1 First Case and Early Spread

In early December 2013, a 2-year-old boy in the village of Méliandou in the remote, largely deforested, and resource-poor Prefecture of Guéckédou, Republic of Guinea, fell sick with fever, vomiting, and black stool, dying a few days later (WHO 2014a; Baize et al. 2014; Mari Saez et al. 2014) (Figs. 1 and 2). The boy was reported to have previously played in a hollow tree housing a colony of the insectivorous bat Mops condylurus, a possible Ebola virus (EBOV) reservoir (Mari Saez et al. 2014). Over the following weeks and months, multiple waves of transmission and disease occurred in family members, healthcare workers (HCWs) who cared for them, and persons with contact with corpses during funeral rituals. On March 21, 2014, Guinean health authorities notified the World Health Organization (WHO) of a “rapidly evolving outbreak.” On March 23, EBOV infection was confirmed on patient samples sent to Biosafety Level 4 laboratories in Lyon, France, and Hamburg, Germany, and an outbreak of Ebola virus disease (EVD) was declared. Unbeknownst to all at the time, at least 49 cases with multiple but often poorly defined chains of transmission had already occurred in Guinea and the virus had already slipped across the border, smoldering quietly at first, into neighboring Liberia and Sierra Leone (WHO 2014b, 2015c).

Fig. 1
figure 1

Adapted from WHO Ebola Response Roadmap Situation Reports with publically available data. World Health Organization

Epidemiologic curve of the West Africa 2013 Ebola virus disease (EVD) outbreak. The dashed-vertical lines indicate key events during the outbreak: a First suspected case in Méliandou, Guinea, b Laboratory confirmation of EVD and disease reported by Guinean Health Authorities, c WHO declares Public Health Emergency of International Concern, d U.S. President Obama announces major initiative to help control EVD in Liberia; Creation of the United Nations Mission for Ebola Emergency, e Publication of preliminary results from first EVD Phase III vaccine efficacy study (rVSIV-EBOV), f Publication of preliminary results of first EVD Phase III therapeutic efficacy trial (convalescent plasma).

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Fig. 2
figure 2

Reprinted with permission from Bausch and Rojek (2016)

Map of West Africa showing the epicenter of the 2013–2016 outbreak of Ebola virus disease (red) and imported cases (orange and arrows). The village of Meliandou, Guinea, where the first case is thought to have occurred, is indicated by a blue star. The total number of cases seen in each country is shown in parentheses.

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2 Virus Introduction

Five members of the Filoviridae family are known to cause disease in humans: EBOV (formerly designated Zaire Ebola virus), Bundibugyo, Sudan, and Taï Forest viruses of the genus Ebola virus and Marburg and Ravn viruses of the genus Marburg virus, with characteristic geographic distributions (Table 1 and Fig. 3). Prior to 2013, only a single case of EVD had been reported in West Africa, due to Taï Forest virus (Formenty et al. 1999a, b). When EVD appeared in neighboring Guinea in 2013, most experts predicted that Taï Forest virus would again be the culprit, and thus were surprised when the causative virus turned out to be a new variant of EBOV, subsequently named Makona after the Makona River in Guinea, close to the border with Liberia and Sierra Leone (Baize et al. 2014). How EBOV, which had never been noted outside of the Congo Basin of Equatorial Africa, found its way to West Africa remains unknown (Bausch and Schwarz 2014). Migration and transmission from infected bats, putative EBOV reservoirs, is considered the most likely modality (Mari Saez et al. 2014; Bausch and Schwarz 2014). Comparative phylogeographic analysis suggests that fruit bats of three species are theoretically capable of dispersing EBOV directly from the Congo Basin to Guinea: African straw-colored fruit bats (Eidolon helvum), hammer-headed fruit bats (Hypsignathus monstrosus), and Egyptian fruit bats (Rousettus aegyptiacus), although definitive evidence of EBOV infection in any type of bat anywhere has yet to be found (Hassanin et al. 2016).

