Ebolavirus in West
Africa, and the use of experimental therapies or vaccines
Thomas Hoenen and Heinz Feldmann*
- *Corresponding
author: Heinz Feldmann feldmannh@niaid.nih.gov
Laboratory of Virology, Division of Intramural Research,
NIAID, NIH, 903 S 4th St, Hamilton 59840, MT, USA
For all author emails, please log on.
BMC Biology 2014, 12:80 doi:10.1186/s12915-014-0080-6
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Response to the current ebolavirus outbreak based on
traditional control measures has so far been insufficient to prevent the virus
from spreading rapidly. This has led to urgent discussions on the use of
experimental therapies and vaccines untested in humans and existing in limited
quantities, raising political, strategic, technical and ethical questions.
The ongoing outbreak in West Africa of ebolavirus
hemorrhagic fever (EHF) [1], lately also
referred to as Ebola virus disease (EVD), has led to a surge in public interest
and concern regarding this virus, which was first discovered in 1976 during
simultaneous outbreaks in Zaire (now the Democratic Republic of the Congo) and
Sudan [2]. Humans initially
contract the virus either through contact with the infected reservoir, which is
thought to be fruit bats, or by hunting and butchering of infected wildlife,
particularly great apes. Since their discovery, ebolaviruses have caused
frequent outbreaks almost exclusively in Central Africa. However, the recent
emergence of Zaire ebolavirus in West Africa, resulting in
what is the largest outbreak to date (Figure 1), with
4,390 cases and 2,226 deaths as of 7 September 2014, shows that ebolaviruses
are more widely distributed than previously thought. While EHF is commonly
associated with high case fatality rates (up to 90% for Zaire
ebolavirus, approximately 50% for Sudan ebolavirus, and
approximately 35% for Bundibugyo ebolavirus), the pathogenicity of Taï
Forest ebolavirus, which was discovered in the mid-1990s in Ivory Coast, is
unknown because only a single case has been reported, and Reston
ebolavirus, which is found in the Philippines, is considered apathogenic
for humans. Outbreaks are usually driven by human-to-human transmission as a
result of direct contact with live or deceased patients and their body fluids,
mainly during patient management and care, and participation in traditional
local burial practices. Basic hygiene measures and barrier nursing techniques
are usually sufficient to disrupt ebolavirus transmission and spread in the
community. Nevertheless, because of its high case fatality rate and the absence
of licensed vaccines or treatments, this virus is considered of the highest
biosafety concern, restricting work on infectious virus to a few maximum
containment laboratories worldwide. Despite the restricted and highly regulated
handling of the pathogen, there have been considerable scientific achievements
over the past years; however, many challenges remain in the public health
sector in relation to identifying and managing cases and interrupting virus
spread.
Figure
1. Map of the West African ebolavirus outbreak as of 7
September 2014. Country and province borders according to the CIA
World Factbook are indicated as black or grey lines, respectively. Provinces
with no new cases in the 21 days prior to 7th September
2014 (according to the WHO situation report from 12th September
2014) are highlighted in yellow, provinces with new cases in the 21 days
prior to 7th September in orange, and provinces showing cases
for the first time in the 7 days prior to 7th September
are highlighted in red. Case numbers for each country are indicated, with each
square representing 10 cases. Only countries with extensive person to person
transmission are shown; Senegal and Nigeria are not shown. Inserts show a
typical treatment and isolation facility set up as part of the international response
to the outbreak, with the top insert showing the ELWA III treatment and
isolation site, the middle insert showing the inside of a treatment tent, and
the bottom insert showing a lab worker inactivating patient samples in a
portable isolation chamber (pictures courtesy of Barry Fields (CDC Nairobi) and
Dave Safronetz (NIH)).
The first major challenge lies in outbreak recognition, as
exemplified by the current EHF outbreak in West Africa, which took almost three
months to recognize and even longer to appreciate as a major public health
concern [1]. Initial disease
symptoms, which occur suddenly after an incubation period of up to
21 days, are rather non-specific and include fever, malaise, headaches,
muscle pain, nausea, vomiting and diarrhea [2],[3].
