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Online Discussion: Tracking new emerging diseases and the next pandemic

Ebola Again

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Officials pin hope on experimental drugs in latest Ebola outbreak

13 September 2018 • 1:12pm

The latest outbreak of Ebola in Democratic Republic of Congo is still a long way from being brought under control, a senior World Health Organization official has said.

In an interview with the Telegraph, Peter Salama, WHO's deputy director-general for emergency preparedness and response, said that in the original epicentres of the disease – around the towns of Mangina and Beni in the north east of the country – there were "promising signs" that the disease was coming under control.

But in the city of Butembo – where there have been four cases – the situation was less certain.

“Until we have traced every contact we cannot say for certain that the disease is under control,” he said.

The latest figures from WHO show that there have been 133 cases of the disease, including 91 deaths – making it the eighth largest Ebola outbreak in history.

The outbreak has been ongoing since the beginning of August in the north east of the country, where a number of militant groups operate and security is poor.

The Nord-Kivu and Ituri provinces of DRC, where the outbreak is occurring, are among the country's most densely populated areas with a combined population of around 11 million.

The area borders both Rwanda and Uganda and, because of the poor security situation, there is a constant flow of refugees out of the country.

Working in an area where security is such a concern has complicated the response, said Dr Salama. All responders have had to undergo security training and they are sent out with radios so staff at base can keep track of them.
"If the outbreak was to move further north or eastwards then we would be facing more complicating factors"Dr Peter Salama, WHO

Some 40 contacts living in the high-security "red zones" have been given mobile phones and asked to call in twice a day giving their temperature readings.

WHO and other responders have had to use a military escort to reach people around Oicha where there is considerable unrest.

"If the outbreak was to move further north or eastwards then we would be facing more complicating factors," said Dr Salama.

Dr Salama said that he hoped the use of experimental treatments would have an impact on the control of the disease.

As of September 11 around 29 people had been treated with the new therapies, 14 of whom had recovered and been discharged, eight have died and seven are still on treatment.

"Almost half of patients have been successfully treated so that's good news," said Dr Salama

The five therapies fall into two broad categories: monoclonal antibodies such as ZMapp and broad spectrum anti-viral drugs.

They have been approved for emergency use by the Congolese authorities and a team of clinicians, including representatives from WHO, the DRC ministry of health and NGOs such as Médecins Sans Frontières (MSF), take a range of factors into account before deciding whether to administer them.

François Esmyop, a doctor working in an MSF-run Ebola treatment centre in Mangina, said: "The first choice of drug is ZMapp but that's complex to administer so if we don't have enough capacity we will choose a second-line drug."

ZMapp is administered via an intravenous infusion and the patient needs to be continually monitored to ensure that they're getting the correct dose.

This is the first time such a range of therapies have been available during a live outbreak and doctors are keeping a close eye to work out the impact of the drugs. In previous outbreaks doctors have only been able to offer supportive care.

Dr Esmyop said: "Data is being collected but not in the same way as in a clinical trial. Setting up a clinical trial takes a lot of time and while they're being organised patients that may benefit would be left without access. We're operating under a monitored emergency use framework which allows the drugs to be used."

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An Update on the Current Ebola Outbreak in the Democratic Republic of the Congo

Sep 13, 2018 | Lauren Goodwin | Outbreak News

Since the 2014 West African Ebola outbreak that claimed more than 11,000 lives, the mere mention of Ebola hemorrhagic fever is enough to send the public health world into a frenzy. The thought of another outbreak is alarming enough, but an actual confirmed epidemic calls for immediate action. Since May 2018, there have been two confirmed outbreaks of Ebola in the Democratic Republic of the Congo (DRC). The first occurred in the northwest region of the country, with 54 cases and was declared over on July 24, 2018 (1). Relief swept through the health community, but this was short-lived because on August 1, 2018, a new Ebola outbreak was confirmed by the World Health Organization (WHO), in the northeast region of the country (2). More than a month into this current epidemic, the number of cases has surpassed the previous outbreak, with no definite end in sight.

As of September 11th, 2018, nine cities have reported cases of Ebola, including Masereka, Kalunguta, Beni, Butembo, Goma, Oicha, Mabalako and Musienene in North Kivu, and Mandima in Ituri. There have been 102 confirmed cases of Ebola in the North Kivu and Ituri provinces along the Ugandan border, 61 of which have died from the infectious disease (3). Simultaneously, there are 31 probable cases and 19 suspected cases, of which 31 have died (3). Promisingly, there have been 37 cases of Ebola that have been cured (3). Most Ebola cases have been reported in Mabalako, where there have been 66 confirmed cases and 43 confirmed deaths (3).

Despite advances in the development of a vaccine for the treatment of Ebola, this particular outbreak has a unique challenge. Physicians and public health workers during this outbreak face red zones around the city of Oicha and the Ituri province, making infiltration dangerous. A red zone is a region deemed unsafe to travel by the United Nations, with a high risk of attack and the recommendation that people should not enter the area under any circumstance. Both Oicha and Ituri are active militant zones. However, with this outbreak, there is no choice but to risk safety in order to deliver life-saving care and begin work on tracking the disease. For protection, World Health Organization workers require an armed escort through these to deliver vaccines and prepare outposts for controlling the epidemic (4). The UN peacekeeping force, which has around 20,000 personnel in the DRC has provided critical support in allowing medical teams to reach these regions (5).

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What about that new vaccine for Ebloa? Are any of the people treating Ebola patients willing to take the vaccines developed?
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I think they all are, FluMom. Would you work there without? I wouldn't


Ebola virus disease – Democratic Republic of the Congo: Disease outbreak news, 14 September 2018

Six weeks into the Ebola virus disease (EVD) outbreak in the Democratic Republic of the Congo, the overall situation has improved since the height of the epidemic; however, significant risks remain surrounding the continued detections of sporadic cases within Mabalako, Beni and Butembo health zones in North Kivu Province. While the majority of communities have welcomed response measures, such as daily contact monitoring and vaccination where appropriate, in some, risks of transmission and poor disease outcomes have been amplified by unfavourable behaviours, with reluctance to adopt prevention and risk mitigation behaviours. There have been challenges with contact tracing activities due to the constant movement of people between health zones, individuals hiding when symptoms develop and reports of community resistance. Risks are heightened by continued transmission in local health facilities because of poor infection prevention and control (IPC) measures, sporadic reports of unsafe burials, and the detection of cases in hard-to-reach and insecure areas.

Since the last Disease Outbreak News (data as of 5 September), eight new EVD cases, all of which are confirmed, have been reported: three from Beni, three from Butembo and two from Mabalako health zones. All eight new cases have been directly linked to an, ongoing transmission chain stemming from a community in Beni.

Of the three new cases in Butembo, one was an adult male from Mangina who reported an earlier illness and then was laboratory confirmed post-recovery via testing of a semen sample when his spouse was diagnosed with EVD. Given that he was asymptomatic since travelling to Butembo, the risk of onward transmission from this individual is minimal. The other two cases were health workers who cared for a subsequently-confirmed case (reported in the last Disease Outbreak News) at a small health post and assisted in her transfer to a tertiary hospital. This brings the total to 19 reported cases among health workers: 18 were laboratory confirmed and three have died. All 19 exposures occurred in local health facilities outside of dedicated Ebola treatment centres (ETCs).

As of 12 September 2018, a total of 137 EVD cases (106 confirmed and 31 probable), including 92 deaths (61 confirmed and 31 probable)1 have been reported in seven health zones in North Kivu Province (Beni, Butembo, Kalunguta, Mabalako, Masereka, Musienene and Oicha), and Mandima Health Zone in Ituri Province (Figure 1). An overall decreasing trend in weekly case incidence continues (Figure 2); however, these trends must be interpreted with caution given the expected delays in case reporting and the ongoing detection of sporadic cases. Of the 130 probable and confirmed cases for whom age and sex information is known, adults aged 35–44 years (22%) and females (57%) accounted for the greatest proportion of cases (Figure 3).

Alerts for suspected viral haemorrhagic fever cases in the outbreak-affected areas, other provinces of the Democratic Republic of the Congo, and in neighbouring countries continue to be closely monitored and rapidly investigated. In the outbreak-affected areas, 15–31 new alerts were reported each day during the past week, of which 4–16 alerts were verified as new suspected cases requiring further investigation and testing. As of 12 September, 17 suspected cases are currently pending testing to confirm or exclude EVD. Moreover, EVD was ruled out for recent alerts from Kasaji, Tanganyika, Tshopo and Kinshasa provinces, as well as for all alerts from neighbouring countries.

Public health response

The MoH continues to strengthen response measures, with support from WHO and partners. Priorities include coordinating the response, surveillance, contact tracing, laboratory capacity, IPC, clinical management of patients, vaccination, risk communication and community engagement, safe and dignified burials, cross-border surveillance, and preparedness activities in neighbouring provinces. WHO and partners are also conducting preparedness activities in neighbouring countries.

As of 13 September, 190 experts are deployed by WHO to support response activities including emergency coordinators, epidemiologists, laboratory experts, logisticians, clinical care specialists, communicators, and community engagement specialists.

Over 5500 contacts have been registered to date, of which 1751 remain under surveillance as of 12 September 1. Of these, 75–92% were followed-up daily during the past week. A dip in contact tracing performance rates observed earlier in the week was partly attributed to delays and challenges in establishing contact tracing teams around recent cases in Butembo and Masereka health zones.

Response teams are working to address these challenges and improvements in the proportion of contacts successfully reached have been observed in recent days. Strategies are being reviewed to ensure those at high risk of disease are prioritized, rapidly detected, isolated and admitted for treatment if symptoms develop.

As of 13 September, 52 vaccination rings have been defined, in addition to 17 rings of health workers and other frontline workers. These rings include the contacts (and their contacts) of 55 confirmed cases from the last three weeks. To date, 8902 people consented and were vaccinated, including 2951 health care or frontline workers, and 2054 children.

To support the MoH, WHO is working intensively with a wide range of, multisectoral and multidisciplinary regional and global partners and stakeholders for EVD response, research and urgent preparedness, including in neighbouring countries. The includes the UN secretariat, sister Agencies, including International Organization for Migration (IOM), the United Nations Children's Fund (UNICEF), World Food Programme (WFP), United Nations Office for the Coordination of Humanitarian Affairs (OCHA), Inter-Agency Standing Committee (IASC), multiple Clusters, and peacekeeping operations; World Bank and regional development banks; African Union, and Africa Centres for Disease Control and Prevention (CDC) and regional agencies; Global Outbreak Alert and Response Network (GOARN), Steering Committee, technical networks and operational partners, and the Emergency Medical Team Initiative. GOARN partners continue to support the response through deployment for response, and readiness activities in non-affected provinces and in neighbouring countries.

ETCs are fully operational in Beni and Mangina with support from The Alliance for International Medical Action (ALIMA) and Médecins Sans Frontières (MSF), respectively. MSF Switzerland and the MoH are building a 10-bed ETC in Butembo, which is expected to be operational by 15 September and will replace the current transit centre. In Beni, ALIMA is planning to expand treatment capacity over the next two weeks. A 20-bed ETC is being constructed in Makeke in Ituri Province with the support of International Medical Corps (IMC), which is expected to be operational during the week of 17 September. A MSF transit centre is already operational in Makeke. Samaritan's Purse continues to support the isolation unit in Bunia.

