Eye on ID

Ebola: At last, promising agents for prevention and therapy

Ebola, or more properly, Ebola virus disease (EVD) — the disease that horror writers dream about — is caused by members of a family of filoviruses called Ebolaviruses. It brings the most frightening of infectious disease syndromes to mind. The nonfiction book The Hot Zone by Richard Preston, and the 1995 movie Outbreak, patterned after EVD, are equally terrifying. Imagine victims bleeding from their eyes, ears and noses and, at autopsy, the pathologist finds necrotic organs. Just two transmitted cases in the United States in 2015 were enough to panic the population, as well as the health care system.

Ebola virus species

There are six distinct species of Ebolavirus: Bombali, Bundibugyo, Reston, Sudan, Tai Forest and Zaire. All but Reston are restricted to Africa. Human infection with Bombali is unknown but unstudied. Reston, which is found in primates in the Philippines, seems not to be a human pathogen, although antibodies to it have been found in humans. Tai Forest species has caused only one recorded case. Aside from Reston (no deaths and virtually all asymptomatic) and Tai Forest (one case), Bundibugyo species has a case-fatality rate of about 33%, Sudan has a case-fatality rate of about 50% and Zaire species, the most lethal, until recently has generally had a case-fatality rate of about 70% to 80%.

Epidemiology

EVD is truly a mysterious disease. It appears from nowhere, causes outbreaks and then disappears. For example, there were virtually no cases between 1980 and 1993, and then subsequently there have been outbreaks most years, albeit often in different locations.

Thomas M. Yuill
Donald Kaye

Fruit bats are probably the main reservoirs of the virus because they become infected without becoming ill, and the virus can be found in their saliva. Primates are the major victims of the disease. Primates (chimpanzees, gorillas, monkeys) and rarely other animals in the jungle, such as forest antelope and porcupines, periodically become ill with EVD. Humans become infected by skin or mucous membrane contact with these infected animals and probably also by contact with fruit bats. Meat of bats, as well as that of other animals, is often consumed. Transmission between humans occurs via contact with blood, secretions or other bodily fluids. Sick individuals are highly contaminated with virus. The sicker the patient is, the higher the concentration of virus tends to be. Health care workers and family members caring for sick individuals are at high risk for infection. Historically, infection has also been spread in health care facilities by contaminated needles or syringes. Burials have also served as a means of spread of Ebola virus. Burial preparation, which includes washing of the cadaver, has resulted in transmission of the virus, and ritual close contact with the deceased is common in Africa. Because of the presence of virus in blood and secretions, the patient is literally covered by virus and exposure is easy.

Infection is usually by direct contact with skin (presumably through small abrasions) or mucous membranes. Ingestion of carrier bats or infected bush meat may be the source of the index case in an outbreak. Aerosolization of the pathogen does not seem to be involved as a mechanism of natural infection, but if it was ever weaponized, or if mutations occurred that permitted transmission by aerosol, massive outbreaks could occur. Ebola virus is classified as a Category A biological weapon.

EVD is a relatively newly described disease. It was first identified in the 1970s when there were outbreaks in what is now the Democratic Republic of the Congo (DRC) and in what is now South Sudan. Multiple outbreaks followed in African countries in the ensuing years (mainly the central African countries of Gabon, the Republic of the Congo, DRC, South Sudan and Uganda). Another large focus in 2014-2016 involved West Africa, with most cases in Guinea, Sierra Leone and Liberia. Other African countries that have had relatively few cases (mainly exported from countries mentioned above) are Senegal, Mali, Cote d’Ivoire, Nigeria and South Africa. Over the years, most outbreaks have been in the DRC, and most in both Central and West Africa have involved the Zaire species of Ebola virus. With one exception, as detailed in the next paragraph, each of these involved dozens of cases to hundreds of cases. Until recent years, these epidemics occurred mainly in forested, relatively low-population areas.

In 2014, a major epidemic in West Africa (by far the largest in history) started in Guinea and spread to Liberia and Sierra Leone. By the time it ended in 2016 there had been more than 28,600 cases and 11,300 deaths. This large epidemic, for the first time, involved spread from rural areas to densely populated urban areas. Cases of EVD occurred internationally related to infected patients (often health care workers) either traveling to or being transferred for medical care to other countries. There were cases in Italy, Mali, Nigeria, Senegal, Spain, the United Kingdom and the U.S. Secondary infections resulted, mainly in health care settings, in Italy, Mali, Nigeria and the U.S. In fact, when all was said and done, 11 patients were cared for in the U.S. Nine survived, which is a testimony to the advanced care available in the U.S. Of interest, and also as a testimony to advanced care, all of the three patients treated in Italy, Spain and the U.K. survived.