Table 1 Laboratory-confirmed outbreaks of Ebola virus disease since discovery of the virus in 1976 through September 2017. Cases related to laboratory infections are not shown
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Fig. 3
figure 3

Endemic areas for Filo viruses. Only Filo viruses known to cause hemorrhagic fever are shown. Gray indicates countries where Ebola virus disease has been seen and diagonal lines countries with Marburg virus disease. Incidence and risk of disease may vary significantly within each country

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Epidemiological and phylogenetic analyses during and after the West Africa EVD outbreak are consistent with all cases stemming from a single introduction of the Makona variant in Guinea in 2013 (Kuhn et al. 2014). This finding is consistent with most other EVD outbreaks, which generally result from a single introduction from the wild followed by amplification exclusively through human-to-human transmission. Molecular clock dating analyses suggest that the Makona variant diverged from other EBOVs only about a decade ago (Holmes et al. 2016). Also due to EBOV, sequence analysis makes clear that the much smaller outbreak of EVD that occurred in the Democratic of the Republic of the Congo in 2014 was a separate event unrelated to the outbreak in West Africa.

3 Underlying Geopolitical, Social, and Cultural Factors

There has been much speculation and extensive discussion in the literature regarding the causes for the unprecedented size of West Africa 2013 (Moon et al. 2015; Bausch and Rojek 2016). The outbreak’s roots are undoubtedly multifactorial, entailing a complex web of interrelated social, cultural, ecologic, and economic determinants viewed in the context of the overall geopolitical history of the region (Table 2). Many of these factors and challenges have been encountered in previous EVD outbreaks, but certainly not on the scale and with the intensity noted in West Africa.

Table 2 Underlying geopolitical, social, and cultural factors implicated in the 2013–2016 West Africa Ebola virus outbreak and components of the failed international response (subject extensively reviewed in Bausch and Rojek (2016))
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4 A Failed Response

In the absence of effective therapeutics and vaccines (a work in progress—see below), control of EVD outbreaks is almost completely based on the classic control measures of thorough surveillance for case identification, isolation, and care in the setting of sound infection prevention and control (IPC) practices; contact tracing; and safe burials, all enhanced by effective social mobilization and public education campaigns, and coordinated through a partnership between the national government, WHO, and other international stakeholders. The international community and the governments they supported were accustomed to success in this approach, generally ending outbreaks after a few hundred cases within a few months, and indeed certainly anticipated the same result in West Africa (Table 3). However, a tragically different scenario played out.

Table 3 Comparison of various parameters and possible determinants of previous outbreaks of Ebola virus disease and the 2013–2016 outbreak in West Africa
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Due to a preexisting health project, the nongovernmental organization Médecins Sans Frontières (MSF) was present at the epicenter of the EVD outbreak in Guinea even before its onset. On March 31, seven days after the EVD outbreak was declared, MSF warned of an EVD outbreak unprecedented in magnitude and distribution. Although many international organizations, including WHO, the International Federation of Red Cross and Red Crescent Societies, the U.S. Centers for Disease Control and Prevention, the European Union, and UNICEF, quickly joined MSF and national partners in the three West African countries to mount outbreak response operations, this early effort would prove to be too slow, piecemeal, and disorganized to prevent what would ultimately become a major humanitarian crisis. The shortcomings in the international response have been extensively discussed in the literature, especially with regard to WHO who, although engaged in outbreak control activities since the beginning, did not formally declare the outbreak to be a Public Health Emergency of International Concern, as outlined under International Health Regulations, until August 8, 2014 (Bausch and Rojek 2016) (Fig. 1).

The dramatic rise in cases in West Africa, projections of millions of cases if an aggressive response was not mounted (Meltzer et al. 2014), and increasing numbers of imported cases into surrounding countries in West Africa, the United States, and Europe, finally stirred the international community to more concerted action. Responses generally aligned with historical connections between the United States and European countries and their colonial-era African counterparts. In September 2014, United States President Obama committed to the construction of seventeen 100-bed Ebola Treatment Units (ETUs) in Liberia, deployment of up to 3000 medical military and support personnel, and support to train 500 HCWs a week. The United Kingdom and France soon followed with commitments to combat EVD in their ex-colonies of Sierra Leone and Guinea, respectively.