ETCs continue to provide therapeutics under the monitored emergency use of unregistered and experimental interventions (MEURI) protocol in collaboration with the MoH and the Institut National de Recherche Biomédicale (INRB). WHO is providing technical clinical expertise onsite and is assisting with the creation of a data safety management board.

The MoH, WHO, UNICEF, Red Cross and partners are intensifying activities to engage with local communities in Beni, Butembo and Mangina. Local leaders, religious leaders, opinion leaders, and community networks such as youth groups and motorbike taxi drivers are being engaged on a daily basis to support community outreach for Ebola prevention and early care seeking through active dialogues on radio and interpersonal communication. Community feedback is being systematically collected and their concerns are being addressed. Local frontline community outreach workers are working closely with Ebola response teams to strengthen community engagement and psychosocial support in contact tracing, patient care and safe and dignified burials (SDBs). The current focus is to intensify activities aimed at addressing community concerns through direct partnership with community members.

The Red Cross of the Democratic Republic of the Congo, with support from the International Federation of Red Cross (IFRC) and International Committee of the Red Cross (ICRC), are coordinating SDB. As of 12 September, Red Cross has established three operational bases in Beni, Mangina and Butembo; in total, 10 SDB teams are operational. To date, 124 SDBs are reported to have been successfully conducted. Red Cross has supported the training of civil protection SDB teams to ensure operational capacity in hard-to-reach areas.

Health screening has been established at 37 Points of Entry (PoE) and more than three million travellers have been screened at these PoE.

WHO risk assessment

This outbreak of EVD is affecting north-eastern provinces of the Democratic Republic of the Congo, which border Uganda, Rwanda and South Sudan. Potential risk factors for transmission of EVD at the national and regional levels include the transportation links between the affected areas, the rest of the country, and neighbouring countries; the internal displacement of populations; and the displacement of Congolese refugees to neighbouring countries. The country is concurrently experiencing other epidemics (e.g. cholera, vaccine-derived poliomyelitis), and a long-term humanitarian crisis. Additionally, the security situation in North Kivu and Ituri continues to hinder the implementation of response activities. Based on this context, the public health risk was assessed to be high at the national and regional levels, and low globally.

As the risk of national and regional spread remains high, it is important for neighbouring provinces and countries to enhance surveillance and preparedness activities. WHO will continue to work with neighbouring countries and partners to ensure health authorities are alerted and are operationally ready to respond.

WHO advice

WHO advises against any restriction of travel and trade to the Democratic Republic of the Congo based on the currently available information. WHO continues to closely monitor and, if necessary, verify travel and trade measures in relation to this event. Currently, no countries have implemented any travel restriction to and from the Democratic Republic of the Congo. Travellers should seek medical advice before travel and should practice good hygiene.

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19 Sep 2018

Democratic Republic of Congo: Ebola Virus Disease - External Situation Report 7
from World Health Organization
Published on 18 Sep 2018 — View Original
Download PDF (1.02 MB)

1. Situation update

The Ebola virus disease (EVD) outbreak in North Kivu and Ituri provinces, Democratic Republic of the Congo continues to be closely monitored, with the Ministry of Health, WHO and partners making progress in response to the outbreak. Recent trends (Figure 1) suggest that control measures are working, although these trends must be interpreted with caution. The outbreak remains ongoing in Beni, Mabalako and Mandima health zones, and additional risks remain following the movement of several cases from these areas to Butembo and Masereka in recent weeks.

Since our last situation report on 11 September 2018 (External Situation Report 6), an additional 10 new confirmed EVD cases and six deaths have been reported (Table 1). As of 16 September 2018, there are seven suspected cases under investigation, with five new confirmed cases in Beni, three in Butembo and two in Mabalako, with four new deaths in confirmed cases in Beni and two in Mabalako (Table 1). Two new cases in healthcare workers have been reported in the last week. Cumulatively, 19 health workers have been affected (18 confirmed and one probable), three of whom have died. All health workers’ exposures occurred in health facilities outside the dedicated ETCs.

As of 16 September 2018, a total of 142 confirmed and probable EVD cases, including 97 deaths, have been reported. Among the 142 cases, 111 are confirmed and 31 are probable. Of the 97 deaths, 66 occurred in confirmed cases. Among the 135 cases with known age and sex, 56% (n=75) are female. Among females the most affected age group is 25-34 years, while among men the most affected age group is 35-44 years (Figure 2). As of 16 September 2018, 38 cases have recovered and been discharged from Ebola treatment centres (ETCs).

A total of 16 cases (10 confirmed and 6 suspected) remain hospitalized in Mangina (2), Beni (8) and Butembo (6). On this reporting date, there were nine new admissions to Ebola treatment centres in Beni (5), Butembo (3) and Mangina (1). Two patients were discharged on the same day, one a previously suspected case and one a previously confirmed case who has now recovered.

The epicentres of the outbreak remain Mabalako and Beni health zones in North Kivu Province, reporting 63% (n=89) and 20% (n=29) of all confirmed and probable cases, respectively. However, since late August 2018, most new cases have occurred in Beni or are related to a Beni transmission chain. Of the total deaths to date, 67% (n=65) are from Mabalako, while 24% (n=23) are from Beni (Table 1 and Figure 3). Additionally, six other health zones in North Kivu Province and one in Ituri Province have reported confirmed and probable cases (Table 1 and Figure 3).

The Ministry of Health (MoH), WHO and partners are monitoring and investigating all alerts in affected areas, in other provinces in the Democratic Republic of the Congo (including Kisangani and Tshopo provinces) and in neighbouring countries. As of 16 September 2018, seven suspected cases are awaiting laboratory testing within outbreak affected areas (Table 1). Since the last report was published, alerts were investigated in several provinces of the Democratic Republic of the Congo as well as in Uganda and South Sudan; and to date, EVD has been ruled out in all alerts from neighbouring provinces and countries.

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EBOLA CRISIS: Victims ‘HIDE SYMPTOMS’ due to shock conspiracy fears

THE EBOLA virus has sparked a wide range of bizarre and outlandish conspiracy theories which has led to victims hiding their symptoms in fear of their lives.
By Matt Drake
PUBLISHED: 20:52, Thu, Sep 20, 2018 | UPDATED: 22:17, Thu, Sep 20, 2018

Some of the theories include that the deadly disease is a plot to kill off opposition voters. Others believe it is a money-making scheme by foreign groups.

People are refusing Ebola vaccines as a result and others throw stones at health workers in eastern Democratic Republic of Congo, where an Ebola outbreak has killed almost 100 people since July, according to the Red Cross.

Humanitarian workers hope a better understanding of these beliefs will help them gain trust, after Congo's health minister said that "community resistance is the first challenge to the response."

Emergency coordinator for medical charity Medecins Sans Frontieres, Berengere Guais, said: “People sometimes hide symptoms, refuse vaccination, perform unsafe burials.

"Ebola is a terrifying disease, which creates fear and mistrust."

The outbreak is believed to have killed 97 people so far and infected another 45, according to the health ministry.

It is in an active conflict zone, where rebellion and ethnic killing have persisted since two civil wars in the late 1990s in which millions died, mostly from hunger and disease.

Many people do not understand why scores of foreigners flew in for Ebola, while other problems got little attention, according to Ombretta Baggio, senior advisor for community engagement at the International Federation of Red Cross and Red Crescent Societies (IFRC).

She said: “It's very important that we move away from the same old messages.

“The population is very smart. They have specific questions."

Some have noted that the symptoms of Ebola resemble the effects of poison, she said.

Others think it is suspicious that when most people go to the treatment centre, they die.

This outbreak differs from the one in West Africa in 2014-16 in that political theories are more common than supernatural ones, the Red Cross analysis showed.

Congo is in a tense period leading up to a December election to replace President Joseph Kabila, who has outstayed his mandate since 2016, and Ebola struck in an opposition zone.

Red Cross volunteers try to convey two key messages - that they care about their patients and are gaining nothing, Baggio said.

They also try to find the source of the rumours - sometimes local leaders or politicians - and work backwards from there.

Baggio said: "People need to find an explanation in their belief system.

"It's not their fault."

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Ebola 'PERFECT STORM' as WHO chiefs predict 'major outbreak within weeks'

EBOLA could see a major outbreak "within weeks" as there is "perfect storm" conditions to allow the disease to run rampant, health chiefs have warned.

World Health Organisation (WHO) bosses issued the dire warning over Ebola today at a briefing on the diseased in the Democratic Republic of Congo (DRC).

Dr Peter Salama warned of “perfect storm” conditions which could trigger a massive spread of the disease.

He warned WHO are “extremely concerned” about the current trends in combating Ebola in DRC.

Ebola infected scores people in the African nation earlier this year, with relief efforts hampered by people refusing vaccines.

The health chief warned Ebola could spread because of attacks by armed groups, community resistance and the geographic spread of the disease.



69 confirmed dead in Congo as Ebola outbreak spreads
Virus has sickened 150 people in Congo


Posted: Sep 25, 2018 12:41 AM PDT Updated: Sep 25, 2018 12:44 AM PDT

(CNN) - Ebola virus disease has sickened 150 people and caused the deaths of at least 69 people in the Democratic Republic of Congo's northeastern region, the nation's Ministry of Health reported Monday.

Of these 150 cases, 119 have been confirmed and 31 are probable. An additional 31 deaths have occurred among probable and suspected cases, which would bring total Ebola deaths to 100 once confirmed. Forty-one people have recovered, according to the ministry.

On average, Ebola kills about half of those infected, but case fatality rates in individual outbreaks have varied from 25% to 90%.

In a tweet posted Monday, Dr. Peter Salama, WHO deputy director-general of emergency preparedness and response, stated that a case in Tchioma, an area of Congo that borders Uganda, "raises concern about further spread."

Public health teams are also investigating nine suspected cases not included among the 150, the ministry reported.

Ebola, which causes fever, severe headache and in some cases hemorrhaging, most commonly affects people and nonhuman primates, such as monkeys, gorillas and chimpanzees. This is a second, separate outbreak that has occurred in Congo so far this year, according to the World Health Organization. A previous outbreak, which began in May and ended in July, affected a western region of the country where 54 cases of Ebola virus were recorded, including 33 deaths.

Beginning with the 1976 discovery of Ebola in an area that is now the Democratic Republic of Congo, the country has experienced 10 outbreaks, including this year's outbreaks.

The North Kivu province is the epicenter of the outbreak, though some cases have been reported in neighboring Ituri province as well, according to WHO. Together, the two provinces, which are among the most populated in the nation, border Uganda, Rwanda and South Sudan.

Congo is concurrently experiencing a long-term humanitarian crisis that includes intermittent armed conflict, according to WHO, the United Nations' public health division. As a result, other health epidemics, including cholera, measles and polio, as well as human trafficking, are flourishing there. More than 1 million internally displaced people are in North Kivu and Ituri, according to WHO; the movement of refugees through and out of the provinces is a potential risk factor for spread of Ebola.

In a second tweet, Salama communicated that the Ebola response teams in the city of Beni were on lockdown beginning Sunday. A violent clash in Beni on Sunday led to the death of 18 people, General Bernard Commins, deputy commander of the UN peacekeeping forces, told Radio Okapi, a United Nations newscast.