The latest outbreak of EVD, caused by the Zaire species, started in the DRC (the 10th EVD epidemic in that country) in late July and is ongoing at the time of the writing of this article. Control of this outbreak is especially challenging because it is in an area with a large human population, and because of an armed conflict involoving several insurgent groups in the area. This area borders Uganda, South Sudan and Rwanda, and there is considerable cross-border movement with the risk of the virus being introduced into those countries.

Clinical syndrome

Following an incubation period of 2 to 21 days, the patient develops a typical viral illness with fever, weakness, sore throat, headache and myalgias. This is followed by vomiting and diarrhea. There is a maculopapular rash. The severe illness then occurs with a coagulopathy and, in some, there is bleeding from multiple sites, including the gastrointestinal tract and mucous membranes. Multiorgan damage and necrosis then ensue, with renal and hepatic failure, or in the lucky cases, defervescence and improvement occurs with survival. Systemic and ophthalmic sequelae may occur in what has been named “the post-Ebola syndrome.” Uveitis is the most common finding during EVD convalescence and may lead to severe vision impairment or blindness in 40% of affected individuals. Ebola virus has been found in breast milk, semen, aqueous humor and cerebrospinal fluid of survivors after resolution of the infection. In fact, Ebola virus has been found in semen for up to several months, and in one case, a man infected a woman more than 500 days after recovery from EVD. In addition, a woman infected members of her family 1 year after recovering from EVD; she became ill again after a pregnancy that may have activated the virus.

In addition to visual problems, survivors of the epidemic in West Africa were described to have musculoskeletal pain, headache and multiple other complaints, some of which were also seen in a recovered U.S. physician.

Management

Until very recently, there were no vaccines or antiviral therapies on the horizon. There is now a vaccine and a number of promising therapies. None of these have been approved.

The time-honored approach to stopping an epidemic was by 1) rapid identification of cases; 2) strict barrier isolation of infected people; 3) rapid and effective identification of contacts; and 4) strict isolation of contacts for the maximum incubation period (21 days) from time of contact.

Early recognition of cases by ongoing surveillance is critical, with prompt institution of appropriate isolation with barrier care and use of personal protective equipment (PPE) by caregivers. One of the fortunate aspects of EVD is that the patient is not contagious until becoming ill and then is usually so sick that he or she does not move about. Therefore, wide exposure is unusual, with the exception of funerals.

The populace must be warned to avoid dead or sick animals. Contact with the deceased at burials, where bodies are traditionally washed by hand, should be banned. The consumption of bat meat, a popular meal, should be forbidden, considering that fruit bats are thought to be the natural host of Ebola virus.

One of many social problems is the labeling of EVD treatment centers by the populace as “places of death,” a place to avoid. This results in some families hiding their sick family member, or even in some cases, kidnapping them from EVD treatment centers.

A very recent innovation is the use of the CUBE. The CUBE is a self-contained and easily transportable system, pioneered by the Senegal-based medical charity, Alliance for International Medical Action (ALIMA). The CUBE has transparent walls and external arm entries, and it is air conditioned. The need for entry by health care providers is dramatically reduced. Health workers have less need for PPE, which is often frightening to patients and their families. In addition, attending patients in PPE suits in hot, humid climates limits the time that the user can function in them due to excessive perspiration. The CUBE potentially avoids this limitation.

Care teams, with minimal training, can monitor and treat an infected patient, administering IVs and other treatment from the exterior. The patient benefits from the transparent walls, which allow them to remain in contact with family members, without the risk for contamination.

Vaccines

Added to the above-mentioned approach, now, is ring vaccination of the contacts with V920 — Merck’s experimental, recombinant, replication-competent vesicular stomatitis virus-based vaccine expressing a surface glycoprotein of Zaire Ebolavirus. Health care workers and those conducting the ring vaccinations are also vaccinated to prevent the tragic loss of health care and field personnel that was a major problem in previous outbreaks.

The vaccine was shown to be highly effective in Guinea during the 2014-2016 epidemic when given to contacts and contacts of contacts. However, it was administered at a time when that epidemic was already declining and the attack rate was low. Therefore, it is difficult to determine the magnitude of the vaccine in halting that epidemic. However, the ring vaccination approach with V920 appeared to be helpful in 2018 in bringing the DRC’s ninth Ebola virus outbreak to a successful end.