Ultimately, a vast array of at least 100 government and nongovernmental organizations, including over 5000 military personnel, contributed to the outbreak response, establishing over 70 ETUs, 800 community care centers, a vast network of over 50 laboratories (generally providing reliable diagnostic results within 24 h after receipt of a specimen), and an extensive surveillance and contact tracing operation across the three implicated countries. However, the response remained agonizingly slow, hampered by the logistical challenges of operationalizing work in the poorest countries in the world with fledging governments and poor infrastructure. The dispersal of cases across three West Africa countries, and in both remote rural and densely populated urban areas, ultimately presented too many “battle fronts,” outstripping both local and international capacities. Beds for patients with EVD (Table 4), HCWs to care for them, and field workers to undertake surveillance and contact tracing were woefully insufficient. Consequently, highly infectious patients remained untreated in the community and patients who were admitted to the drastically understaffed ETUs could expect little more than palliative care. Even after laboratories began being rapidly established, the steep increase in the number of samples exceeded local diagnostic capacities in many areas until well into the outbreak. With cases of EVD in HCWs mounting, some ETUs opted to enhance safety by proscribing close contact with patients, including the very controversial measure of not placing IVs for fluid repletion. This move, while perhaps unavoidable, likely further undermined the local population’s already shaky faith in the response operation.

Table 4 Bed capacity and bed requirements for patients with Ebola virus disease in West Africa in October, 2014. Bed capacity in each district was planned on the basis of a need assessment carried out by the relevant Ministry of Health. Source WHO: Ebola Response Roadmap Situation Report, October 8, 2014, World Health Organization
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Coordination of the outbreak response was a major challenge, with each organization largely acting independently or in bilateral concert with the government. In August 2014, the United Nations appointed a Special Envoy on Ebola, followed by the creation in September 2014 of a coordination body, the United Nations Mission for Ebola Emergency, headquartered in Ghana (Fig. 1). Opinions vary on the efficacy of these measures. Without doubt, the enormous scale and complexity of the outbreak, and the sheer number of organizations involved (far more than had ever been involved in an EVD outbreak before and at times compounded by historical frictions between them) made coordination a substantial challenge.

Although HCW infections have occurred in virtually every EVD outbreak to date (Table 1), prior to West Africa 2013, they were relatively uncommon once international support and resources arrived to assist with establishing ETUs and appropriate IPC measures. In contrast, one of the tragic consequences of the poor baseline infrastructure and failed response West Africa 2013 was EBOV infection in over 900 HCWs during the outbreak, including two cases contracted in the United States and one in Spain, with over 500 deaths (WHO 2015a). In the vast majority of HCW infections, no clear exposure risk, such as a needle stick or blood splash to mucous membranes, could be identified. The high number of HCW infections engendered speculation that EBOV Makona is more transmissible than other variants, although no supporting data for this theory are available.

Although IPC entails many diverse measures, many of which were inadequate during the outbreak, most of the focus has been on the issue of personal protective equipment (PPE). In addition to shortages of PPE, especially early in the outbreak, the situation was complicated by the diversity of PPE types advocated by different groups, causing significant confusion with training and safe use (Bausch and Rojek 2016; WHO 2008; Franklin 2016) (Fig. 4). Although PPE guidelines were eventually produced, which for the first time included technical specifications for PPE, the lack of evidence precluded a consensus on efficacy (Hersi et al. 2015). The procedure for doffing contaminated PPE, often considered a confusing and a vulnerable point for infection, is logically a focus of attention but, again, no data are available. Furthermore, it is not always clear the HCW infection resulted from exposure in the ETU. Local HCWs are members of the same communities where EBOV may be circulating during an outbreak, and thus may share many of the same risks. There are also many anecdotal reports of HCWs seeing patients in their homes, where the uses of full PPE and other IPC measures are unlikely to be adequate (Faye et al. 2015; Brainard et al. 2016). More in-depth investigations are needed, and indeed are ongoing, to reveal vulnerable points for HCW infection in the care of EVD, and to develop evidence-based uniform PPE standards to protect them.

