The Ebola epidemic that struck West Africa from 2013-2016 served as a reminder that the world is still very much at risk from exposure to infection. The response of the health authorities was supported by an international coalition of scientists, academic and public health professionals, and proved both vigorous and fundamental in containing an outbreak that took West Africa by surprise: the virus had hitherto been confined to Central Africa. With the official death toll standing at over 11,000, this epidemic killed 25 times more people than the previous episodes of the past 40 years combined. The three years of this outbreak saw advances in research – an experimental Ebola vaccine proved safe and effective – but new questions surrounding this disease also came to light. In this report we look back at this historic epidemic.
In December 2013 the first cases of hemorrhagic fever appeared in Guéckédou, in south-east Guinea in West Africa. A few weeks later, the World Health Organization Collaborating Center (WHOCC) for Viral Hemorrhagic Fevers and Arboviruses, led by Noël Tordo at the Institut Pasteur, was notified by Médecins Sans Frontières. The WHOCC notified Sylvain Baize, director of the National Reference Center for Viral Hemorrhagic Fevers (CNR) at the Institut Pasteur in Lyon, whose Jean Mérieux–Inserm BSL-4 laboratory is the only laboratory capable of handling dangerous samples in France. On March 21, 2014, the CNR confirmed that the causative agent was a filovirus, a family of viruses comprising those that cause hemorrhagic fever such as the Ebola virus and the Marburg virus. Indeed they narrowed down the possibilities to the Ebola virus or Marburg hemorrhagic fever. The next day, the Laboratory for Urgent Response to Biological Threats (also called CIBU, and managed by Jean-Claude Manuguerra) in Paris identified the pathogen as Zaire ebolavirus (ZEBOV) – the most deadly of the Ebola viruses. The World Health Organization (WHO) was informed, and issued an alert on March 23. At that time there were 49 reported cases, including 29 deaths.
The Ebola virus first identified in Guinea
Along with scientists from Inserm, the National Reference Center for Viral Hemorrhagic Fevers – which operates under the Institut Pasteur's Biology of Emerging Viral Infections Unit, led by Sylvain Baize – analyzed the first samples from Guinea and established the characteristics of the virus that had been discovered. Virological investigations led to the identification of Zaire ebolavirus (ZEBOV) as the pathogenic agent responsible for this epidemic. Whole genome sequencing and analysis were carried out in less than two weeks, and showed that the virus present in Guinea was a distinct variant of the strains previously identified in the Democratic Republic of the Congo and Gabon. Epidemiological investigations also established a link between laboratory-confirmed cases and the first deaths reported from December 2013 onwards.
Read the press release, Inserm and the Institut Pasteur identify a new variant of the Ebola virus in Guinea
An epidemic on an unprecedented scale
Transmission via road and air links rapidly led to an epidemic in the rest of Guinea and then in Liberia, Sierra Leone and, to a lesser extent, Nigeria, Senegal and the Republic of Mali. By September 2014, cases numbered almost 4,000, including 2,000 deaths. In other words the mortality rate was 50%. "Even the most trivial actions took on a new significance: nobody shook hands anymore," recalled Prof. Christian Bréchot, President of the Institut Pasteur, in a forum on medias24.com (in French) following a visit to Macenta – a rural village in Guinea’s forest region close to the source of the outbreak.
Ebola is a severe acute viral disease.
• The incubation period (the time between infection and the first symptoms) varies widely from 2 to 21 days.
• Early symptoms are "flu-like": sudden onset of a fever above 38°C, weakness, muscle pain, headache and sore throat.
• More specific symptoms follow: vomiting, diarrhea, rash, impaired kidney and liver function and, in some cases, internal and external bleeding.
• Diagnosis: laboratory testing is the only way to confirm the diagnosis; samples are analyzed under extremely strict containment conditions.