Those on lockdown include the teams that distribute vaccinations, those who track family, friends and others who came in contact with those infected, and those who educate the public by working directly with the community. In its daily report, the Ministry of Health stated that "many residents of the city of Beni took to the streets on Sunday to protest the growing insecurity in the area." The Ministry added that field activities will resume "as soon as calm returns to the city."

This suspension of activity in Beni was addressed by Dr. Oly Ilunga Kalenga, Minister of Health, in a separate statement posted Monday.

"All the pillars of the response remain fully operational," he wrote. He specified that the Beni Ebola Treatment Center remains open to patients, vaccinations continue and free health care remains available at approved centers, including to victims of violence.

Teams of health care personnel in areas outside Beni are continuing to conduct field work, including providing vaccinations, according to WHO.

Since August 8, the Ministry has been inoculating people at high risk of an Ebola infection: primary and secondary contacts of those with confirmed Ebola infections. Since that date, 11,563 people, including medical staff, have been vaccinated, according to the Ministry of Health, which is leading the vaccination program with support from WHO and international partners, including Médecins Sans Frontières (Doctors Without Borders).

The experimental rVSV-ZEBOV vaccine, made by pharmaceutical company Merck, proved highly protective against the deadly virus in a major trial in Guinea, according to WHO.

Ebola virus spreads through direct contact with either bodily fluids or objects contaminated by someone ill with the disease, according to the US Centers for Disease Control and Prevention. In some cases, the virus is spread from contact with someone who has died from the disease. The virus enters the body through broken skin or mucous membranes in the eyes, nose or mouth. People can get it through sexual contact, as well.

"Beyond the medical response, the only way to end the Ebola Virus Disease epidemic remains the mobilization and commitment of the community alongside the health authorities," Kalenga said in a statement.


*Please add pinch of salt - the Daily Star is a bit of a comic.
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DRC Ebola outbreak: 100 dead of infection, rebel attacks intensify

September 25, 2018

Almost 2 months into the Democratic Republic of the Congo’s 10th Ebola outbreak, the virus has killed at least 100 people and escalating violence by armed government opposition groups continues to complicate the response, a WHO official said today.

At a news conference, Peter Salama, MBBS, MPH, WHO deputy director-general for emergency preparedness and response, said the response in North Kivu province has reached “a critical juncture.”

According to Salama, there have been 150 confirmed and probable cases of Ebola and at least 100 deaths from the virus in the current outbreak, but he said overall the trends have been positive in recent weeks, with case counts falling from about 40 per week to 10. Additionally, response teams have been able to contact and treat nearly 100% of all confirmed case contacts through the ring-vaccination method.

“We’ve seen some real breakthroughs in the tools we have at our disposal, particularly the vaccination program using the investigational Merck vaccine,” Salama said. “It has now reached more than 11,700 people, which is the largest scale use of an Ebola vaccine that we’ve ever seen.”

However, Salama said the response is facing a series of “grave obstacles,” including an increase in attacks by armed opposition groups in the area of the outbreak. He said there have been attacks on seven occasions: on Aug. 24 and six attacks now between Sept. 3 and Sept. 22.

Salama characterized the most recent attack in the city of Beni — the base for WHO’s response operation — as the most violent and dramatic attack thus far. He said it resulted in at least 21 deaths, including 17 civilians, and was the first in which civilians were indiscriminately targeted instead of state forces or United Nations peacekeepers.

“I’ve previously referred to the Ebola outbreak in North Kivu as arguably the most difficult context we have ever faced,” Salama said. “We are now extremely concerned that several factors may be coming together over the next weeks to months to create a potential perfect storm, a perfect storm of active conflict, limiting our ability to access civilians; distrust by segments of the community already traumatized by decades of conflict; and of murder, driven by a fear of a terrifying disease but also exploited and manipulated by local politicians prior to an election, and of course a frightening high-threat pathogen that will exploit these community and political fault lines and not respect borders whether they are provincial or international.”

Salama said residents of Beni and surrounding communities would be protesting and mourning through Friday, effectively shutting down WHO activities. The more than 80 WHO staff in Beni have been confined to the Emergency Operation Center or to their hotels for the time being, he said, having a negative impact on Ebola outreach.

“Yesterday, we only reached 20% of contacts of confirmed and probable cases, meaning 80% of people at risk were unable to be reached,” Salama said. “This whole week we may have cases that become more symptomatic and infectious.”

Salama explained that although most of the community has been responsive, there are large pockets of community distrust and resistance being exploited by politicians and rebel group leaders. This exploitation is causing people to refuse active follow-up and care, and flee in to surrounding forests, contributing to missed cases and the spread of Ebola into red zones and border countries, he said.

“We call again on all parties and any governances or groups that have influences over these parties to help protect responders and civilians and our access to them,” Salama said. “We call on the international community to continue to fund response in North Kivu and neighboring provinces and surrounding countries with priority on Uganda, Rwanda, South Sudan, and Burundi, and we call on those countries [to prepare].” – by Caitlyn Stulpin

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WHO: Congo Ebola outbreak could worsen rapidly

At least 100 people have died in the outbreak, out of 150 cases in North Kivu and Ituri provinces.

GENEVA - The World Health Organisation (WHO) said on Tuesday that an Ebola outbreak in northeastern Democratic Republic of Congo (DRC) could worsen rapidly because of attacks by armed groups, community resistance and the geographic spread of the disease.

“We are now extremely concerned that several factors may be coming together over the next weeks and months to create a potential perfect storm,” WHO’s head of emergency response Peter Salama told a news conference in Geneva.

At least 100 people have died in the outbreak, out of 150 cases in North Kivu and Ituri provinces.

The response was at a critical juncture, and although the weekly number of new cases has fallen from about 40 to about 10 in the past few weeks and more than 11,700 people have been vaccinated, there were kilometres obstacles ahead, Salama said.

Attacks by armed opposition groups had increased in severity and frequency, especially those attributed to the Alliance of Democratic Forces, most dramatically an attack that killed 21 in the city of Beni, where WHO’s operation is based.

The city has declared a run-up Neighbouring, a period of mourning until at least Friday, obliging WHO to suspend its operations.

On Monday 80% of Ebola contacts, people at risk of developing the disease and so requiring monitoring, and three suspected cases in and around Beni could not be reached for disease monitoring.


Pockets of “reluctance, refusal and resistance” to accept Ebola vaccination were generating many of the new cases, Salama said.

“We also see a very concerning trend. That resistance, driven by quite natural fear of this terrifying disease, is starting to be exploited by local politicians, and we’re very concerned in the run up to elections, projected for December, that that exploitation...will gather momentum and make it very difficult to root out the last cases of Ebola.”

Some people were fleeing into the forest to escape Ebola follow-up treatment and checks, sometimes moving hundreds of kilometres, he said.

There was one such case to the south of Beni, and another to the north, close to the riverbanks of Lake Albert. Both were inaccessible for security reasons.

Neighbouring Uganda was now facing an “imminent threat”, and social media posts were conflating Ebola with criticism of the DRC government and the United Nations and “a range of conspiracy theories”, which could put health workers at risk.

“We will not yet consider the need to evacuate but we are developing a range of contingency plans to see where our staff are best located,” he said.

“If WHO and its partners had to leave North Kivu...we would have grave concerns that this outbreak would not be able to be well controlled in the coming weeks or months.”

Absence of proof is not proof of absence.
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Thanks for tracking this news, Techno!

As always, the threat is if Ebola becomes established in a crowded African slum, with access to the outside world via air travel.

When I was in India during the last big outbreak in 2014, the Indian government was freaked out about the possibility of imported Ebola. Considering the squalid conditions of the streets and slums, I can see why....Ebola would cut through their population like a hot knife.
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Technophobe Quote  Post ReplyReply Direct Link To This Post Posted: September 27 2018 at 12:48am

DRC resumes battle against Ebola after militia attack

Vaccinations in North Kivu and Ituri set to continue as fears grow over impact of armed groups on disease spread

Efforts to fight the continuing Ebola outbreak in the Democratic Republic of Congo were set to resume on Wednesday after a 48-hour suspension following a attack by militia in which 21 people were killed.

At least 10 people have died so far from the recent outbreak of the disease, and 150 people are known to have been infected. The decision to resume the effort to vaccinate thousands of people in the provinces of North Kivu and Ituri will go some way to reassure worried health officials.
Ebola: medics brace for new cases as DRC outbreak spreads
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The World Health Organisation (WHO) said on Tuesday that the outbreak could worsen rapidly because of the attacks by armed groups, as well as because of community resistance and the broad geographic spread of the disease.

The outbreak has occurred in one of the most violent parts of DRC, a base for dozens of armed groups that contest government authority and exploit mineral resources in the region.

The militia attack on Saturday took pace on the outskirts of the city of Beni. In a second incident, in the town of Oïcha, about 12 miles north of Beni, armed men burned houses, killed one man and kidnapped 14 children and one woman on Monday night, according to two local officials.

Both attacks have been blamed on a group known as the Allied Democratic Forces (ADF), which has a history of targeting civilians and is considered one of the most active and violent of the armed groups operating in the region.

The insecurity in the region and a mobile population has made vaccination campaigns – like the one that helped overcome an Ebola outbreak that killed 33 people in the DRC’s north-west this year – less effective. Insecurity is likely to intensify as tensions rise with the approach of elections later this year, observers said.

“We are now extremely concerned that several factors may be coming together over the next weeks and months to create a potential perfect storm,” Peter Salama, the World Health Organisation’s emergencies chief, told a news conference in Geneva.

Although the weekly number of new cases has fallen from about 40 to about 10 in the past few weeks, and more than 11,700 people have been vaccinated, significant obstacles remained, Salama said.

Nyonyi Masumbuko Bwanakawa, the mayor of Beni, said vaccination of people had resumed. “All stakeholders including civil society leaders have agreed to resume the work on Wednesday because suspending it can be dangerous to those infected ... everybody understands the severity of the epidemic.”
Congo enters uncharted territory as it faces gravest Ebola challenge to date
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The Congolese army has launched new operations against the ADF to try to ensure the campaign against Ebola can continue safely. A military spokesman said the militia attacked on Saturday at about 6:30pm and clashed with the army for nearly six hours. The militia’s long-term aim appeared to be to establish a base close to Beni. After the attack Beni declared a “ville morte”, a period of mourning, until at least Friday.

On Monday 80% of Ebola contacts (people at risk of developing the disease and so requiring monitoring) and three suspected cases in and around Beni, could not be reached for disease monitoring, officials said.

The town of Oïcha, which is almost entirely surrounded by territory held by the ADF, has two confirmed cases of the virus and one probable case.

Pockets of “reluctance, refusal and resistance” to accept vaccination were generating many of the new cases, Salama said. Some people were fleeing into the forest to escape Ebola follow-up treatment and checks, sometimes moving hundreds of miles.

Uganda, to the east, is now facing an imminent threat, and social media posts were conflating Ebola with criticism of the DRC government and the UN and a range of conspiracy theories, a development that could put health workers at risk.

The DRC, whose heavily forested interior makes it a natural home for Ebola, is at the forefront of a global campaign to combat the disease. The biggest recorded outbreak of Ebola killed an estimated 11,300 people across Guinea, Liberia and Sierra Leone, from 2014 to 2016. The disease was first seen near the northern Ebola river in DRC in the 1970s. It has twice reached Kinshasa but, on both occasions, was contained.