Fig. 4
figure 4

Photos by Thomas Fletcher and Frederique Jacquerioz

Examples of various types of personal protective equipment used during the care of patients with Ebola virus disease during the 2013–2016 outbreak in West Africa. The equipment shown are for demonstration only, and should not be construed as implying as advocating or confirming efficacy for any specific equipment.

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5 Virus Evolution During the Outbreak

Whole genome sequencing was performed on hundreds of samples from West Africa 2013, a far greater number than had been sequenced from all previous EVD outbreaks combined (Gire et al. 2014; Park et al. 2015; Matranga et al. 2014). There are conflicting reports and considerable controversy over whether EBOV Makona evolved genetically more rapidly during West Africa 2013 relative to the causative viruses of other EVD outbreaks (Holmes et al. 2016) and whether virus adaptation to humans occurred (Li et al. 2016; Urbanowicz et al. 2016). What is clear, however, is that the prolonged course of the outbreak provided sufficient time for the emergence of at least three distinct viral lineages (Gire et al. 2014; Urbanowicz et al. 2016; Carroll et al. 2015; Quick et al. 2016; Simon-Loriere et al. 2015). Most of these major lineages circulated locally, with only sporadic cross-border transmission.

The highest level of EBOV genetic amino acid diversity generated during West Africa 2013 occurred in the EBOV glycoprotein (GP) (Holmes et al. 2016; Ning et al. 2017). Because of its key role in virus–host interactions, with the potential for altered interaction with the EBOV host receptor Niemann-Pick C1, GP sequence variation is of particular interest. In the laboratory, minor changes in the GP have been shown to impact viral entry into cells from different mammalian species (Ning et al. 2017). Pseudo-typed virion particles incorporating synthetically generated amino acid substitutions observed during the outbreak more efficiently entered human cells, with possible implications for viral fitness, host specificity, and transmissibility (Urbanowicz et al. 2016). Early in the West Africa outbreak, a variant in lineage SL2 emerged with sequence changes in the GP receptor-binding site (Holmes et al. 2016).

Despite evidence for a degree of EBOV evolution during West Africa 2013, no clear phenotypic significance (i.e., changes in transmissibility, virulence, antigenicity, or influence on the efficacy of diagnostic assays, vaccines, or therapeutics) has been noted between the lineages of EBOV Makona or between Makona and other variants of EBOV; the range of reported case fatality rates in West Africa (31–76%), calculated basic reproduction number R 0 (1.5–2.5), and duration of virus shedding are comparable to those noted in previous outbreaks, with no evidence for heritable changes during the course of the outbreak (Holmes et al. 2016; Bausch and Rojek 2016). An EBOV vaccine developed against the 1995 Kikwit variant of EBOV was 100% protective against the Makona variant in both animal models (Marzi et al. 2015a) and a Phase III trial in humans (Henao-Restrepo et al. 2016), suggesting that the genetic differences between the two virus variants did not result in significant differences in immunogenicity. Nor have laboratory studies shown EBOV Makona to be appreciably different from other variants of EBOV with regard to virulence in nonhuman primates (Marzi et al. 2015b), entry into cells (Dunham et al. 2015; Hofmann-Winkler et al. 2015), or detection via polymerase chain reaction assays (Sozhamannan et al. 2015). One exception, however, is the results from experiments in humanized laboratory mice, in which a longer mean-time-to-death was noted with EBOV Makona compared to the 1976 Yambuku variant (Bird et al. 2016), leading to speculation that the seemingly high attack rates in West Africa 2013 could be the result of prolonged virus shedding and thus opportunity for transmission. Despite high-profile speculation to the contrary, there is no evidence or reason to believe that EBOV Makona or any other EBOV variant or even any other Ebola virus has or will evolve naturally to be capable of aerosol or airborne transmission (Osterholm et al. 2015).

