Ebola: Do we need to worry?
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Ebola: Do we need to worry?
By Rebecca Ryznar, Ph.D., Nerac Associate Analyst
Zaire Ebola virus (EBOV), the particular Ebola viral strain currently spreading across West Africa,
causes the most virulent hemorrhagic fever known to man, and kills up to 90% of those infected.
Ebola sets the immune system in overdrive and perturbs clotting mechanisms, causing a victim to
bleed to death within an average of a week after contracting the virus. In the early stages of
disease, patients initially present with flu-like symptoms, followed by a hemorrhagic phase
associated with vomiting of blood, reddening of the eyes, internal and subcutaneous bleeding,
eventually leading to organ failure and death.
The WHO reported that there have been 25 outbreaks of this deadly disease, with the most
recent outbreak being the largest yet in recorded history. There are no licensed drugs or vaccines
yet for Ebola, although in response to the most recent scare, there are some candidates that
have begun to enter clinical trials. Due to its highly virulent nature, zombie-like symptoms, and
lack of appropriate treatment schemes or a cure, multiple books and controversial articles,
including The Hot Zone and The Coming Plague have been written addressing the potential of
this pathogen to be utilized as a weapon of bioterror or as a form of population control.
As of now, the CDC reports that over 1300 people have died from Ebola as a result of the
outbreak in four countries in West Africa including Guinea, Sierra Leone, Liberia and Nigeria.
th
The outbreak does not seem to be under control. On August 16 , residents in Liberia looted a
clinic, stealing infected patients and infected items. The government responded by quarantining
the entire area in an effort to contain the spread of Ebola infection. This resulted in resistance
from locals who turned angry and violent, storming barricades. The WHO recently has warned of
the existence of what they call “shadow zones,” or areas that have unreported infection cases.
The UN has urged exit screening for Ebola at some airports and has also suggested for countries
unaffected by the outbreak to strengthen their ability to detect and contain new cases of Ebola.
Throughout this recent outbreak, two medical missionaries from the United States contracted the
virus and were transported back to the United States to receive highly experimental treatment,
which had not yet been approved as safe in humans. Both patients receiving the experimental
treatment, known as ZMapp, have fully recovered and have been released from Emory Hospital
in Atlanta. As of today, US Hospitals have had 68 Ebola scares (CDC website). Two patients,
one in California and a second in New Mexico are being tested for the deadly virus (News
release). Test results are forthcoming.
Is Ebola easy to contract?
According to the CDC and WHO, in order to transmit the virus, infected bodily fluids such as
blood, urine, saliva, semen or stools must come into contact with mucus membranes or a region
of broken skin. After reading the indicated transmission routes, one would conclude that Ebola
poses no risk for airborne transmission. That two health care workers from the US who reportedly
contracted the virus did so despite wearing full hazmat suits, begs some serious consideration.
Does Ebola actually possess airborne and/or aerosolized transmissibility? In support of Ebola
posing no airborne threat, a recent study conducted with non-human primates suggested that the
virus could not be spread this way (Alimonti et al 2012). Other studies contradict this finding. One
research study found that Ebola can be transmitted from pigs to non human primates via an
airborne route (Weingartl et al 2012). Two other experimental studies have shown that
aerosolized droplets containing the virus can be lethal to monkeys (Johnson et al 1995,
Jaax et al 1995). Also, there is circumstantial evidence that during the EBOV outbreak of 1995,
some patients became infected through aerosol transmission (Roels et al 2010). According2
Ebola: Do we need to worry?
to the “Infection Prevention and Control Recommendations for Hospitalized Patients with Known
or Suspected Ebola Hemorrhagic Fever in US Hospitals,” the CDC offers standard, contact AND
droplet precautions for management of hospitalized patients with known or suspected Ebola
disease, including avoiding AGPs (aerosol generating procedures). Additionally, according to the
Public Health Agency of Canada, the infectious dose for Ebola is indicated as “1-10 aerosolized
organisms are sufficient to cause infection in humans.”
At the end of July, President Obama signed an amendment to an executive order that would
allow physical and medical detainment of any patient suspected of having respiratory symptoms
associated with fever. Furthermore, research done in labs studying viral pathogenesis has shown
that TIM1 (T-cell immunoglobulin and Mucin Domain containing protein) is a receptor for Zaire
Ebola virus (Kondratowicz et al 2010). TIM1 expression is found on mucosal epithelia from the
trachea, cornea and conjunctiva (Kondratowicz et al 2010). This offers insight into potential
transmission routes involving inhalation of droplets or hand to eye contact.