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Ebola viral dynamics in nonhuman primates provides insights into virus immuno-pathogenesis and antiviral strategies

    Vincent Madelain, Sylvain Baize, Frédéric Jacquot, Stéphanie Reynard, Alexandra Fizet, Stephane Barron, Caroline Solas, Bruno Lacarelle, Caroline Carbonnelle, France Mentré, Hervé Raoul, Xavier de Lamballerie & Jérémie Guedj


Despite several clinical trials implemented, no antiviral drug could demonstrate efficacy against Ebola virus. In non-human primates, early initiation of polymerase inhibitors favipiravir and remdesivir improves survival, but whether they could be effective in patients is unknown. Here we analyze the impact of antiviral therapy by using a mathematical model that integrates virological and immunological data of 44 cynomolgus macaques, left untreated or treated with favipiravir. We estimate that favipiravir has a ~50% efficacy in blocking viral production, which results in reducing virus growth and cytokine storm while IFNα reduces cell susceptibility to infection. Simulating the effect of delayed initiations of treatment, our model predicts survival rates of 60% for favipiravir and 100% for remdesivir when treatment is initiated within 3 and 4 days post infection, respectively. These results improve the understanding of Ebola immuno-pathogenesis and can help optimize antiviral evaluation in future outbreaks.

The 2013–2016 Ebola virus disease (EVD) outbreak in West Africa has been the deadliest occurrence of the disease since its discovery in 1976, resulting in 28,616 cases, of which 11,310 were fatal1. There is no validated therapeutic protocol against EVD and none of the clinical trials performed during the outbreak, using either small molecules2,3, monoclonal antibodies4, siRNA5 or convalescent plasma6 could demonstrate a statistically significant reduction of mortality in EVD.

In absence of cases during inter-epidemic period, NHP models are central to understand virus pathogenesis and to assess the efficacy of treatments against Ebola virus and other related hemorrhagic fever viruses7,8. In 2016, our group implemented in cynomolgus macaques a model of EVD which well recapitulates the disease in humans, with virus being detectable at day 3, followed by an exponential increase of virus up to day 7 and death between days 8 and 119. The experimental model was used to assess the efficacy of favipiravir, a broad spectrum RNA polymerase inhibitor10, demonstrating that high doses of favipiravir administrated intravenously significantly increased survival rate11. Of note, the route of treatment administration may be important, as per os administration of favipiravir led to a lower survival rate12. Using another NHP model of EVD, promising results were also obtained by USARMIID with a novel polymerase inhibitor, GS-5734 (remdesivir), showing that the course of the infection could be reversed with 100% survival rate when a dosing regimen of 10 mg kg−1 QD was initiated 3 days after viral challenge13. Although experiments with favipiravir and GS-5734 evidenced that direct antiviral drugs can limit virus replication and increase survival, it is yet unknown how these drugs act in vivo and to what extent they could be useful outside prophylaxis or early post exposure in NHPs and, a fortiori, in humans.

For that purpose, it is critical to get a more detailed understanding of the effect of antiviral treatment on the pathogenesis of EVD, and how it may potentiate the innate and adaptive immune response. Studies performed in EVD patients during the previous outbreaks consistently highlighted the deleterious effect of the inflammatory response on the vital prognosis14,15,16 and in particular the negative correlation between high levels of pro- or anti-inflammatory cytokines at study inclusion (IL6, IL10, IL1β, TNFα, MIP1α, MIP1β, and MCP1) and disease outcome16,17. Furthermore global immunosuppression state and altered adaptive responses, as suggested by the high level of T cells expressing inhibitory molecules CTLA-4 and PD-1, were also associated with fatal outcome16. In contrast a strong CD8 T cell response was reported in survivor patients18, suggesting that the adaptive immune response is key to achieve viral clearance. However, the mechanisms involved in viral clearance are still poorly known, due to the clinical, technical, and ethical difficulties to collect large dataset in humans. Here we collected repeated measures of various markers of the inflammatory and the immune responses during acute infection in 44 untreated and treated cynomolgus macaques19,20. Taking advantage of the fact that animals treated with favipiravir had an extended survival while untreated ones died within 11 days, we could describe the dynamics of these markers not only from infection to death but also, in some animals, to viral clearance. This allowed us to assess the relationship between viral replication, inflammatory response and lymphopenia14,15,16,17, and to explore the role of antiviral treatment in potentiating innate and adaptive immune response in viral clearance18.

Mathematical modeling has provided a quantitative understanding of viral dynamics for a number of acute infections, including influenza, dengue or Zika virus21,22,23,24. In this study we use the techniques of mathematical modeling to analyze the large amount data collected in these animals and in particular to characterize the role of antiviral treatment in potentiating the innate and adaptive immune responses18 and improving survival. We discuss the implications of these results to optimize antiviral treatment in future Ebola outbreaks.
Survival and virological response

A total of 44 animals were challenged with Ebola virus Gabon 2001 strain and followed for 21 days over 4 successive experiments (Fig. 1)9,11. This included 28 animals untreated and 16 treated with doses of 100, 150, or 180 mg kg−1 (N = 6, 5, and 5, respectively) of favipiravir given intravenously twice a day (BID) for 14 days, starting 2 days before infection. All animals left untreated died within 11 days post infection. In contrast, increasing doses of favipiravir significantly extend animal survival (p value = 0.022; p value < 0.001, and p value < 0.001 in macaques receiving 100, 150, and 180 mg kg−1 BID respectively, logrank test), leading to an overall survival rate of 50% (5/10) at day 21 in macaques receiving 150 or 180 mg kg−1 (Fig. 1). Survivor macaques at D21 post infection normalized their clinical score and achieved undetectable levels of infectious titers in plasma11, as well in liver and spleen (Supplementary Table 1).

Survival and virological data. a Design of the four infected NHP experiments. b Survival curves. c Ebola virus plasma viral load. d Favipiravir plasma concentrations. Dosing regimen groups were untreated (black), 100 mg kg−1 BID (green), 150 mg kg−1 BID (blue), and 180 mg kg−1 BID (red). Gray areas correspond to dosing periods
Description of cytokines and CD8 T cell dynamics

All untreated animals had a cytokine storm characterized by a continuous increase in cytokines levels, in particular pro inflammatory IL6, TNFα, IFNα, from day 5 post infection (D5) to the time to death (Fig. 2). Animals treated with 150 or 180 mg kg−1 favipiravir BID showed a delayed peak of cytokine levels and much lower levels of pro-inflammatory than untreated animals, even for those that did not survive up to D21.
Description of cytokines and CD8 T cell dynamics

Cytokine and immunological data. Plasma pro inflammatory cytokines Interleukin-6, Interferon α and Tumor necrosis factor α, and CD8 T cells expressing perforin in macaques left untreated (black, left panels), receiving favipiravir 150 mg kg−1 BID (blue, middle panels) or 180 mg kg−1 (red, right panels). Gray areas correspond to dosing periods

In the subset of 10 animals where these data were available, a profound lymphopenia was observed in all lymphocyte subpopulation, with a nadir time occurring between D7 and D11, with median [min–max] value of 511 [49–993] cells per mm3, consistent with what is observed during EVD15,20. In the 4 animals that had an extended survival, CD4 and CD8 T cell counts rapidly increased after D10, in particular those expressing cytotoxic surface markers (granzyme B, perforin), activation surface markers (CD95 + ) and memory markers (CD27-, CD28-, CD45RA-) (Fig. 2 and Supplementary Figure 1).
Association between cytokine levels and disease progression

At D7, viremia significantly correlated with a number of cytokines, in particular IFNα (r = 0.89, q value < 0.001, Spearman correlation test), and IL6, IFNγ, MIP1β, MCP1, G-CSF (all q values < 0.05, Spearman correlation test) to a lesser extent (Supplementary Table 2). The association between levels of inflammation at day 7 and survival times was even greater, with a large number of cytokines having a significantly negative correlation with survival times (Supplementary Table 2, Supplementary Figure 2). The largest association between cytokine value at D7 and survival time was found for IL6 (r = −0.93, q value < 10−5, Spearman correlation test), consistent with clinical observations17, and this correlation was larger than that between viremia and survival (r = 0.79, p value = 3.4×10−5, Spearman correlation test). Overall six cytokines (IL6, IFNα, G-CSF, IL10, IL1RA, and IFNγ) had a higher correlation rate with survival time than viremia (Supplementary Table 2).
Integrated model of viral and immune response dynamics

Mathematical models of increasing complexity were used to fit EBOV viremia in untreated and treated animals (Supplementary Table 3). All models shared a number of assumptions, in particular the facts that (i) blood compartment was a good reflect of infection, (ii) a single compartment was used for the target cell populations, (iii) infected cells went through an eclipse phase before being productively infected, and the duration of this eclipse phase was exponentially distributed, (iv) favipiravir reduced viral production in a concentration dependent manner (detailed in Supplementary Methods). The model focused on the systemic infection, relying on measurement in blood, and did not include specific immune preserved sites such as genital tract or eyes where the kinetic of the infection may be different. As the virus has a broad cell tropism and disseminates early in the infection in blood and lymph circulation, the model assumes that the various cellular types targeted by the virus (including monocytes, hepatocytes, adrenocortical cells, fibroblast, and epithelial cells25) can be summarized into one target cell population, with homogenous repartition in the body.

The first model was a standard target cell limited model, which predicts that peak viremia occurs when the pool of susceptible cells has been largely depleted21. Although the model could provide a good fit to each individual viremia, model based predictions showed that it under-predicted the effect of high doses of treatment (Supplementary Methods), suggesting that the exhaustion of susceptible cells was not sufficient to explain viral dynamics.

Next, we analyzed whether viral load description could be improved by taking into account the effects of the innate immune response on viral replication (Supplementary Methods). We assumed that the production of type I IFN by activated macrophages26 was proportional to the number of infected cells. We tested in the model the main mechanisms by which the upregulation of IFN stimulated genes26 impacted viral replication, namely increasing cell refractoriness to infection27,28, reducing viral replication from infected cells28,29, increasing the loss rate of infected cells29,30 or increasing target cell availability31,32 (see Methods). Models assuming that pro-inflammatory cytokines increased cell refractoriness to infection consistently provided the best fit to the viral load, allowing to capture the dose effect relationship on viremia (Supplementary Methods). Given their high level of correlations, a similarly good prediction of the viremia was obtained when assuming that this effect was driven by either IFNα, IL6, or TNFα. Because the effects of IFNα is supported by in vitro experiments27,33, we decided in the following to include only the effect of IFNα; given the high level of correlation and the variability in cytokine dynamics, we kept IL6 and TNFα in the model as instrumental variables reflecting the overall level of cytokine response.

Thirdly, the model was extended to include the adaptive response, assuming a decline of non-specific cells and an expansion of specific cytotoxic cells. Including CD8 T cells expressing perforin provided the best improvement of the viremia data description and could reproduce both the cytokine-mediated lymphopenia observed in early infection and the rapid viral decline in NHPs after peak viremia. The ordinary differential equation system and a schematic representation of the final selected viral dynamic model are given in Fig. 3. The corresponding code to estimate the model parameters and performe simulations is provided in Supplementary Software.

