June 2021: https://www.nature.com/articles/d41586-020-01950-0
 Manguvo A, Mafuvadze B. The impact of traditional and religious practices on the spread of Ebola in West Africa: time for a strategic shift. Pan African Med J 2015;22.
 Regeneron. Regeneron's Antibody Cocktail REGN-EB3 (Inmazeb®) Is First FDA-Approved Treatment For Ebola (Zaire Ebolavirus). October 14, 2020. Access valid on June 6 2021: https://investor.regeneron.com/news-releases/news-release-details/regenerons-antibody-cocktail-regn-eb3-inmazebr-first-fda
 Kasereka MC, Ericson AD, Conroy AL, Tumba L, Mwesha OD, Hawkes MT. Prior vaccination with recombinant Vesicular Stomatitis Virus–Zaire Ebolavirus vaccine is associated with improved survival among patients with Ebolavirus infection. Vaccine 2020; 38:3003-7.
 Bausch DG. The need for a new strategy for Ebola vaccination. Nature Med 2021; 27:580-1.
 Doshi RH, Fleming M, Mukoka AK, Carter RJ, Hyde TB, Choi M, Nzaji MK, Bateyi SH, Christie A, Nichol ST, Damon IK. Vaccination of contacts of Ebola virus disease survivors to prevent further transmission. The Lancet Global Health 2020;8: e1455-6.
 Unicef.org. UNICEF, WHO, IFRC and MSF announce the establishment of a global Ebola vaccine stockpile, 11 Jan 2021. Access valid on 8 March 2021: https://www.unicef.org/press-releases/unicef-who-ifrc-and-msf-announce-establishment-global-ebola-vaccine-stockpile
 Qureshi AI. Ebola virus disease epidemic in light of other epidemics. Ebola Virus Disease 2016:39.
 Towner JS, Sealy TK, Khristova ML, Albariño CG, Conlan S, Reeder SA, Quan PL, Lipkin WI, Downing R, Tappero JW, Okware S. Newly discovered ebola virus associated with hemorrhagic fever outbreak in Uganda. PLoS Pathog 2008; 4:e1000212.
 Nsio J, Kapetshi J, Makiala S, Raymond F, Tshapenda G, Boucher N, Corbeil J, Okitandjate A, Mbuyi G, Kiyele M, Mondonge V. 2017 outbreak of ebola virus disease in northern Democratic Republic of Congo. J Infect Dis 2020; 22:701-6.
 Centers for Disease Control and Prevention. 2017 Democratic Republic of the Congo, Bas Uélé District, 28 July 2017. Access valid on 7 June 2021: https://www.cdc.gov/vhf/ebola/outbreaks/drc/2017-may.html
 Cohen, J. Hoping to head off an epidemic, Congo turns to experimental Ebola vaccine. Science (news), 15 May 2018. Access valid on 5 June 2021: https://www.sciencemag.org/news/2018/05/hoping-head-epidemic-congo-turns-experimental-ebola-vaccine
 Mbala-Kingebeni P, Pratt CB, Wiley MR, Diagne MM, Makiala-Mandanda S, Aziza A, Di Paola N, Chitty JA, Diop M, Ayouba A, Vidal N. 2018 Ebola virus disease outbreak in Equateur Province, Democratic Republic of the Congo: a retrospective genomic characterisation. The Lancet Infect Dis 2019; 19:641-7.
 Ilunga Kalenga O, Moeti M, Sparrow A, Nguyen VK, Lucey D, Ghebreyesus TA. The ongoing Ebola epidemic in the Democratic Republic of Congo, 2018–2019. NEJM 2019; 381:373-83.
 Rohan H, McKay G. The Ebola outbreak in the Democratic Republic of the Congo: why there is no ‘silver bullet’. Nature Immunol 2020; 2:591-4.
 Maxmen, A. 2020. World’s second-deadliest Ebola outbreak ends in Democratic Republic of the Congo, 26 June 2020. Nature (news) 2020. Access valid on 6 June 2021: https://www.nature.com/articles/d41586-020-01950-0
 World Health Organization. Ebola virus disease — Guinea, 17 February 2021. Access valid on 3 May 2021: https://www.who.int/csr/don/17-february-2021-ebola-gin/en/
 Centers for Disease Control and Prevention. 2021 Democratic Republic of the Congo, North Kivu Province, 3 May 2021. Access valid on 2 June 2021: https://www.cdc.gov/vhf/ebola/outbreaks/drc/2021-february.html
 Centers for Disease Control and Prevention. 2021 Guinea, N'Zérékoré Prefecture, 15 March 2021. Access valid on 7 June 2021:https://www.cdc.gov/vhf/ebola/outbreaks/guinea/2021-february.html
 Relief Web. ACAPS Short note: Guinea - Ebola outbreak, 30 March 2021. Access valid on 7 June 2021: https://reliefweb.int/report/guinea/acaps-short-note-guinea-ebola-outbreak-30-march-2021 UN News. Latest deadly Ebola virus outbreak in DR Congo declared over, 3 May 2021. Access valid on 5 June 2021: https://news.un.org/en/story/2021/05/1091162
Conflict of interest: none declared
1 Jagiellonian University Medical College, School of Medicine in English, Cracow, Poland
122 Highbourne rd.
Toronto ON M5P2J6
Telephone: +48 693 918 623
To cite this article: Maghen E, Ali D, Lucinskaité K, Galazkowski T. Ebola - the deadly filamentous virus which continues to plague Africa. World J Med Images Videos Cases 2021; 7:e44-62.
Submitted for publication: 14 June 2021
Accepted for publication: 21 June 2021
Published on: 30 June 2021
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