6 A Heavy Toll Before Final Outbreak Control

The EVD outbreak in West Africa would ultimately last 3 years and officially result in over 28,616 cases and 11,310 deaths (numbers widely considered underestimates), eclipsing by far and by every measure all previous EVD outbreaks combined (Table 1). In addition to the toll in terms of cases counted and lives lost, the outbreak resulted in billions of dollars in lost economic growth in West Africa (Bank TW 2016), upward of 3500 orphaned children (UNICEF 2016), delayed or impaired child development since school was canceled for a year, widespread job loss resulting in economic and food insecurity, and deep but less easily measurable mental health and sociocultural impacts. Furthermore, as the region’s resources were funneled to EVD, an estimated 10,000+ excess deaths occurred due to untreated malaria, HIV/AIDS, and tuberculosis (Parpia et al. 2016). Reductions in vaccination coverage and a rise in teenage pregnancy were also noted (Elston et al. 2015). In addition to the cases in Africa, there were 27 cases, 5 of which were fatal, imported, or medically evacuated to the United States and Europe (Fig. 2) (System Ebola Epidemiology Team IM 2014; WHO 2015b)—a pittance compared to the massive humanitarian disaster in West Africa, but a situation that nevertheless fomented considerable panic and expenditure of resources in those industrialized areas of the world.

The success of EVD outbreak control measures is highly dependent on community engagement to arrive at a common understanding of the nature of the disease threat and cooperation with the plan for control. A combination of historical distrust of authority and slow and poor messaging conspired to impede such engagement, understanding, and cooperation in many communities during West Africa 2013, providing a major impediment. Whether the major factors in ultimate control of the outbreak were the classic response measures implemented by national and international public health agencies or a more grassroots autonomous behavioral adaptation of the indigenous population is a matter of debate, and certainly varies by country and community. In some cases, additional measures were implemented, such as quarantine of affected villages and exit and entrance screening for fever and other clinical manifestations of EVD of travelers between affected regions and in airports, often controversially and with uncertain effect. One novel control method that may have had a significant impact on transmission in the later stages of the outbreak was vaccination (see below and chap. 9 by Higgs).

7 Sequelae, Virus Persistence, and Recrudescence

One of the unforeseen issues in West Africa 2013 was the high frequency of sequelae, virus persistence, and, more rarely, recrudescence in EVD survivors. Although a host of both short- and long-term post-EVD sequelae has been noted dating back to the first recognized outbreak in Zaire (current Democratic Republic of the Congo) in 1976, little attention was typically afforded to survivors, in part due to the limited infrastructure for study in the outbreak areas (Vetter et al. 2016b). However, early anecdotal observations and subsequent more formal study on the estimated over 15,000 EVD survivors from West Africa 2013 reveal a wide range of medical and psychosocial challenges, including persistent arthralgia, ocular complications (including potentially sight-threatening uveitis that may result in early cataract formation) abdominal pain, extreme fatigue, and anorexia, sleep and memory disturbances, anxiety disorders, depression, post-traumatic stress disorder, and survivors’ guilt in not only survivors, but also other family and community members (Vetter et al. 2016b). The challenges facing survivors created an urgent moral imperative to provide clinical care, only partially met by national programs with international support, including clinical care guidelines for EVD survivors developed by (WHO 2016a).

The underlying pathogenesis of EVD sequelae is not well understood, but anecdotal observations increasingly suggest that at least some relate to persistent virus in selected immunologically protected tissue compartments and fluids, including the testes/semen, chambers of the eye, cerebrospinal fluid (CSF), and the fetus, placenta, and amniotic sac/fluid of women infected during pregnancy (Vetter et al. 2016a, b). EBOV RNA has been found by RT-PCR in a host of body fluids for weeks or even months after resolution of acute disease and clearance of virus from the blood (Fig. 5), although the significance of these findings is often unknown since, in most cases, infectious virus could not be isolated by cell culture after a few weeks after disease onset.