Schematic and mathematical model of Ebola virus infection. As the virus early disseminate in blood and lymph circulation, the model assumes only one target cell compartment. After infection by free virus (V), target cells (T) enter an eclipse phase (I1) before becoming productively infected (I2), which activate macrophage and production of cytokines. Cytokine release, in particular IFNα, leads to an increase of cells that are refractory to infection (R), and triggers apoptosis of non-specific CD8 T cells (E1), which creates room for proliferation of EBOV-specific CD8 T cells (E2) that eliminate productively infected cells I2 Polymerase inhibitors as favipiravir inhibit viral production with efficacy ε
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Impact of viral and cytokine dynamics on disease progression

Next, we investigated the impact of viral and cytokine dynamics on survival times. Tissue damage in EBOV-infected individuals is caused by direct viral-induced cytopathic effects and indirect organ injury mediated by host inflammatory responses, endothelial dysfunction, and disordered coagulation34. Activation of the monocytes/macrophages induces the release of multiple pro inflammatory mediators, including (TNF)-α, interleukin (IL)-1, IL-6, and nitric oxide, which induces cell apoptosis or necrosis35. Thus in our model, we assumed that viral load (including a lag-effect) could impair the instantaneous risk of death. We found that this model provided a less good description of the distribution of time to death than a model assuming that it was impacted by either one of IL6, TNFα or IFNα (including a lag-effect). Only the effect of IFNα on survival was kept in the model, which well recapitulated the mortality rate observed until D21 in all dosing group regimens (Fig. 4). The lag effect constant was estimated to 0.3 per day corresponding to an average delay of 3.1 days to impact NHP survival.

Model-based predicted survival rate (plain lines) and Kaplan–Meier survival curves and 95% confidence interval (shaded areas) for each dosing regimen group. Top left: cynomolgus experiment control pooled from the 4 experiments (N = 28), top right: favipiravir 100 mg kg−1 BID (N = 6), bottom left: favipiravir 150 mg kg−1 BID (N = 5), bottom right: favipiravir 180 mg kg−1 BID (N = 5). In each panel, model-based predicted survival rate was calculated by simulating 1000 individuals for each dosing regimen and taking the medians of the predicted individual survival functions at each time
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Viral dynamic model predictions and parameters

In acute infection, peak viremia occurs when the number of newly infected cells does no longer compensate for the loss of infected cells. In our integrated model the main cause of reduction in cell infection was not due to the depletion of target cells (like in the target cell limited model) but to the fact that IFNα increases the number of target cells that are refractory to the infection. In fact, the model predicted that low levels of IFNα of about 1.7 pg mL−1 (Table 1) are sufficient to induce half of the maximal conversion rate of susceptible cells to an antiviral state. However, IFNα concentrations greater than about 17 pg mL−1 provide very little additional benefit for cell protection. Thus, in untreated animals the infection leads to a massive release of IFNα (with median levels of 400 pg mL−1 at peak viremia, Fig. 5) that negatively affects survival rate while having only little effect on limiting cell infection. On the contrary, in treated animals, favipiravir reduces viral production, and hence the number of infected cells and IFNα concentrations are lower. This is sufficient to confer a nearly similar effect on cell infection, reduce and delay peak viremia while limiting the deleterious effect of cytokine storm on survival (Fig. 5). We also verified that including target cell regeneration did not modify the model predictions, assuming a proliferation rate value no greater than 1 per day.
Table 1 Parameter estimates of the final viro-immunologic model of Ebola virus disease in cynomolgus macaques
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Table 1 Parameter estimates of the final viro-immunologic model of Ebola virus disease in cynomolgus macaques

From: Ebola viral dynamics in nonhuman primates provides insights into virus immuno-pathogenesis and antiviral strategies
Parameter      Name      Unit      Fixed effect      sd of the random effect
                 Estimate      r.s.e.(%)      Estimate      r.s.e.(%)
Baseline clearance rate of productively infected cells      δ      Per day      0.224      9      0.169      40
Viral production      p      Virion per cell per day      4.15×104      71      1.76      18
Clearance rate of virions      c      Per day      20      –      0      –
Initial number of target cells      T 0      Cells per mL      108      –      0      –
Inoculum size      V 0      Virion per mL      10−4.1      11      1.5      17
Virion infectivity      β      mL per virion per day      7.9×10−11      73      0      –
Rate of transition to productively infected cells      k      Per day      4      –      0      –
Favipiravir maximal effect      E max            1      –      0      –
Drug concentration giving 50% of maximal effect      EC50      µg per mL      191      20      0      –
IFNα production rate      q      pg per cell per day      0.0074      69      0      –
IFNα elimination rate      d F      Per day      0.4      –      0      –
IFNα concentration giving 50% of max effect      θ T      pg per mL      1.73      35      1.05      16
Maximal rate of transition from target to refractory cells      ϕ      mL pg per day      2.67      17      0      –
CD8 T cell perforin+ baseline value      C 0      Cell per mL      36,900      30      0.775      23
Initial proportion of EBOV-specific CD8 T cell perforin+      P 0            0.001      –      0      –
CD8 T cell perforin+ elimination rate      δ E      Per day      0.001      –      0      –
CD8 T cell perforin+ elimination rate mediated by viremia      ζ      mL per virion per day      0.455      41      0      –
Specific CD8 T cell perforin+ growth constant      ρ      Per day      0.338      11      0      –
Non specific CD8 T cell perforin+ growth constant      σ      cell per mL per day      3050      87      0      –
IFNα concentration providing 50% of max effect on CD8 T cell perforin+ depletion      θ E      pg per mL      6.5×10−4      233      0      –
CD8 T cell perforin+ mediated infected cell elimination rate      κ      Per day per cell per mL      2.08×10−5      31      0      –
IL6 production rate      q L      pg per cell day      0.0097      65      0.76      37
IL6 elimination rate      d L      Per day      0.4      –      0      –
TNFα production rate      q N      pg per cell per day      0.0046      69      1.03      30
TNFα elimination rate      d N      Per day      0.4      –      0      –
Maximal hazard of death      λ m      Per day      1.12      2      0      –
IFNα effect compartment concentration inducing 50% of the maximal hazard      F 50      pg per mL      103      12      0      –
Transfer constant      k s      Per day      0.319      3      0      –
Hill coefficient      γ            2      –      –      –

    Parameter of the longitudinal and the joint models were sequentially estimated
    sd: standard deviation, r.s.e.: relative standard error

Individual observation (dots) and median model predictions (line) in animals left untreated (black) or treated with 180 mg kg−1 BID favipiravir (red). Top left: Ebola virus viral load; top middle CD8 T cells expressing perforin; top right: model prediction of productive infected cell elimination rate, increasing concomitantly to adaptive response; middle left: IFNα concentrations; middle: IL6 concentration; middle right: TNFα concentration; bottom left: predicted ratio of protected cells on the concentration of IFNα (R/F); bottom middle: model prediction of the ratio of infected on protected cells (R/I2); bottom right: Kaplan Meier curves and survival rate prediction. Shaded areas represent the predictions within the 10th and 90th percentiles of 1000 simulations
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Impact of CD8 T cell dynamics on infected cell half-life

The main effect of the specific adaptive response in the model was to increase the clearance rate of productively infected cells, and this was supported by the fit of the CD8 T cells expressing cytotoxicity surface markers. In the days that follow infection, the half-life of infected cells was estimated to about 3 days (δ = 0.22 per day), suggesting that in absence of adaptive response, it would take several weeks to clear viremia. However the loss rate of infected cells increased with the levels of CD8 T cell, in particular those expressing perforin, leading to a much shorter half-life of about 16 h (δ = 1 per day) at D21 in animals that survived, which explains the rapid clearance of viremia observed after peak in surviving animals (Fig. 5).
Antiviral effectiveness of favipiravir

Given the pharmacokinetics of the drug (see Supplementary Methods), one can estimate the in vivo drug EC50, equal to 191 µg mL−1 (Table 1). Importantly this estimate was robust in all the viral kinetic models considered and in the sensitivity analysis (Supplementary Table 4, Supplementary Methods). Accordingly, the effect of favipiravir in impairing viral replication was modest with maintenance doses of 150 and 180 mg kg−1 BID leading to a median effectiveness of 40 and 50%, respectively. Simulation suggested that higher doses (250 and 300 mg kg−1 BID) may increase median effectiveness to 66 and 72% respectively, and survival rate at day 21 to about 80% (Supplementary Figure 3).
Validation of the model on rhesus macaques receiving GS-5734

We assessed whether the mathematical model could be applied to a different animal model and another antiviral drug, namely GS-5734, a potent nucleotide polymerase inhibitor. In this experiment from literature13, 12 rhesus macaques were challenged by 1000 focus forming unit (ffu) of EBOV and 6 animals were treated with 10 mg kg−1 QD of GS-5734 initiated at D3 post infection (see Methods and Supplementary Figure 4)13. The drug antiviral effectiveness was estimated to 88%, and this could well fit the viral load data observed in all animals, in particular the sharp reduction in viral levels after treatment initiation (Supplementary Figure 4). With this level of efficacy, the model well reproduced the survival rates of 0 and 100% observed in untreated and treated animals, respectively, showing that the model could be relevant to predict survival in a different experimental setting.
Impact of drug efficacy and timing of initiation on survival

Next we used the model to predict the impact of various levels of efficacy and timing of treatment initiation on survival. For that purpose we neglected PK related variations and assumed constant drug effectiveness of 50 and 90%, respectively, which correspond to the median efficacy observed with favipiravir 180 mg kg−1 BID and GS-5734 10 mg kg−1 QD, respectively. In the case of favipiravir, delaying treatment initiation up to 3 days after viral challenge was predicted to marginally affect survival, with a survival rate between 60 and 70% in all cases (Fig. 6). However treatment initiated at D5 or after led to a survival rate of less than 10%. Treatment with a more potent drug such as GS-5734 could achieve 100% survival if initiated to D4 and 70% survival if initiated to D5. Yet, treatment initiated at D6 or after led to a predicted survival rate of 0%.

Viral load and survival rate predictions for various levels of drug efficacy and timing of treatment initiation, assuming no pharmacokinetic variability. Left: ε = 50% (eg, favipiravir), middle: ε = 90% (eg, GS-5734); right: ε = 99%. Dark blue: treatment initiation at D0, magenta: D2, light blue: D3, yellow: D4, green: D5, brown: D7. Results show the median of 1000 simulations
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Given these levels of efficacy, the combination of the two drugs may only slightly improve survival compared to GS-5734 alone, with a combined drug effectiveness of 95% (Supplementary Figure 5). However, associating favipiravir with another drug having a similar potency would result in a combined effectiveness of 75%. This may allow to achieve 100% survival if treatment is initiated up to D3 and 90% if treatment is initiated up to D4 (Supplementary Figure 6).

In order to achieve 100% survival up with a treatment initiated at D5, we estimated that drug antiviral effectiveness would need to be larger than 99%, i.e., larger than what is achieved with GS-5734 alone or in combination with favipiravir. However, despite reducing viral load levels, such level of high effectiveness would yet not be sufficient to reverse the course of the disease if treatment is initiated after D5 (0% survival). This reinforces the idea that, in order to be effective, a purely antiviral treatment needs to be administered at least 2 days before peak viremia and cytokine storm (Fig. 6). However, simulations assuming other mechanism of action of the drug, such as increasing the loss rate of infected cells, could extend the time window of intervention (Supplementary Figure 7).