Two years later, in June 2016, when WHO announced that the epidemic was over, the official figures told a dismal tale: at least 28,000 confirmed and probable cases, including 11,000 deaths. The actual figures are undoubtedly higher. "Since its discovery in the Democratic Republic of the Congo [formerly Zaire] in 1976, the Ebola virus had never spread in such a way and claimed so many lives," explained Jean-Claude Manuguerra, the virologist in charge of the Laboratory for Urgent Response to Biological Threats (CIBU) at the Institut Pasteur in Paris. "Prior to that, the epidemic with the highest number of cases (425) had been in Uganda in 2000, and had claimed 224 lives."
However, although Ebola has killed fewer people than other infectious diseases since 1976, "the death rate from Ebola viruses is significantly higher, ranging from 30 to 90% of patients dying," explained Dr Maria Van Kerkhove, Head of the Outbreak Investigation Task Force at the Institut Pasteur’s Center for Global Health and a technical consultant for WHO. "We must respond to the Ebola virus by maintaining the highest level of vigilance, since the only thing we currently know for certain is that there will be another Ebola outbreak. With the rapid growth in world travel and trade, this virus now poses a threat beyond the borders of its country of origin."
International efforts in the field
At the start of the epidemic, WHO and its partners joined forces to provide a rapid response and give support to the populations affected in Guinea, Liberia and Sierra Leone. The contribution of these partners proved crucial, in particular the involvement of NGOs such as Médecins Sans Frontières (MSF), the Alliance for International Medical Action (ALIMA) and the Red Cross, as well as numerous other academic and public health professionals from Germany, the UK, Canada, China, Japan the US and Russia. In this first international response phase, WHO cites a number of drivers for action, including "an increase in the number of Ebola treatment centers and patient beds, and rapid recruitment and training of teams for burying the dead under risk-free but dignified conditions."
International efforts were stepped up and, "the Institut Pasteur played an active role in this global initiative," said Christian Bréchot, President of the Institut Pasteur. "The Institut Pasteur in Dakar, mandated by WHO, set up the first African laboratory, in Guinea, at Donka hospital in the capital, Conakry, and analyzed samples of suspected Ebola cases," said Kathleen Victoir, from the Institut Pasteur Department of International Affairs. "And they remained there for over two years."
"We set up a laboratory in Macenta, in Guinea’s forest region," added Christian Bréchot, "installed and run by Sylvain Baize’s unit." In total, there were 44 teams deployed and 37 volunteers assigned to the field, hailing not only from Sylvain Baize's Lyon unit, but also many teams from the Institut Pasteur in Paris (including the CIBU, see interview below), BioAster (a Technology Research Institute specialized in technological innovation in microbiology), École Normale Supérieure and various universities.
The building housing the high-tech diagnostic laboratory set up by the Institut Pasteur at the Ebola treatment center in Macenta, in the forest region of Guinea, in November 2014. © Institut Pasteur
The establishment of this laboratory in Macenta over such a long period and to such an extent was a first in the history of the Institute. This response was made possible by the involvement of local members of the International Network, in particular those from West Africa such as the Institut Pasteur in Dakar, and the Department of International Affairs in the Institut Pasteur in Paris. This Department, with the scientific coordination of Sylvain Baize, mobilized all the volunteers from the Institut Pasteur, in close collaboration with the French Red Cross, and with the financial support of AFD, the French government and the European Commission.
An extensive mobilization of France and many national and international operators
France has been one of the countries that has made a strong commitment to international mobilization to fight the Ebola epidemic, with a contribution of € 158 million in 2014-2015 and the widespread involvement of many health and safety professionals. The Institut Pasteur worked closely with Inserm and the IRD, and more broadly with the National Alliance for Life and Health Sciences, which was entrusted with the implementation of the Macenta Center (50 beds and a laboratory for biological analysis). NGOs Médecins sans frontières and the Red Cross have also been essential partners, working closely with the populations. Lastly, action on the ground was also conducted with the French operators of Expertise France (EF) and l’Agence française de développement (AFD), in conjunction with numerous national and international health stakeholders including le Haut conseil de la santé publique, l’Institut de veille sanitaire (Santé publique France), the World Health Organization (WHO), and the European Centre for Disease Control (ECDC).
endif; ?>We developed a faster and more robust test to diagnose the disease.