Therapy

There are now a number of experimental treatments, some of which are being used in the DRC at present.

ZMapp (Mapp Biopharmaceutical) is a cocktail of three antibodies produced in tobacco plants. It is now being produced by molecular methods in fermenters. It was credited with helping to cure a number of patients in the 2014-2016 epidemic. In a study of 72 patients with EVD in the outbreak, death occurred in 13 of 35 patients (37%) who received the current standard of care alone and in eight of 36 patients (22%) who received the current standard of care plus ZMapp. Although the estimated effect of ZMapp appeared to be beneficial, the result did not meet the prespecified statistical threshold for efficacy. ZMapp is impractical to use in remote situations because it requires several doses administered by IV infusion under constant supervision, and the drug must be refrigerated.

mAb114 is a monoclonal antibody that targets the Ebola virus surface glycoprotein and has potent neutralizing activity. It was developed by the NIH using the antibodies of the survivor of an Ebola outbreak in the western Congolese city of Kikwit in 1995.

Remdesivir (Gilead Sciences) and favipiravir (Toyama) are experimental antivirals with activity against filovirus infections. REGN3450, REGN3471 and REGN3479 (Regeneron) are three human IgG1 monoclonal antibodies directed against three different epitopes on Ebola virus glycoprotein.

In an early report from the current outbreak in the DRC, only six of the 26 patients who have been treated with mAb 114, remdesivir or ZMapp have died.

Conclusions

We have not seen the last of EVD outbreaks in Africa. One hopes that the lessons learned in West Africa and during the two most recent DRC outbreaks are not forgotten either by those involved in Africa and their organizations nor those in the U.S. who treated infected patients here or prepared for the eventuality of caring for infected patients. We do not know when and where these outbreaks will occur but happen they will.

The approach must be ongoing education about Ebola and its avoidance (eg, safe funerals and elimination of bush meat), ongoing effective surveillance for early cases and prompt involvement of relevant governmental, nongovernmental and other resources when an outbreak is discovered.

Editor’s note: Read more about the CUBE — a biosecure emergency care unit for outbreaks of highly infectious diseases — in this accompanying article.

Disclosures: Kaye and Yuill report no relevant financial disclosures.

Ebola, or more properly, Ebola virus disease (EVD) — the disease that horror writers dream about — is caused by members of a family of filoviruses called Ebolaviruses. It brings the most frightening of infectious disease syndromes to mind. The nonfiction book The Hot Zone by Richard Preston, and the 1995 movie Outbreak, patterned after EVD, are equally terrifying. Imagine victims bleeding from their eyes, ears and noses and, at autopsy, the pathologist finds necrotic organs. Just two transmitted cases in the United States in 2015 were enough to panic the population, as well as the health care system.

Ebola virus species

There are six distinct species of Ebolavirus: Bombali, Bundibugyo, Reston, Sudan, Tai Forest and Zaire. All but Reston are restricted to Africa. Human infection with Bombali is unknown but unstudied. Reston, which is found in primates in the Philippines, seems not to be a human pathogen, although antibodies to it have been found in humans. Tai Forest species has caused only one recorded case. Aside from Reston (no deaths and virtually all asymptomatic) and Tai Forest (one case), Bundibugyo species has a case-fatality rate of about 33%, Sudan has a case-fatality rate of about 50% and Zaire species, the most lethal, until recently has generally had a case-fatality rate of about 70% to 80%.

Epidemiology

EVD is truly a mysterious disease. It appears from nowhere, causes outbreaks and then disappears. For example, there were virtually no cases between 1980 and 1993, and then subsequently there have been outbreaks most years, albeit often in different locations.

Thomas M. Yuill
Donald Kaye

Fruit bats are probably the main reservoirs of the virus because they become infected without becoming ill, and the virus can be found in their saliva. Primates are the major victims of the disease. Primates (chimpanzees, gorillas, monkeys) and rarely other animals in the jungle, such as forest antelope and porcupines, periodically become ill with EVD. Humans become infected by skin or mucous membrane contact with these infected animals and probably also by contact with fruit bats. Meat of bats, as well as that of other animals, is often consumed. Transmission between humans occurs via contact with blood, secretions or other bodily fluids. Sick individuals are highly contaminated with virus. The sicker the patient is, the higher the concentration of virus tends to be. Health care workers and family members caring for sick individuals are at high risk for infection. Historically, infection has also been spread in health care facilities by contaminated needles or syringes. Burials have also served as a means of spread of Ebola virus. Burial preparation, which includes washing of the cadaver, has resulted in transmission of the virus, and ritual close contact with the deceased is common in Africa. Because of the presence of virus in blood and secretions, the patient is literally covered by virus and exposure is easy.