So let’s assume that Ebola cannot be transmitted naturally from the air. What would it take in
order to mutate so that it could be highly transmissible via the air? A study published in 2012,
showed that just five changes in the sequence of the H5N1 virus could confer aerosol
transmissibility in ferrets (Herfst et al 2012). Ebola, like an influenza virus, is a negative sense
single stranded RNA virus. RNA viruses are replicated by an RNA-dependent RNA polymerase,
an enzyme which lacks efficient proofreading ability and therefore, has the highest documented
mutation rate per viral generation (Domingo et al 1996, Sanjuan et al 2010, Drake et al 1998).
−6 −8
Specifically, double-stranded DNA viruses have mutation rates of between 10 and 10
−4
mutations per bp per generation, whereas RNA viruses have mutation rates of between 10 and
−6
10 mutations per bp per generation (Drake et al 1998). Therefore, it is plausible that a variant
with an extremely high mutation rate and one that is replicating enough times throughout the
population, could potentially mutate to become airborne. Can we rule out the possible Ebola viral
evolutionary path to airborne transmission? The possibility of the virus mutating such that it would
be highly transmissible in the air is a scary thought, so why take a chance?
According to epidemiological modeling, the Ebola virus is about as infectious as influenza or
potentially more than influenza. In particular, each infected person will likely infect 2 to 4 others
(Gatherer 2014). Measles or polio have numbers of around 5 to 18, resuling in higher rates of
transmission, but a number above 1 suggests that it is possible for Ebola to cause a pandemic
(Gatherer 2014). Why haven’t we seen an Ebola pandemic? Four criteria have been offered as
essential for a virus to become a real pandemic:
1) the population should lack immunity to the virus,
2) it should be pathogenic,
3) it should have a short generation period and
4) it should have a basic reproductive number (R nought) greater than 1 (Martina et al 2009).
Does Ebola not satisfy these criteria? Many claim that Ebola could not spread rapidly throughout
the population because of its short incubation period, but the Public Health Agency of Canada
also mentions on their website that the incubation period for the Ebola virus can range anywhere
from 2-21 days, more often 4-9 days. Also, studies have shown that the viral transmission can
occur through reproductive fluids up to 2 months after convalescence (Rowe et al 1999). Knowing
the high mortality rate associated with this pathogen, progressive symptoms, and possible
aerosolized transmission route, it is better to be safe than sorry in case natural infection rates
spiral out of control. Even worse, what if an engineered form of Ebola with airborne
transmissibility is utilized as a form of bioterror? We need an approved and licensed vaccine or
appropriate treatment as a safeguard. Currently, there are none.
Ebola drug development; where do we stand?
Nerac Inc. www.nerac.com
1 Technology Drive 860.872.7000 telephone
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Ebola: Do we need to worry?
Due to the fact that throughout history Ebola is typically associated with more localized outbreaks
of infection endemic to Africa, efforts to develop appropriate treatments or vaccines have not
gained sufficient financial backing. Ebola has been touted as a “neglected tropical disease.”
Development for drugs has been a market failure because this disease usually affects
impoverished people in poor countries, so it has fallen to smaller companies for research.
Nevertheless, in response to the most current epidemic of Ebola cases raging across West
Africa, governmental agencies have been working to finance research endeavors to get
experimental drugs through the pipeline to put out the Ebola wildfire.
A survey of current Ebola drugs in the pipeline are listed in Table 1. ZMapp, the experimental
drug used to treat two Americans infected with Ebola, contains an antibody cocktail engineered in
tobacco plants. Other drug candidates utilize clever RNAi strategies, like Tekmira’s TKM-Ebola
or Sarepta’s AVI-7537 drug. Additional strategies to combat Ebola infection include drugs that
function with more of a broad spectrum mechanism of action, inhibiting viral replication or acting
as a nucleoside analogue, like that of BCX4430 from BioCryst Pharma and Favipiravir from
FujiFilm Group. One company in Connecticut, Nanoviricides, is developing a drug that uses
nanoparticles to trick the virus into thinking it is attaching to a host cell. The majority of the drugs
in the pipeline for treating or protecting against Ebola have only made it to animal study trials and
have yet to be tested on humans. Even though it appears that ZMapp was used successfully on
two infected Americans, it is not entirely clear whether it was the drug that worked or their native
immune system that cleared the virus. Future trials will provide insight into the safety and efficacy
of these above mentioned therapeutics.
Table 1. Current status of drug development for Ebola virus infections. The particular company,
funding source, drug target/mechanism and trials are indicated
Drug Name/ Funding Source Vaccine/Treatment Trials/Success
Pharmaceutical
Company
ZMapp/Mapp US Three “humanized” ZMapp
Biopharmaceutical Government/Public monoclonal antibodies TM
Health Agency of manufactured in plants has shown
Canada (Nicotiana) efficacy in a
monkey model of
Ebola in studies
conducted
by the Public Health
Agency of Canada
(submitted for
publication)
TKM-Ebola/Tekmira $140 million US RNAi therapeutic using 100% protection in
Pharmaceuticals Department of LNP (lipid nanoparticle) Nonhuman primates
Defense technology (Geisbert et al
2010), clinical trials
underway as of Jan.