This study provided an integrated picture of EVD pathogenesis and the role of viral polymerase inhibitors to avert disease progression. The systematic approach used to construct our model showed that the best description to the data was obtained assuming that the main role of the innate response during early infection was to increase the number of target cells refractory to the infection, while the cytotoxic adaptive response, in particular the CD8 T cells expressing perforin, significantly increased the elimination rate of infected cells after peak viremia (D7). In this interplay between the host and the virus, favipiravir inhibits viral production from infected cells, with an efficacy close to 50% at the highest doses used, allowing to delay the exponential growth of infected cells and the deleterious effect of cytokine storm on survival. This virtuous interaction between treatment and innate immune response explains our prediction that about 60% survival could obtained if treatment is given in the first 3 days of infection (Fig. 5).

The cytokine dynamics were largely consistent across animals, with uncontrolled levels of cytokines in untreated animals, strongly associated with time to death and reflecting the shock state leading to multi-organ failure and death observed in these animals36. In contrast, animals treated with 150 or 180 mg kg−1 BID favipiravir exhibited much lower levels of pro-inflammatory cytokines than untreated animals. By comparing the dynamics in animals that survived and those that did not survive, the model proposes a quantitative understanding of the antagonist effects of the inflammatory response observed in our data here and elsewhere14,15. The model predicts that low concentrations of circulating IFNα of only 1.7 pg mL−1 are sufficient to induce half of the maximal conversion rate of target cells to refractory cells. This is much lower than the values observed in untreated animals, which increased up to 400 pg mL−1. Thus in untreated animals large amount of IFNα are released that negatively affects survival rate without increasing much the level of immunity. This is consistent with the dual roles played by type I IFN during infections. Indeed, besides their beneficial direct antiviral effect, type I IFN may be deleterious when released at high levels and for a prolonged period. These effects include increase of inflammatory mediator release, depletion of T cells, destruction of the secondary lymphoid architecture, and inhibition of hematopoiesis, all of them likely occurring also during severe Ebola virus disease in humans37,38. Reversely, treatment with favipiravir reduces viral replication, which downregulates IFNα and other cytokines release and confers a nearly similar level of cell protection while limiting the deleterious effect of the inflammatory response. This allows the animals to pass the peak viremia and to give time for the induction of an effective adaptive immune response after D7. Consistent with our assumption on IFNα limiting cell infection, we previously reported that EBOV viral dynamics in type I IFN receptor knock out mice could be captured by a simple target cell limited model ignoring the impact of the innate immune response39. Further, untreated mice had an extensive hepatic cytolysis40 while the levels of ALT observed here were much lower (median peak value < 500 IU L−1), supporting the hypothesis that the innate response limits cell depletion in NHP.

The adaptive CD8 T cell response could only be observed in animals that had an extended survival, which were all treated with 180 mg kg−1 BID. Including the effect of the CD8 T cell response in reducing infected cell half-life significantly improved data fitting. In the days that follow infection, the half-life of infected cells was estimated to about 3 days, suggesting that in absence of an adaptive response, it would take several weeks to clear viremia. However, the increase in the cytotoxic adaptive response led to a rapid decrease of the infected cell half-life (16 h at D21), allowing viral clearance to occur in about 10 days after the peak, at least in peripheral blood. These results, albeit obtained on a limited number of animals, are consistent with the description of a strong cellular response in survivor patients18 and with the potential role played by this response in the control of EBOV infection. Although the model used for the adaptive immune response could well reproduce the limited body of data available, more complex models may be needed in the future to take into account other factors such as T-cell redistribution or bystander activation of non-antigen specific T-cells41.

Our analysis therefore supports the following chain of events: exponential viral replication during acute infection leads to a rapid increase in cytokine levels, which in turn limits cell infection and viral spread but also increase lymphopenia and inflammation with direct impact on vital prognosis. The introduction of an antiviral drug in prophylaxis or post exposure, even with a moderate effectiveness, impairs the viral replication, and thus limits the pro-inflammatory cytokines production, sparing time to induce an effective adaptive response and finally improves survival. Therefore, favipiravir allows the induction of adaptive immunity but also decreases the pathogenesis due to cytokine storm. Our estimate of favipiravir EC50 against EBOV is about 191 µg mL−1, which, assuming a binding fraction of 50%42, would correspond to a free concentration of 96 µg mL−1. This value is above the IC50 reported in the literature, ranging from 10.5 to 62 µg mL−1 40,43,44, and explains why the group treated with 100 mg kg−1 BID, targeting trough concentrations close to the IC50, did not show strong antiviral efficacy. Simulations predict that dosing increase to 250 or 300 mg kg−1 BID may allow to reach average efficacy ε of about 66 and 73% respectively (Supplementary Figure 3) but toxicity issues at these dosing regimens have been reported45.

Using the model to simulate various antiviral strategies we found that delaying initiation of favipiravir up to 3 days post infection should not have a major impact on survival rate. Applying the model to the dynamics observed during treatment with the polymerase inhibitor GS-573413 predicted 100% survival if treatment is initiated up to 4 days post infection, but not after. As survival appears to be directly related to the level of the cytokine storm, antiviral treatment, even if strongly effective, needs therefore to be administered at least 2 days before viral peak to be effective (Fig. 6). In the future it will be important to see if favipiravir initiated few days after viral challenge in NHPs could provide survival rate matching with the model predictions. Whether this model can be applied to other therapeutic classes, in particular monoclonal antibodies such as ZMapp4, is another question to be addressed. Assuming that monoclonal antibodies act mainly by reducing the lifespan of infected cells, we estimated that a reduction of the lifespan by a factor 5 could reproduce the high survival rate observed in NHP experiments4, even if initiated until day 5 or day 6 post infection (Supplementary Figure 7). In spite of the large amount of data available, our model made a number of hypotheses. First, some parameters had to be fixed to grant identifiability. Although the sensitivity analysis showed that the model predictions were robust to changes in the fixed parameters (Supplementary Table 4), more data on the phenotype of infected cells will be needed to improve the understanding of EBOV pathogenesis. Second, as done in previous works46,47, we relied on total concentration measurement of favipiravir as the driver of antiviral efficacy, an assumption supported by the short half-life of intracellular active favipiravir ribosyl triphosphate44,48.

Obviously, the translation of results from NHP experiments to patients needs to be done cautiously. First, unlike what is obtained in the NHP model, EVD is not uniformly lethal and mortality rate during the last outbreak is close to 40%49. Thus, it is possible that our model is more stringent and that treatment initiation of a potent drug, close to peak viremia, may nonetheless have an impact on the disease and the survival, when infection is made with lower inoculum and supportive care is provided. In the last outbreak, the time from symptom onset to admission was between 3 and 5 days2,4,50, when the maximal viral load is 4–5 days after symptom onset50. Based on these observations, it is likely that most patients included in EVD clinical trials, such as JIKI (favipiravir) or Prevail (ZMapp) initiated therapeutics close to the viremia peak and several days after virus replicated at high levels2,4. Consistent with our prediction that antiviral drugs should be initiated as early as possible to reach maximal therapeutic benefit, the effect on survival in these studies was modest for favipiravir47, and stronger but yet not statistically significant for ZMapp4. Even in the case of a more potent drug such as GS-5734, our results suggest that the efficacy may also be largely contingent on the timing of treatment initiation. In the future, it will thus remain critical to administrate drugs not only to confirmed or suspect cases, but also to contact individuals as early as possible, in a context where the NHP model demonstrated their efficacy. This may meet the wish of field teams during the Western African EVD outbreak to propose an early oral treatment to suspected cases, even before their transfer to care centers. Antiviral strategy may also offer an alternative to vaccine, or be complementary to it, for exposed people, as the vesicular stomatitis virus-based vaccine provide high level protection after a 10 days delay, but its efficacy in post exposure in both humans and NHPs is less clear51,52. Interestingly, as written in53 favipiravir has been used as post-exposure prophylaxis in at least five health-care workers with percutaneous accidents and suspected Ebola virus exposures during the west Africa outbreak. None of these individuals developed laboratory or clinical evidence of Ebola virus infection, but whether any infections were prevented by the use of post-exposure prophylaxis, as supported by our model, is not possible to determine from this small number of uncontrolled cases.

In conclusion, we proposed a mechanistic mathematical model to assess the virological and immunological dynamics of EBOV infection in NHPs and to assess the efficacy of favipiravir in reducing virus pathogenesis. Applying the model to different levels of antiviral strategies with various efficacy and delay of initiation, our simulations predict that in order to be effective, antiviral treatment should be given at least one or 2 days before peak viremia. These results support a window to preventive or post exposure therapeutic strategies, with the aim to define what should be the drugs and the dosing to evaluate in case of new EVD outbreak.
Description of the experiments

We used data of four successive experiments performed in the Inserm-Jean Mérieux biosafety level 4 laboratory in Lyon in cynomolgus macaques that were left untreated or were treated by intravenous favipiravir (Fig. 1a, Supplementary Table 3). Briefly, female cynomolgus macaques from Mauritius (3 years aged and weighting 2.8-4 kg) were challenged intramuscularly with dose inoculum of 10, 100, or 1000 focus forming units (ffu) of Ebola virus Gabon 2001 strain, with no difference in survival or viral kinetics across the different inoculum groups9. Zaire Ebola virus Gabon 2001 strain was chosen due to its high observed lethality in patients and its availability at the beginning of the experiments. Treatment was initiated 2 days before infection, and favipiravir was administered twice a day every 12 h, by 10 min infusion, after intramuscular anesthesia using Zoletil (Tiletamine/Zolazepam). Overall, the data of 44 animals were analyzed, 28 left untreated and 16 treated with maintenance doses of 100, 150, and 180 mg kg−1 BID (N = 6, 5, and 5, respectively). Animals were euthanized at the latest at D21 (study endpoint) but moribund animals were euthanized before to alleviate unnecessary suffering. All untreated animals died within 11 days of infection, and study endpoint was achieved in 0, 2, and 3 animals receiving 100, 150, and 180 mg kg−1 BID, respectively (i.e., 0, 40, and 60%, respectively). Animals were housed and monitored in accordance with the guidelines of the European directive 2010/63 and procedures established for use of animals in BSL4 facilities. Protocols and experiments received ethical authorizations, number P4-2014-008, 2017APAFIS#6097, and 2016062713281115 from the CECCAPP C2EA15 ethical committee, registered with the French Ministry of Research. The design of the experiments has been described in detail elsewhere9,11.
Data collected

Blood samples were collected at days 0, 2 or 3, 5, 7, 9, or 10, 12, 14, 17, 19, and 21 post infection, within 15 min before of the first administration of favipiravir of the day. EBOV plasma molecular viral load (Fig. 1) was measured by real time PCR using the Gibbs system9. Plasma favipiravir concentrations (Fig. 1) were assessed using HPLC coupled to UV detector following a previously validated procedure47, with a limit of quantification of 1 µg mL−1.