PAGE BREAK

Infection is usually by direct contact with skin (presumably through small abrasions) or mucous membranes. Ingestion of carrier bats or infected bush meat may be the source of the index case in an outbreak. Aerosolization of the pathogen does not seem to be involved as a mechanism of natural infection, but if it was ever weaponized, or if mutations occurred that permitted transmission by aerosol, massive outbreaks could occur. Ebola virus is classified as a Category A biological weapon.

EVD is a relatively newly described disease. It was first identified in the 1970s when there were outbreaks in what is now the Democratic Republic of the Congo (DRC) and in what is now South Sudan. Multiple outbreaks followed in African countries in the ensuing years (mainly the central African countries of Gabon, the Republic of the Congo, DRC, South Sudan and Uganda). Another large focus in 2014-2016 involved West Africa, with most cases in Guinea, Sierra Leone and Liberia. Other African countries that have had relatively few cases (mainly exported from countries mentioned above) are Senegal, Mali, Cote d’Ivoire, Nigeria and South Africa. Over the years, most outbreaks have been in the DRC, and most in both Central and West Africa have involved the Zaire species of Ebola virus. With one exception, as detailed in the next paragraph, each of these involved dozens of cases to hundreds of cases. Until recent years, these epidemics occurred mainly in forested, relatively low-population areas.

In 2014, a major epidemic in West Africa (by far the largest in history) started in Guinea and spread to Liberia and Sierra Leone. By the time it ended in 2016 there had been more than 28,600 cases and 11,300 deaths. This large epidemic, for the first time, involved spread from rural areas to densely populated urban areas. Cases of EVD occurred internationally related to infected patients (often health care workers) either traveling to or being transferred for medical care to other countries. There were cases in Italy, Mali, Nigeria, Senegal, Spain, the United Kingdom and the U.S. Secondary infections resulted, mainly in health care settings, in Italy, Mali, Nigeria and the U.S. In fact, when all was said and done, 11 patients were cared for in the U.S. Nine survived, which is a testimony to the advanced care available in the U.S. Of interest, and also as a testimony to advanced care, all of the three patients treated in Italy, Spain and the U.K. survived.

PAGE BREAK

The latest outbreak of EVD, caused by the Zaire species, started in the DRC (the 10th EVD epidemic in that country) in late July and is ongoing at the time of the writing of this article. Control of this outbreak is especially challenging because it is in an area with a large human population, and because of an armed conflict involoving several insurgent groups in the area. This area borders Uganda, South Sudan and Rwanda, and there is considerable cross-border movement with the risk of the virus being introduced into those countries.

Clinical syndrome

Following an incubation period of 2 to 21 days, the patient develops a typical viral illness with fever, weakness, sore throat, headache and myalgias. This is followed by vomiting and diarrhea. There is a maculopapular rash. The severe illness then occurs with a coagulopathy and, in some, there is bleeding from multiple sites, including the gastrointestinal tract and mucous membranes. Multiorgan damage and necrosis then ensue, with renal and hepatic failure, or in the lucky cases, defervescence and improvement occurs with survival. Systemic and ophthalmic sequelae may occur in what has been named “the post-Ebola syndrome.” Uveitis is the most common finding during EVD convalescence and may lead to severe vision impairment or blindness in 40% of affected individuals. Ebola virus has been found in breast milk, semen, aqueous humor and cerebrospinal fluid of survivors after resolution of the infection. In fact, Ebola virus has been found in semen for up to several months, and in one case, a man infected a woman more than 500 days after recovery from EVD. In addition, a woman infected members of her family 1 year after recovering from EVD; she became ill again after a pregnancy that may have activated the virus.

In addition to visual problems, survivors of the epidemic in West Africa were described to have musculoskeletal pain, headache and multiple other complaints, some of which were also seen in a recovered U.S. physician.

Management

Until very recently, there were no vaccines or antiviral therapies on the horizon. There is now a vaccine and a number of promising therapies. None of these have been approved.

The time-honored approach to stopping an epidemic was by 1) rapid identification of cases; 2) strict barrier isolation of infected people; 3) rapid and effective identification of contacts; and 4) strict isolation of contacts for the maximum incubation period (21 days) from time of contact.