Fig. 5
figure 5

Updated and reprinted with permission from Vetter et al. (2016b)

Virus persistence after the day of disease onset in various body compartments in survivors of Ebola virus disease as detected by reverse-transcription polymerase chain reaction (RT-PCR, green) and cell culture (blue). Red bars represent the day of the first negative RT-PCR detection in the patient’s blood, when available.

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Fig. 6
figure 6

Republic of the Congo. Reprinted with permission from Bausch and Rojek (2016)

Sizes and population densities of Guinea, Liberia, and Sierra Leone combined compared with the Democratic Republic of the Congo. To illustrate the difference in size, the three West African countries are shown superimposed on the Democratic.

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Fig. 7
figure 7

Photos by Frederique Jacquerioz

“Bush taxis” in Guinea traveling back-and-forth between remote areas and major cities.

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Virus persistence in the semen is of most concern since it has occasionally resulted in sexual transmission, sometimes initiating small case clusters in the wake of the acute outbreak (Eggo et al. 2015; Christie et al. 2015; Mate et al. 2015). Albeit in low copy numbers and in a small minority of EVD survivors, EBOV RNA has been detected in the semen up to a year or more and infectious virus by cell culture up to 82 days after acute disease (Deen et al. 2015). A few cases of recrudescence associated with prolonged virus persistence have been noted, including uveitis with EBOV isolated from the aqueous humor of the eye at 14 weeks after disease onset (Varkey et al. 2015) and severe meningitis with seizures with isolation of virus from the CSF 9 months after resolution of acute disease (Jacobs et al. 2016). Anecdotal reports exist of recrudescent disease and viremia in West Africa, in some cases thought to be related to underlying HIV-1 infection, although this association remains to be validated (Howlett et al. 2016). A few cases have been noted in which women infected with EBOV during pregnancy, possibly with no or atypically mild disease, have recovered and remained pregnant, only to spontaneously abort a macerated and nonviable fetus in subsequent weeks or months (Bower et al. 2015; Caluwaerts et al. 2015). EBOV RNA was found in the products of conception, although cell culture results confirming the presence of infectious virus were generally not reported (Bower et al. 2015; Caluwaerts et al. 2015; Baggi et al. 2014; Oduyebo et al. 2015). With the exception of sexual transmission, no cases of secondary transmission resulting from EVD survivors have been suspected. Nevertheless, the possibility of virus persistence and renewed transmission from EVD survivors illustrate the need for continued non-stigmatizing but heighted surveillance even after the immediate threat of EVD from more common modes of transmission has been extinguished.

8 Research During the Outbreak

As the gravity of the situation in West Africa rose, the global community felt increasingly compelled to consider use of various experimental therapeutics and vaccines. Albeit unwelcome, the magnitude of the outbreak provided an important opportunity and obligation for prospective clinical research that had never before been possible. In August 2014, WHO convened a meeting in Geneva, Switzerland, of the diverse stakeholders, including representatives from the ministries of health, pharmaceutical companies, drug regulatory agencies, nongovernmental organizations providing clinical care, and experts in virology and medical ethics. WHO then quickly created a Scientific and Technical Advisory Committee for Ebola Experimental Interventions to guide the process, which required consideration not only of the evidence for safety and efficacy, but also the anticipated feasibility and utility of conducting clinical trials in the setting of limited production capacities or intermittent drug availability. While various therapeutic trials were undertaken (Table 5), the many complex scientific, logistical, and sociocultural challenges could not be met quickly enough to take full advantage of the large case numbers potentially affording statistical power. By the time most therapeutic trials were implemented, case counts in West Africa had fallen to a level insufficient to meet clinical endpoints. There was also an opportunity missed to enroll more patients in clinical trials in resource-rich settings.