2014
VSV-EBOV/National Government of Attenuated recombinant 100% protection in
Microbiology Canada vesicular stomatitis Nonhuman primates
Laboratory virus vectors expressing (Jones et al 2005)
either the EBOV
glycoprotein or MARV
glycoprotein Vaccine
BCX 4430/BioCryst Department of Broad Spectrum Protection in non
Nerac Inc. www.nerac.com
1 Technology Drive 860.872.7000 telephone
Tolland, Connecticut 06084-3900 860.872.6026 facsimile4
Ebola: Do we need to worry?
Pharmaceuticals Defense’s Threat antiviral therapeutic, human primates
Reduction viral RNA-dependent (Warren et al 2014)
Agency/National RNA polymerase
Institutes of Health (RdRp) inhibitor
National Institute of (nucleoside analogue)
Allergy and Infectious
Disease/U.S. Army
Medical Research
Institute of Infectious
Diseases
$4.1 million
BPSC1001/NewLink 1$ million contract rVSV with the VSV-G Protection in mice
Pharmaceuticals with the US Defense envelope protein gene and non human
Threat Reduction removed (VSV-deltaG) primate studies are
Agency and EBOV variant ongoing (Hirschberg
Kikwit GP1,2 gene et al 2014)
inserted
Favipiravir/Fujifilm US Department of T 705/Viral RNA Ongoing study that
Holdings Corp. Defense polymerase inhibitor tests drug in Ebola-
infected monkeys
AVI-7537/MB- US Department of PMO-Plus technology, Protection in mice
003/Sarepta Defense (withdrew in blocks expression of (Enterlein et al
Pharmaceuticals 2012) VP24 protein by binding 2006) and ongoing
to viral RNA
Okairos, owned by National Institutes of Not yet given a name/ Protection in non
GlaxoSmithKline Health Vaccine containing a human primates
Pharmaceuticals chimpanzee-based (Kobinger et al
adenovirus 2005)
Profectus National Institute of VesiculoVax/ 100% protection of
BioSciences Allergy and Infectious VesiculoVax™ vectors non-human
Diseases are negative-strand, primates against
non-segmented RNA challenge with
viruses of the order 1,000 times the
Mononegavirales that lethal dose of both
have been modified to Ebola and Marburg
enable the delivery of viruses (from
vaccine immunogens company website)
NanoViricides TBD/chemically Animal studies
attached virus-binding (from Company
ligand to a nanomicelle website)
flexible polymer, broad
spectrum
.
How do we stop future outbreaks?
The exact causes underlying the start of an Ebola outbreak are not entirely understood. As a
trend, we have seen Ebola cases in poor countries whose economy and public health systems
are in disarray. Ultimately, identifying the natural reservoir is a key to stopping the initial
transmission of disease. Research suggests that fruit bats native to affected areas are the most
probable reservoir. Hypsignathus monstrosus, Epomops franqueti and Myonycteris torquoata are
all bat species that have tested positive for Ebola virus (Pourrut et al 2009, Leroy et al 2009).
Nerac Inc. www.nerac.com
1 Technology Drive 860.872.7000 telephone
Tolland, Connecticut 06084-3900 860.872.6026 facsimile5 Ebola: Do we need to worry? While these have been deemed “likely candidates,” we still have no definitive reservoir that has been established for Ebola. Another obvious solution to quelling an infectious disease outbreak is to be armored with drugs powerful enough to combat the virus’ replication cycle or even better, administer a vaccine that will prevent infection in the first place. Once drugs are administered, antiviral drugs will help to increase the low survival rate and vaccination of especially endemic areas may help to prevent future outbreaks of disease. With the WHO’s warning they could be vastly underestimating the magnitude of the outbreak and the potential for this virus to spread to other countries, it is imperative that there is a concerted effort to identify the origin of this disease and find a way to treat it appropriately before it is too late. About Nerac Nerac Inc. is a global research and advisory firm for companies developing innovative products and technologies. Nerac provides expert insights that equip clients with the knowledge to develop or refine a technology, explore market growth opportunities, evaluate intellectual property strategies and respond to regulatory changes. Nerac serves approximately 20,000 users worldwide and answers over 5,000 research questions each year. Nerac has a long, successful consulting history in a wide-range of industries with a strong focus in the areas of pharmaceutical, food and nutraceuticals, medical device, engineering, energy and advanced materials. Nerac Inc. www.nerac.com 1 Technology Drive 860.872.7000 telephone Tolland, Connecticut 06084-3900 860.872.6026 facsimile
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