Can you explain the purpose of your laboratory – the CIBU?
The Laboratory for Urgent Response to Biological Threats was set up in 2002 by the French Ministry of Health and the Institut Pasteur to respond to biological emergencies requiring specialist expertise. By "specialist expertise" we mean the capacity to deal with epidemics, accidents (such as serious food poisoning outbreaks, for example) or the potential use of biological weapons. In other words, any situation presenting a risk to public health.
What was the role of the CIBU in Africa during the Ebola epidemic in 2014?
In the first instance, colleagues from the CIBU and the Institut Pasteur in Dakar spent two weeks in Guinea in April 2014, at the start of the epidemic. At that time we believed that the epidemic was coming to an end, as the number of cases was decreasing, and the epidemic was confined to Guinea. WHO and the Guinean government enlisted the help of our colleague Amadou Sall at the Institut Pasteur in Dakar to support the health authorities in their response. In September, Sylvain Baize’s unit set up a laboratory in Macenta – a village in Guinea’s forest region close to where the epidemic broke out. With the epidemic rife in urban areas, colleagues at the Institut Pasteur in Dakar remained in Donka hospital – the main hospital in Guinea’s capital, Conakry. Together, we tested thousands of samples from Guinea and its neighboring countries. My own team trained Guinean technicians in diagnosing the Ebola virus and in methods of taking samples from patients.
So did this training phase last until 2016?
Absolutely. Between July 2015 and April 2016 the Institut Pasteur in Dakar and the Institut Pasteur in the Ivory Coast trained some forty health care workers (from ten countries in West Africa) to enable them to diagnose Ebola. Ten of these people came to the CIBU in Paris during the summer of 2016 to learn how to train staff themselves and be capable of passing on their knowledge.
The CIBU developed a rapid diagnostic test.
Indeed, we developed a test for diagnosing the disease that was more rapid and, crucially, more reliable. We were already leading the field in this area, with our program for "detecting bacteremia in children under 5 in sub-Saharan Africa", funded by Médecins Sans Frontières (MSF) and the Institut Pasteur. Our aim was to develop a low-cost system that would be unaffected by power outages and easy to use in the field. Conventional diagnostic tests (based on RT-PCR) are very expensive, and the standard process takes two to three hours to provide a diagnosis. Our technique known as LAMP (Loop amplification mediated polymerization) is a cheaper alternative that uses small, lightweight equipment and, most importantly of all, gives a result within 15 minutes.
How did your presence in Guinea help your work to move forward?
We were able to conduct a clinical trial in the mobile laboratory in Macenta. This laboratory was adjacent to a patient treatment center built by MSF and managed by the French Red Cross. Proximity to patients was crucial. We were able to use samples from patients who had already had a positive diagnosis in order to validate and compare the performance of our own diagnostic test. Of course, treating the patient remains a highly complex process, but it is vital that a diagnosis is made as quickly as possible.
Is there currently other ongoing work on Ebola?
Of course, but media and public interest in this disease has, unfortunately, receded. When the risk subsides, it is sometimes difficult to amass the necessary funds to continue research into such diseases, even when the risk is only temporarily at bay. Our team is working on the resistance of the virus outside the host, and on the immunological properties of the virus. We are working with a virus called Cuevavirus, which is related to Ebola but which does not affect humans and is proving less dangerous to handle.
At the Institut Pasteur, a number of research programs have been set up for developing rapid diagnostic tests that are inexpensive and easy to use in the field or in hospitals. Pierre Lafaye, Head of the Antibody Engineering Platform, is coordinating these projects.