Table 5 Registered clinical trials reporting results of experimental therapeutics for Ebola virus disease during the 2013–2016 West Africa outbreak. Adapted and reprinted with permission from (Hayden et al. 2017)
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While there is disappointment that therapeutic trials during West Africa 2013 did not produce definitive evidence of an efficacious drug for EVD, the experience cannot be considered completely futile. Many difficult but valuable lessons were learned regarding the challenges of inconsistent reproducibility of in vitro experiments, poorly predictive animal models, and the operational demands of conducting trials overseas in an ETU during an outbreak without any preexisting research infrastructure. Rigorous debate continues regarding the scientific and ethical merit of the various clinical trial designs used in this outbreak. Nevertheless, numerous drug candidates progressed through Phase I, II, and III clinical trials at an unprecedented pace and the recognition that some agents are ineffective, along with promising interim results for a few, provide a starting point for prioritization in future outbreaks. However, much work remains to be done to capitalize on the lessons learned from West Africa 2013 and make the accelerated pace of therapeutic trials during outbreaks the norm, including prioritizing drug candidates, working out trial designs, prepositioning protocols and ethics committee reviews, and setting logistical frameworks for rapid operationalization.

As with therapeutics, the urgency of West Africa 2013 thrust vaccines for EVD from a conventional protracted research and development timeline into high gear. After rapid Phase I and II clinical trials were undertaken at various sites in the United States, Europe, and Africa (outside the EVD epidemic zone), a large Phase III trial of an experimental vaccine composed of a recombinant vesicular stomatitis Indiana virus expressing the EBOV GP was implemented in Guinea with a ring vaccination approach. The trial showed 100% vaccine efficacy (Henao-Restrepo et al. 2016) and was employed in the later stages of the outbreak to help stem spread from reintroduced virus from sexual transmission. Adverse effects were frequent but mostly minor, although vaccine-induced arthritis, dermatitis, and vasculitis were reported (Henao-Restrepo et al. 2016; Huttner et al. 2015).

In addition to the aforementioned prospective clinical investigations on therapeutics and vaccines, a vast amount of information was generated from informal observations and empiric experience with the large number of cases. This included noting relatively rare clinical presentations—at times challenging accepted case definitions—sequelae, and modes of transmission (Bausch and Rojek 2016). In particular, the spectrum of disease and transmission modes in pregnant women and their offspring brought many new and often unforeseen challenges (Akerlund et al. 2015). The 20 medically evacuated cases to the United States and Europe were generally cared for in advanced medical settings that allowed for more detailed clinical observation and laboratory analysis of both acute disease and sequelae than was typically possible in West Africa (Uyeki et al. 2016).

Although, as discussed above, clinical trials generally evolved too slowly to provide firm conclusions on efficacy, it is interesting to note that the CFR in the 27 cases who received care in the United States and Europe was only 18.5% (Uyeki et al. 2016), compared to 31–76% reported from West Africa 2013, depending upon the specific ETU and time during the outbreak. It is unknown whether this discrepancy in outcome relates to use of experimental therapies (of which 85% of patients in high-resource setting received one or more), better fluid and electrolyte monitoring and organ support (including mechanical ventilation and renal replacement therapy), genetic predisposition, and/or diminished comorbidities relative to the West African population. Observational studies on sequelae and persistence in EVD survivors, including the Partnership for Research on EBOV in Liberia (PREVAIL) III, a large multiyear controlled cohort study of EVD being undertaken in Liberia, promise to eventually yield a wealth of information (NIH 2015).