Early recognition of cases by ongoing surveillance is critical, with prompt institution of appropriate isolation with barrier care and use of personal protective equipment (PPE) by caregivers. One of the fortunate aspects of EVD is that the patient is not contagious until becoming ill and then is usually so sick that he or she does not move about. Therefore, wide exposure is unusual, with the exception of funerals.

PAGE BREAK

The populace must be warned to avoid dead or sick animals. Contact with the deceased at burials, where bodies are traditionally washed by hand, should be banned. The consumption of bat meat, a popular meal, should be forbidden, considering that fruit bats are thought to be the natural host of Ebola virus.

One of many social problems is the labeling of EVD treatment centers by the populace as “places of death,” a place to avoid. This results in some families hiding their sick family member, or even in some cases, kidnapping them from EVD treatment centers.

A very recent innovation is the use of the CUBE. The CUBE is a self-contained and easily transportable system, pioneered by the Senegal-based medical charity, Alliance for International Medical Action (ALIMA). The CUBE has transparent walls and external arm entries, and it is air conditioned. The need for entry by health care providers is dramatically reduced. Health workers have less need for PPE, which is often frightening to patients and their families. In addition, attending patients in PPE suits in hot, humid climates limits the time that the user can function in them due to excessive perspiration. The CUBE potentially avoids this limitation.

Care teams, with minimal training, can monitor and treat an infected patient, administering IVs and other treatment from the exterior. The patient benefits from the transparent walls, which allow them to remain in contact with family members, without the risk for contamination.

Vaccines

Added to the above-mentioned approach, now, is ring vaccination of the contacts with V920 — Merck’s experimental, recombinant, replication-competent vesicular stomatitis virus-based vaccine expressing a surface glycoprotein of Zaire Ebolavirus. Health care workers and those conducting the ring vaccinations are also vaccinated to prevent the tragic loss of health care and field personnel that was a major problem in previous outbreaks.

The vaccine was shown to be highly effective in Guinea during the 2014-2016 epidemic when given to contacts and contacts of contacts. However, it was administered at a time when that epidemic was already declining and the attack rate was low. Therefore, it is difficult to determine the magnitude of the vaccine in halting that epidemic. However, the ring vaccination approach with V920 appeared to be helpful in 2018 in bringing the DRC’s ninth Ebola virus outbreak to a successful end.

Therapy

There are now a number of experimental treatments, some of which are being used in the DRC at present.

ZMapp (Mapp Biopharmaceutical) is a cocktail of three antibodies produced in tobacco plants. It is now being produced by molecular methods in fermenters. It was credited with helping to cure a number of patients in the 2014-2016 epidemic. In a study of 72 patients with EVD in the outbreak, death occurred in 13 of 35 patients (37%) who received the current standard of care alone and in eight of 36 patients (22%) who received the current standard of care plus ZMapp. Although the estimated effect of ZMapp appeared to be beneficial, the result did not meet the prespecified statistical threshold for efficacy. ZMapp is impractical to use in remote situations because it requires several doses administered by IV infusion under constant supervision, and the drug must be refrigerated.

PAGE BREAK

mAb114 is a monoclonal antibody that targets the Ebola virus surface glycoprotein and has potent neutralizing activity. It was developed by the NIH using the antibodies of the survivor of an Ebola outbreak in the western Congolese city of Kikwit in 1995.

Remdesivir (Gilead Sciences) and favipiravir (Toyama) are experimental antivirals with activity against filovirus infections. REGN3450, REGN3471 and REGN3479 (Regeneron) are three human IgG1 monoclonal antibodies directed against three different epitopes on Ebola virus glycoprotein.

In an early report from the current outbreak in the DRC, only six of the 26 patients who have been treated with mAb 114, remdesivir or ZMapp have died.

Conclusions

We have not seen the last of EVD outbreaks in Africa. One hopes that the lessons learned in West Africa and during the two most recent DRC outbreaks are not forgotten either by those involved in Africa and their organizations nor those in the U.S. who treated infected patients here or prepared for the eventuality of caring for infected patients. We do not know when and where these outbreaks will occur but happen they will.

The approach must be ongoing education about Ebola and its avoidance (eg, safe funerals and elimination of bush meat), ongoing effective surveillance for early cases and prompt involvement of relevant governmental, nongovernmental and other resources when an outbreak is discovered.

Editor’s note: Read more about the CUBE — a biosecure emergency care unit for outbreaks of highly infectious diseases — in this accompanying article.

Disclosures: Kaye and Yuill report no relevant financial disclosures.