Repeated measurements of immunological markers were assayed in treated macaques and control macaques of the corresponding experiment. A panel of 37 plasma cytokines, chemokines, growth factors, chemotactic factors were assayed using Luminex technology, Magpix instrument, at days 0, 3, 5, 7, 10, 12, 14, 17, and 21 post infection, and on day of euthanasia, in treated (N = 10) and untreated (N = 10) animals of the third and fourth experiments evaluating the doses of favipiravir of 150 and 180 mg kg−1 BID, respectively (Supplementary Table 2). The panel included IL1β, IL1RA, IL2, IL4, IL6, IL8, IL10, IL15, IL18, IL23, eotaxin, fractalkine, MCP1, MIP1a, MIP1β, CXCL10, IFNγ, TNFα, TNFβ, FGFb, G-CSF, GM-CSF, VEGF, sCD40L, sCD95L, and sCD137. In addition, interferon α (IFNα) plasma concentration was assayed using ELISA method in the same animals, however data from untreated animals in the study 3 could not be obtained (hence these data were obtained in N = 15 animals). Second, the distribution of lymphocyte populations was explored in the animals of experiment 3 (N = 10) with the expression or absence of expression of 12 biomarkers reflecting activation status, cytotoxic activity and memory phenotype: HLADR, KI67, granzyme B, perforin, CD154, CD69, CD152, CD45RA, CD27, CD28, CD95, CD137, and NKp80. Of note among these 10 animals, 5 were untreated and died within 10 days (Fig. 1), 4 treated animal had an extended survival while 1 treated animal died at D11.

Viral loads in liver and spleen homogenates (after grinding of 30 mg) were measured by plaque assay. Standard 12 well microplates of VeroE6 cells were prepared one day before titration. Cells were infected with serial dilutions of samples during 1 h at 37 °C. After incubation, 1.5 ml of CMC per well were added and incubated at 37 °C for 7 days. Titres were determined by immunohistochemistry after staining with a specific antibody.
Descriptive analysis of immunological measurements

Associations between cytokine value at D7 and (i) viremia at D7 (ii) death time were assessed using Spearman correlation test, with p values adjusted (q values, Hochberg Benjamini method). Seven cytokines showed no increase greater than 25 pg mL−1 at peak in more than 50% of the animals in each group (IL1β, IL16, IL23, eotaxin, fractalkine, TNFβ, and soluble Fas ligand) and were excluded from the analysis.
Favipiravir pharmacokinetics

Favipiravir pharmacokinetics in macaques was described using a model developed previously in uninfected animals46. The model was used to fit PK data, to predict the drug concentrations over time and to assess a potential effect of infection on pharmacokinetic parameters (Supplementary Methods, Supplementary Table 5, Supplementary Figures 8, 9 and 10).
Modeling the interplay between EBOV and the immune response

We aimed to build a comprehensive model of the host-pathogen-drug interaction during EBOV infection. For that purpose, we developed a model of progressive complexity in a four stages strategy (detailed in Supplementary Methods). Of note the nonlinear mixed effect model approach (see below) allowed us to incorporate data collected in all animals at each stage of the analysis, even in case of missing data. In order to ensure model comparability, the different models were compared on their ability to fit the viremia data only.

In the first stage viral dynamics was characterized assuming a standard target cell limited model with an eclipse phase21. Favipiravir is a puric basis analog, with several potential effects hampering the RNA virus replication. The most characterized was the inhibition of the RNA polymerase, it blocks the production of new viral genomes and hence the production of new viral particles48. The effect of this polymerase inhibitor was assumed to inhibit viral production in a concentration dependent manner as: [Math Processing Error]

where ε is potency of the drug, Emax the maximal effect, EC50 the concentration providing 50% of the maximal effect and C the plasma concentration of favipiravir (Supplementary Methods, Supplementary Table 6). There was no difference in survival or viral loads at the different time points across the different inoculum groups11. Thus, we assumed that the initial viral load was proportional to the size of the inoculum, and we noted V0 the normalized initial viral load concentration (with a reference inoculum dose of 1000 ffu), such that the initial viral load was on average 10 and 100 folds lower in the 100 ffu group and the 10 ffu group respectively.”

In the second stage the model was extended to incorporate the effects of the innate immune response, taking the cytokine levels from D0 to D21 as a marker of the innate response (Supplementary Tables 7, 8 and 9, Supplementary Figure 11). Four putative models were considered based on literature results22,54,55, assuming that cytokine release could either (i) increase the number of cells refractory to infection27,28, (ii) increase the availability of target cells31,32, (iii) decrease viral production28,29, (iv) increase the clearance of infected cells29,30. To limit the number of models to test, we focused only on pro-inflammatory cytokines and cytokines related to cellular response (IFNα, IL6, TNFα, IL2, IFNγ, IL15, IL18, and perforin) that were significantly associated with survival time in the descriptive analysis (Supplementary Table 2).

In the third stage, we evaluated the role of T-cell populations. Based on the descriptive analysis result and given the limited number of data, we focused only on the cytotoxic response and CD8 T cell populations expressing cytotoxic surface markers, i.e., perforin, granzyme B and NKp80 from D0 to D21 (Supplementary Tables 10, 11). For each of these populations the dynamics was modeled assuming one compartment of nonspecific cells having a cytokine-driven apoptosis and one compartment of specific cells that increased over time and eliminate infected cells.
Modeling the effect of viral and cytokine dynamics on survival

The last step of the model aimed to incorporate the impact of viral and cytokine dynamics on time to death, an approach called joint modeling in the statistical literature56. For each animal we note T the time of death and we assumed that the instantaneous risk of death, noted h(t), was defined by [Math Processing Error]
where Xk(t) is the current or delayed (using an effect compartment) values of viral load or cytokine predicted by the model, λm is the maximal hazard in presence of infection, X50 is the current or lag- value of viral load or cytokine inducing hazard value equal to 50% of the maximal hazard, and γ the Hill coefficient. The probability to survive up to time t can then be reconstructed and [Math Processing Error]

. The model variable included in the hazard function was selected using the Bayesian information criterion (BIC, the lower the better) (Supplementary Tables 12, 13).
Parameter estimation

All model estimations were performed using non-linear mixed effect models and the SAEM algorithm implemented in Monolix software (, an approach that borrows strengths from the inter-individual variability to increase the precision of parameter estimation57. Model of increasing complexity were kept only if they improved the description of the viral load data, and the most parsimonious model was selected at each stage using the log-likelihood of the viremia data (Supplementary Figures 12, 13, and 14). Random effect selection was performed after the best model was selected, using a backward procedure. Model evaluation was performed for the final model using individuals fits (Supplementary Figure 15) and visual predictive check per dose (Supplementary Figure 16)58. Time to event model was evaluated using Cox-Snell residuals (Supplementary Figure 17)59.

To ensure model practical identifiability24,60 the following parameters were fixed in all models: the free virion elimination rate, c, was set to 20 per day, similar to what was found in other RNA virus61; the initial concentration of target cells, T0, was set to 108 cells mL−1, a proxy of the liver size in NHPs, the largest solid organ targeted by EBOV62; the eclipse phase duration, noted 1/k, ranges between 2 and 15 h63,64, and was set to 6 h (k= 4 per day). To take into account the different levels of viral challenge, we assumed that the initial viral load was proportional to the size of the inoculum, and we noted V0 the initial viral load concentration in animals infected by 1000 ffu, such that the initial viral load was equal to V0, 10×V0, and 100×V0 in NHP infected with 10, 100, and 1000 ffu, respectively. Given the limited amount of individuals, no random effects was assumed for the parameters related to CD8 T-cell dynamics, except for the observed concentration of lymphocyte on the day of challenge. A sensitivity analysis was performed to evaluate the impact of the choice of fixed parameters on model predictions (Supplementary Table 4).
Model validation using rhesus macaques treated with GS-5734

Next we evaluated if the model could also characterize viral dynamics in animals treated with GS-5734. For that purpose we used already published data where 12 rhesus macaques were left untreated or were treated three days after infection with 10 mg kg−1 of GS-5734, a potent nucleotide analog polymerase inhibitor13. All model parameters were fixed to the values found above, except the constant drug efficacy, ε, to account for differences in antiviral efficacy between favipiravir and GS-5734, and the viral infectivity β, to account for differences in viral dynamics between cynomolgus and rhesus macaques. The model was fitted to viral load data to estimate β and ε using individual data provided in ref. 13.
Simulation study

The model was used to evaluate by simulations the impact of various drug efficacy and treatment initiation timings, on viremia and survival. For each scenario 1000 in silico profiles were generated using mlxR package ( using the estimated distribution parameters (Table 1).
Code availability

The mlxtran code of the final joint model is provided in the Supplementary Software file.
Data availability

Virological and pharmacokinetic data used to build the model were already published in refs. 9,10,13. The authors declare that all other data supporting the findings of this study are available within the Article and its Supplementary Information files, or are available from the authors upon request.
Additional information

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


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We would like to thank the team involved in molecular and PK analyses (G. Piorkowski, K. Barthelemy, B. Pastorino, and L. Molina) as well as the teams of the Inserm Jean Merieux BSL4 laboratory for their help, expertise, management (E. Chevillard) and night and day work: animal facility staff (L. Barrot, A. Duthey, M. Langry, and A. Vallve) and in vitro analysis team (A. Bocquin, S. Godard, S. Mely, E. Moissonier, S. Mundweiler, D. Pannetier and D. Thomas). This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 666092, and from the St. Luke’s International University (Tokyo, Japan) in the framework of Research Program on Emerging and Re-emerging Infectious Diseases of the Japan Agency for Medical Research and Development (AMED).
Author information

    IAME, UMR 1137, INSERM, Université Paris Diderot, Sorbonne Paris Cité Paris, 75018, Paris, France
        Vincent Madelain, France Mentré & Jérémie Guedj
    UBIVE, Institut Pasteur, Centre International de Recherche en Infectiologie, 69007, Lyon, France
        Sylvain Baize, Stéphanie Reynard & Alexandra Fizet
    Laboratoire P4 Inserm-Jean Mérieux, US003 Inserm, 69365, Lyon, France
        Frédéric Jacquot, Stephane Barron, Caroline Carbonnelle & Hervé Raoul
    Aix-Marseille Univ U105, APHM, SMARTc CRCM Inserm UMR1068 CNRS UMR7258, Hôpital La Timone, Laboratoire de Pharmacocinétique et Toxicologie, 13005, Marseille, France
        Caroline Solas & Bruno Lacarelle
    UMR “Emergence des Pathologies Virales” (EPV: Aix-Marseille university - IRD 190 - Inserm 1207 - EHESP) - Institut Hospitalo-Universitaire Méditerranée Infection, 13385, Marseille, France
        Xavier de Lamballerie


V.M., F.J., C.C., F.M., H.R., X.L. and J.G. designed the experiments. Sy.B., F.J., S.R., A.F., St.B., C.C., H.R., and X.L. performed the experiments. C.S., B.L., and X.L. performed the drug measurements. V.M., F.M., and J.G. performed the modeling analysis. V.M., Sy.B., S.R., F.M., H.R., X.L., and J.G. wrote the manuscript.
Competing interests

The authors declare no competing interests.
Corresponding author

Correspondence to Vincent Madelain.
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20 March 2018

23 August 2018

01 October 2018


[Apologies for the lack of images in this article. I was unable to copy them as part of the information. The links provided are the best I could do. The original article also contains many links to additional figures, tables and even software. - I was a bit overwhelmed at this point! There is also a pdf download.]
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Technophobe Quote  Post ReplyReply Direct Link To This Post Posted: October 02 2018 at 2:11pm
Officials fear Ebola epidemic may be spinning beyond their control, threatening regional spread

By Helen Branswell @HelenBranswell

October 2, 2018     

Public health officials are expressing deepening concern that the latest Ebola outbreak in the Democratic Republic of the Congo may be spinning beyond their control and could soon spill over into neighboring countries including Uganda and Rwanda.