Significant progress was made on development and validation of new laboratory diagnostic platforms for nucleic acid detection of EBOV as well as progress on rapid tests (Dhillon et al. 2015). West Africa 2013 also set a new benchmark in providing real-time large-scale molecular epidemiologic data to guide response efforts during an outbreak (Holmes et al. 2016; Matranga et al. 2014). Such high-resolution genetic analysis is generally available only retrospectively. However, despite often difficult conditions, toward the end of the West Africa outbreak, novel field-applicable genome sequencing platforms were developed and deployed that were capable of generating results in less than 24 h (Holmes et al. 2016; Quick et al. 2016). These genomic data may allow accurate ongoing estimates of various important outbreak parameters, including of reproduction numbers R 0 and R 1, to determine the impact of specific interventions such as border closures and quarantine; elucidation of transmission chains and virus provenance when classically collected field epidemiologic data are unclear, including identification of super-spreaders and cases where sexual or other transmission from survivors is suspected; identification of signatures of host adaptation; identification and monitoring of diagnostic targets; and characterization of responses and resistance to treatments and vaccines (Matranga et al. 2014; Quick et al. 2016; Mate et al. 2015; Whitmer et al. 2016; Lau et al. 2017; Keita et al. 2016; Diallo et al. 2016).

9 Conclusions and Future Challenges

The unprecedented scale of West Africa 2013 took the world by surprise and sadly added another tragic event to a region already struggling to escape decades of poverty and war. The outbreak also shook the international response community, laying bare deficiencies in our response capacity to complex humanitarian crises involving highly infectious and lethal pathogens. Although much remains to be learned, West Africa 2013 also represents a tragic but nevertheless watershed moment in our understanding not only of the biology and epidemiology of EVD, but equally important, the many economic, social, political, ethical, and logistical challenges in confronting emerging diseases in the modern era. As the global population surges and becomes more interconnected, the risk of such outbreaks is destined to increase. In the absence of redoubled efforts to build capacity for surveillance and response, outbreaks such as West Africa 2013 threaten to become the “new norm.” One need not look much further for the proof than to the Zika virus disease outbreak that swept through the Caribbean and Latin America starting in 2015.

West Africa 2013 has challenged the world to respond better. The pressure is on to capitalize on the lessons learned during the outbreak both from failures and the glimpses of innovation and research progress to create a new norm of comprehensive surveillance and organized response. In response to numerous internal as well as external evaluations (Moon et al. 2015), WHO has created a new Health Emergencies Programme designed to streamline response operations to such crises under one clear line of authority (WHO 2016b). However, the funding to fully implement the new program is still in question. Furthermore, reform and improved performance must extend far beyond only WHO. Many national governments and independent stakeholders have also created rapid response teams. Whether this revamped structure and national capacity will result in a more effective response to the next outbreak remains to be seen. Coordination of the many different partners and programs during the next outbreak will undoubtedly remain one of the key challenges.

Lastly, let us remember that, while important, science and technological advancement alone will never be sufficient; poverty and lack of the fundamental human right to health consistently underlie outbreaks of emerging pathogens (Nations 1948). EVD is but the proverbial “canary in the coal mine,” indicative of the world’s most vulnerable populations. We must advocate for and work toward restitution of the right to health in low- and middle-income countries (LMICs). This will entail much more than simply building a laboratory or conducting a research project. Local educational institutions must be strengthened and career opportunities created to stop the “brain drain” of HCWs to high-income countries and produce future “home grown” leaders in the health sciences. Novel and technology-appropriate approaches to local problems must be sought, as well as the funding mechanisms that enable their execution. Furthermore, after the major struggle to implement the quantity of medical care necessary in West Africa 2013, the outbreak rightly brought up the issue of quality of care. Implicit in this is a just rejection of a perhaps long-held but implicit acceptance of disparate qualities of care between patients in LMICs and resource-rich countries, an archaic notion whose time must now be passed. Regardless of country of origin or personal wealth, patients should have the right to HCWs with the right training for their condition and who implement evidence-based standards of care. Of course, this gap between rich and poor cannot be closed overnight. There is much work to be done with regard to both scientific research to generate the best evidence and advocacy and organization to ensure thorough and equitable implementation. Responsibility falls also on LMICs to create strong and transparent governmental and public health administrative frameworks capable of capitalizing on international collaboration and support. Long after West Africa 2013 is over, these will be our true measures of success.