The importance of supporting local populations
The Ebola virus is spread between people via direct contact with the blood or bodily fluids of infected people, or through indirect contact with environments that have been contaminated by these fluids. "Fortunately, there is no risk of transmission during the incubation period [before those infected develop symptoms], and very little during the first few hours following the appearance of symptoms (high fever, bleeding or hemorrhaging, etc.)," stressed Félix Rey, who heads up the Structural Virology Laboratory at the Institut Pasteur. "The risk of contagion is highest once the disease has taken hold. This, in principle, enables better containment of an epidemic." However, one of the first facts to emerge from this epidemic was that the virus could be spread via sexual contact by survivors of the disease, during the months following recovery (see below, "Better understood but still no treatment"). Before this, it was hypothesized that patients who had recovered from the disease were no longer infectious but this discovery made it clear there was still a risk of transmission post-recovery. It is therefore essential to educate populations so as to avoid spreading the disease, both during the epidemic and following recovery.
WHO has always placed much emphasis on gaining the support and cooperation of local populations because, if they do not follow public health advice "it is difficult to identify sufferers or their contacts, which leads to a situation where transmission chains may continue unchecked." As early as 2014, Amadou Sall, Managing Director of the Institut Pasteur in Dakar, Senegal, whose team confirmed the first case of Ebola in Conakry, Guinea, explained that "this could lead to the teams in charge of this type of situation being completely unaware of the spread of the epidemic."
The teams led by Amadou Sall and Simon Cauchemez (the Mathematical Modeling of Infectious Diseases Unit at the Institut Pasteur in Paris) succeeded in reconstructing the chains of transmission of the Ebola virus and their context early in the outbreak, via a survey of local inhabitants carried out by local colleagues in the Guinean capital between February and August 2014. "While the risks of transmission were high in March 2014, either during burial ceremonies or in hospitals, viral transmission fell dramatically from April onwards, when safe funeral practices were put in place and a specific treatment center was opened," explained Simon Cauchemez, co-author of the study. These data demonstrate the positive impact of control measures on the spread of the epidemic, and highlight the challenges that had to be overcome to contain this epidemic in the main urban areas.
Hygiene measures to prevent viral transmission
The only way to curb epidemics and human-to-human transmission is to take appropriate precautions to avoid infection, including regular hand-washing, isolating patients and not allowing skin or mucosa to come into contact with infected fluids (which includes safe sex practices in the months following recovery). Physical protection, such as gloves, masks, goggles, gowns and boots, is vital.
Better understood but still no treatment
Advances in our knowledge of this disease were made by scientists all over the world during and after the 2013-2016 epidemic. It is essential to continue this research in order to develop a vaccine as well as diagnostic tools and therapies for screening and treatment of Ebola. Below is a list of lessons that medical research has been able to draw from this epidemic.
- The 2013-2016 epidemic allowed a more extensive observation of the virus and the way in which it progressively spreads to populations, in view of its scale (number of cases) and duration (two and a half years)*. Scientists were able to confirm that the virulence of the Ebola virus varies according to its species and strain. However, we need to know which viral genes contribute to virulence before we can understand their mechanisms of virulence and what led to such a severe outbreak in West Africa.
*The Ebola virus struck West Africa, a region hitherto unaffected by the disease. From 1976 onwards the virus was observed only in Central Africa (especially in the Democratic Republic of the Congo [formerly Zaire], which explains the origin of the name ZEBOV (Zaire ebolavirus).
- In people who survive the disease, ZEBOV can persist in immune-privileged sites within the human body, such as the eyes, breast milk and especially the testicles. In survivors, sexual transmission is possible in the weeks and months following recovery. We still need to understand how ZEBOV gains access to these immune-privileged sites within the human body and which cell types support viral replication, as well as the mechanisms of viral persistence.
- The Ebola virus adapted to better infect humans during the 2014-2016 epidemic (see inset below). It remains to be proven whether this viral genetic adaptation contributed to the devastating scale of the epidemic. This opens up a vast field of research for scientists as they seek to understand how these viruses evolve during the various stages of an epidemic, so that they can be better equipped to anticipate similar public health problems in the future.
Some viral variants increased their ability to infect humans
* University of Nottingham (United Kingdom); Institut Pasteur (Paris, France); CNRS (France); Institut Pasteur in Dakar (Senegal); Public Health Agency of Canada (Canada); University of Manitoba (Canada); University of Bonn Medical Center (Germany); University of Sydney (Australia); Université Laval (Canada); University of Pennsylvania (United States).