With Ebola response teams facing restrictions on their movements in a conflict zone, officials fear containment efforts are falling further behind the virus. And if response teams lose sight of where the virus goes, it could spread undetected and unchecked in places where they cannot safely travel.

“At this point in an epidemic, we’d probably be peaking in terms of knowing where the virus is. And now with the insecurity, that’s compromised,” said Dr. Mike Ryan, assistant director-general of the World Health Organization’s emergency preparedness and response program.

To date in this outbreak — DRC’s 10th — there have been 161 cases and 105 deaths.
With short outbreaks and complex permissions, testing critical Ebola treatments is a challenge

The threat of a widening epidemic was compounded with a discovery last week that two people infected with Ebola had fled from the Congolese city of Beni to Tchomia, near the border with Uganda, prompting the WHO to warn that the risk that the virus will spread to DRC’s eastern neighbors is “very high.” Previously the risk of regional spread had been assessed as high. (The risk of spread outside the region remains low.)

Uganda and Rwanda, with the help of the WHO, the Centers for Disease Control and Prevention, and other international partners, have been preparing for weeks to deal with the possibility of imported cases.

Uganda’s drug regulatory agency has been going through the process of approving a protocol to use an Ebola vaccine being developed by Merck; that vaccine is currently being deployed in DRC in a “ring vaccination” strategy. Under the approach, people who have been in contact with an Ebola case — and the contacts of each contact — are vaccinated to block the virus’s ability to spread.

Uganda is planning to adopt the ring vaccination strategy as well.

But it also intends to pre-vaccinate health workers in high-risk health zones near the DRC border. Initial supplies of vaccine are already in the country and that work could start within days.

“We hope this will start very soon,” said Dr. Socé Fall, regional emergencies director for the WHO’s regional office for Africa. Fall said he expects health workers in Uganda will agree to be vaccinated with the still-experimental vaccine. Uganda has a long history of Ebola outbreaks — it has had more than any other country except DRC.

“Ugandan health care workers — they know Ebola already. They know the risks,” Fall said.
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The CDC currently has staff in Uganda working on the vaccination program, said Ray Arthur, a co-leader of the Ebola coordination team for the agency. “The protocols are with the institutional review board, with the government, and the vaccine is in Entebbe,” he said.

Uganda — which has been conducting fever checks at border crossings to identify any possible Ebola cases — is monitoring the health of two people who recently entered the country and who may have been exposed to the virus.

“They are being monitored on the Uganda side to make sure that if something happened they will be isolated very quickly,” Fall said of the two, who haven’t been tested because as yet they haven’t shown symptoms of illness.

Although DRC originally said the pair may have been exposed to Ebola during the burial of an Ebola patient there, officials later determined that was not the case. (Traditional burial ceremonies, in which attendees may touch or kiss the corpse of the deceased, can be major Ebola transmission events. That’s because around the time of death and even after, the skin of a person who died from Ebola teems with viruses.)

There is a sense that Uganda, in particular, is well prepared to cope with imported cases. “Uganda has done a fine job,” Ryan said.

Arthur concurred. CDC has a country office in Uganda, he explained, and other staff from the agency have traveled to the country to help its health ministry identify where Ebola patients could be treated if cases occur. The CDC has also advised the staff on border health issues and infection control — which is critical to ensuring people with Ebola do not infect other patients or the health workers caring for them.

“Should cases come into the country, we would expect transmission would be quite limited,” Arthur said.
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Preparedness efforts are also underway in Rwanda, which is further from the outbreak epicenter, and in South Sudan.

While experts have some confidence DRC’s neighbors are ready to spot and isolate Ebola cases if there are importations, they appear to feel less assured about how containment efforts are progressing in DRC.

A rebel attack on Beni about 10 days ago killed a number of civilians and led to the declaration of several days of city-wide mourning — days in which shops and schools closed and during which the response teams had to cut back their efforts.

Most importantly the tracking of case contacts suffered, at a time when this critical effort was already failing to register all the people who had been in contact with confirmed cases.

“Our whole strategy is based on knowing where the virus is, identifying cases, identifying contacts, contacts of contacts, isolation, vaccination, community education,” Ryan explained. “And that whole strategy is predicated on a deeper and deeper and more and more precise day-by-day knowledge of where the virus is.”

The health of contacts who are being followed is monitored regularly; if they get sick, authorities ask to take them to Ebola treatment units — in Ebola parlance an ETU — where they can be treated in isolation and where the risk is low that they will infect anyone else.
WHO warns of ‘perfect storm’ for Ebola in eastern Congo

But contacts who don’t make it onto the follow-up lists don’t get offered vaccine. Because they are not recognized as potential Ebola cases, if they get sick their illness may evade detection. They may end up being cared for at home and being buried without proper precautions if they die. That can result in new infections among caregivers or funeral attendees.

In the last couple of weeks, a number of newly diagnosed Ebola patients were people who were not on a contact list. Five such cases were reported late last week by the WHO.

“You should not have cases occurring which weren’t on a contact list,” Arthur said. “There’s been too many of those in the past two weeks.”

Fall said further investigation showed all five had been in contact with a known case — which is moderately reassuring.

In the midst of an Ebola outbreak, realizing your contact list was incomplete is bad. But finding a case with no discernible link to other cases is worse. That signals that there are chains of transmission that response teams aren’t aware of and aren’t tracking. “Then you lose the virus,” Ryan said. “The virus leaves the trail.”

Drawing up a full list of the contacts of a case is slow and painstaking work, Ryan said — work that isn’t well-suited to a conflict zone.

“Each one of those is an individual detective story. You need to spend time and sit with the family … ‘What happened here? And when did you move there? And what wedding did you go to?’” Ryan explained.

“If you’re looking over your shoulder worrying about a bullet coming through the window or the door, these encounters become very, very strained,” Ryan continued. “Surveillance officers are nervous. And then if you add into that community mistrust and the misinformation, that participation and the acceptance of the community is affected.”

The effort isn’t helped by the fact that there are now cases in multiple different communities in North Kivu and Ituri provinces. That expansion of the area the response teams need to cover has created huge logistical challenges.

“We’re now in nine health zones,” Arthur said. “And the longer the transmission occurs, obviously the greater risk for it to get into an area where’s not good contact tracing or there aren’t vaccination programs in place.”

“Each time there’s extension into a new area, all that infrastructure — laboratories, ETUs, contact tracing, vaccination teams — has to be re-established. And that takes time,” he said. “So I think we’re in a position now where we’re playing catch up and that’s not the kind of position we want to be in.”

Correction: A previous version of this story misspelled Dr. Socé Fall’s name.


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Post Options Post Options   Thanks (0) Thanks(0)   Quote Technophobe Quote  Post ReplyReply Direct Link To This Post Posted: October 06 2018 at 1:17am
Rapid risk assessment: Ebola virus disease outbreak in North Kivu and Ituri Provinces, Democratic Republic of the Congo – first update
from European Centre for Disease Prevention and Control
Published on 04 Oct 2018 — View Original
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This rapid risk assessment addresses the public health risk associated with the current Ebola virus disease outbreak in the Democratic Republic of the Congo and its implications for EU/EEA citizens. This is the first update of a rapid risk assessment originally produced on 9 August 2018.

Executive summary

As of 30 September 2018, the Ministry of Health of the Democratic Republic of Congo (DRC) reported 161 probable and confirmed cases of Ebola virus disease (EVD) in the Provinces of North Kivu and Ituri, making this the fourth largest outbreak of EVD recorded in DRC. Genetic analysis of the viral strains showed that there is no link between this outbreak and the one in Equateur province of DRC, reported in May this year.

The DRC Ministry of Health is implementing its EVD response plan in the affected areas, supported by the World Health Organization and a range of regional and global partners. Contact tracing and monitoring of case contacts are ongoing. The rVSV-ZEBOV experimental vaccine has been offered to healthcare and frontline workers, case contacts and their contacts. Preparedness activities are ongoing in neighbouring Congolese provinces and bordering countries.

Although no confirmed cases have been documented in neighbouring countries as of 30 September, the fact that the outbreak is ongoing in areas with important cross-border population flows (with Rwanda and Uganda) is of particular concern. In addition, implementation of response measures in the field remains challenging because the outbreak is occurring in areas affected by prolonged humanitarian crises and an unstable security situation arising from a complex armed conflict.

The probability that EU/EEA citizens living or travelling in EVD-affected areas of DRC will be exposed to the disease is low, provided they adhere to the precautionary measures recommended below.

There are no international airports in the affected areas of DRC that offer direct flights to EU/EEA Member States, which limits the risk of the virus being introduced into the EU/EEA. The overall risk of introduction and further spread of Ebola virus within the EU/EEA is very low. However, the risk can only be eliminated by stopping transmission at local level.

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Post Options Post Options   Thanks (0) Thanks(0)   Quote Technophobe Quote  Post ReplyReply Direct Link To This Post Posted: October 06 2018 at 1:24am
There is also an article here( ) from the Lancet on the current outbreak.
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Technophobe Quote  Post ReplyReply Direct Link To This Post Posted: October 06 2018 at 3:22pm

EBOLA CRISIS: DR Congo confirm MORE outbreak cases - WHO warns ‘we are VERY concerned’

THE EBOLA outbreak has claimed more victims with the Congolese health ministry today reported a further five confirmed cases, blaming the higher-than-normal daily increase on community resistance to disease response efforts.

By Joey Millar
PUBLISHED: 20:07, Sat, Oct 6, 2018 | UPDATED: 20:17, Sat, Oct 6, 2018
More Ebola cases have been registered in DR Congo (Image: GETTY)

The current epidemic in Congo's North Kivu and Ituri provinces has seen 140 confirmed cases since July, 108 of whom have died, according to the ministry's daily bulletin, which has been reporting an average of one to two new confirmed cases per day in recent weeks.

The ministry said the five new cases were located in the regional hub of Beni, where attacks by rebel groups in the area and local mistrust of the Ebola response campaign have disrupted treatment and vaccination programmes.

"The town of Beni has become the new focus point of the disease, registering the highest percentage of cases reported in recent weeks following community resistance of certain families," it said in a statement.

The fight against Ebola has advanced more in recent years since it was discovered near the Congo River in 1976, but rumours, misinformation and a preference for traditional medical practices have hampered the roll-out of effective treatments during the current outbreak.
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Last week, the World Health Organization (WHO) warned that the epidemic was at a critical juncture due to security threats, community mistrust and an increased geographical spread of the disease.

"We are very concerned about the potential for the virus to spread into Uganda, but also into Rwanda, South Sudan and Burundi," WHO Director General Tedros Adhanom Ghebreyesus said at a UN Security Council meeting on Wednesday.

Last month the WHO warned ongoing violent disputed between armed groups, community resistance to the advice of public health officials, and the geographic spread of the disease were making a bad situation worse.

Dr Peter Salama said: "We are now extremely concerned that several factors may be coming together over the next weeks and months to create a perfect storm.

"A perfect storm active conflict limiting our ability to access civilians, distrust by segments of the community already traumatised by decades of conflict and of murder, driven by a fear of a terrifying disease, but also exploited and manipulated by local politicians prior to an election.”

The WHO’s warnings echo those of Dr Inger Damon of the US-based Centre for Disease Control.

He told earlier last month: “Education is key – this is something we find with every outbreak.

"Good engagement with the community is critical.

"If they don't have the right type of information they tend to be very reactive.

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