- Preventive treatment has proven effective. Vaccine candidates (based on recombinant vectors rVSV and rAd) have proved safe and immunogenic in clinical trials. A recent publication (December 23, 2016) proves the efficacy of the experimental Ebola vaccine rVSV-ZEBOV in a clinical trial involving 11,841 people in Guinea conducted in 2015. This trial was led by WHO, together with Guinea’s Ministry of Health, Médecins sans Frontières and the Norwegian Institute of Public Health, in collaboration with other international partners. Some factors remain to be studied, such as the length of immunity conferred by the vaccine.
- Curative treatments are being trialed. Antiviral treatments, which inhibit the replication or translation of Ebola virus or limit its propagation, have entered clinical trials. Scientists are speculating about whether new therapies will be necessary to eliminate the virus in privileged sites in the human body where the virus can persist. Questions also remain on routes of drug administration that could enable better targeting of the Ebola virus, particularly in immune-privileged sites, such as the eyes or the testicles.
Anticipating future pandemics of Ebola, Zika, etc.
A conference on November 8, 2016 organized by the Society of Exotic Pathology brought together top-level experts, in particular from the CNRS, Inserm, the Research Institute for Development (IRD), Bordeaux University Teaching Hospital and the Institut Pasteur. Scientists issued the following warning: "Given the risk of resurgence of the disease, former epidemic foci in Guinea, Liberia and Sierra Leone could suffer new outbreaks." Enhanced vigilance and health surveillance are therefore essential.
In the face of the seriousness of the situation in 2014, the Institut Pasteur set up a task force. "This working group involved scientists from the Institut Pasteur and fostered scientific collaborations around the Ebola virus," explained Kathleen Victoir, project leader, and Félix Rey, Head of the Structural Virology Laboratory, who are both driving forces behind this group at the Institut Pasteur. The task force, which met again on January 10, 2017, showed that most of these collaborations are now highly effective in the short term (sequencing), medium term (diagnosis) and longer term (fundamental research).
The Institut Pasteur in Guinea
It is clear that a coordinated international effort is essential for improving epidemic response strategies. Moreover, this effort must be maintained even in the interval between two epidemics. The Institut Pasteur has extended its commitment with the creation of the Institut Pasteur in Conakry, a decision made in 2014 in response to the Ebola crisis but with the goal of providing a permanent response to emerging epidemics. Construction began on the Institut Pasteur in Guinea – the 33rd institute within the Institut Pasteur International Network – on November 11, 2016. It is managed by Noël Tordo, who also heads up the WHO Collaborating Center for Viral Hemorrhagic Fevers and Arboviruses.
"The Institut Pasteur in Guinea is a branch of Gamal Abdel Nasser University in Conakry," explained Noël Tordo. "In spring 2017, we will be moving to a renovated laboratory within the university because the work is currently reaching completion. The new Institut Pasteur in Guinea building should be handed over in 2018. It will house the first BSL-3 laboratory* in Guinea." This institute, the 33rd and most recent member of the International Network has already conducted a review of Guinea's expert laboratories: "With the university we intend to set up Master's [thesis supervised by a doctoral school] to boost local skills, thanks in particular to the laboratory which will be operational in 2017 and will provide the necessary facilities for student training", added Noël Tordo.
* BSL-3, or biosafety level 3, concerns pathogenic agents whose contagion can be airborne and pose a threat (potentially fatal). Examples: anthrax, West Nile virus, SARS, tuberculosis, typhus, yellow fever, etc.
Other research into Ebola at the Institut Pasteur
- A safe and effective protective vaccine against the Ebola virus
Within the Viral Genomics and Vaccination Unit, and in collaboration with the Biology of Emerging Viral Infections Unit, led by Sylvain Baize, Frédéric Tangy is working on a preventive vaccine for the Ebola virus.
- A scalable treatment to reach as many people as possible
The team led by Pierre Charneau (Molecular Virology and Vaccinology Unit) is working on the development of a therapeutic Ebola vaccine.