More characteristic symptoms, such as hemorrhagic manifestations including
vomiting of blood, nosebleed, bloody or tarry stool, and bleeding from
injection sites, as well as a characteristic rash, appear later in the disease
course, and are only obvious in about half of all patients. Pathogenesis
involves a combination of immune suppression, vascular dysfunction,
coagulopathy, and the dysregulation of cytokine responses similar to systemic
inflammatory response syndrome (SIRS), ultimately resulting in multi-organ
failure and death [2],[4].
Importantly, similar symptoms, particularly in the initial stages of disease,
can also be seen in patients infected with malaria and typhoid fever, as well
as many other endemic infectious diseases [2],[3]
with which EHF can be confused. For non-endemic countries the fear of
importation is justified, as demonstrated by past importations of ebolavirus
into South Africa and the closely related marburgvirus into the USA and the
Netherlands, although these remain rare events. However, the likelihood of
importations has increased in association with the current outbreak in West
Africa, where four capital cities that have multiple international travel
connections are now affected, and with the evacuation of confirmed cases among
foreign aid workers. Nevertheless, it is very important to realize that in most
non-endemic countries ongoing person-to-person transmission, as we currently
see in West Africa, is extremely unlikely, due to better access to professional
health care, higher standards of hospital hygiene, patient management and
diagnosis, safer burial practices, and the current high level of awareness
among health care providers. Past experience has shown that even when diagnosis
was delayed, secondary infections have not occurred during the rare incidences
of imported infections, further indicating the critical importance of basic
personal protection and hospital hygiene as key measures to control ebolavirus
transmission.
Once an EHF outbreak is confirmed, rapid diagnosis based on
quantitative real-time polymerase chain reaction (qRT-PCR) methodology, as well
as serology and antigen detection, is available. However, given the remote
locations in which outbreaks usually occur, this either involves time-consuming
shipping of samples to more centrally located reference laboratories, or
dispatching of mobile laboratories directly into the outbreak area [5].
The main strategy for outbreak management focuses on the reduction of secondary
transmission by isolating infected individuals, the implementation of safe
burial practices, contact tracing to disrupt infection chains, and education of
the local population regarding risk reduction [6]. From a public
health perspective, this strategy is paramount, and it has been successful in
the past in controlling ebolavirus outbreaks; but it has so far had only
limited effect on the current outbreak in West Africa. In terms of the
individual patient, at this time, care is limited to supportive treatment to
maintain vital function. The importance of providing the best possible care to
patients is not only in helping to reduce case fatality rates, but also because
it increases compliance with isolation procedures and, therefore, contributes
to overall outbreak control.
To address the need for more rapid recognition of future EHF
outbreaks, awareness among the medical community about EHF needs to remain high
between outbreaks. Once cases are identified, a multidisciplinary approach,
including the open and timely sharing of all relevant information, is
imperative for a successful outbreak response.
Currently no licensed vaccines or therapeutics are available
for ebolaviruses. Over the past decade, however, funding has been made
available for research into such countermeasures, resulting in encouraging
progress on the preclinical level (Figure 2) [7].
Further, reverse genetics technologies have generated non-infectious systems
that allow modeling of the complete ebolavirus life cycle without the need for
maximum containment laboratories. Together with reporter-expressing recombinant
ebolaviruses, these systems have significantly improved our ability to identify
new antivirals [8]. The most
promising antivirals at this point include the combinations of three monoclonal
antibodies, which were protective in non-human primates (the most stringent
disease model) up to two days after challenge, and when used in combination
with interferon alpha were even protective if treatment was initiated three
days after challenge, that is, after the onset of symptoms [9],[10].
This approach is now further being developed as ZMapp, an improved antibody
cocktail that is able to protect non-human primates with treatment starting as
late as five days after challenge [11], and was
recently administered to a small number of infected aid workers. Another very
promising approach is the use of small interfering RNAs (siRNAs), which was
also protective in non-human primates if given after exposure [12].
This approach is currently being developed as a commercial drug called
TKM-Ebola, and while a phase I clinical trial was put on hold by the FDA in
July 2014, on 7 August 2014 this ban was partially lifted, enabling the
potential use of this drug in EHF patients.
Figure
2. Promising countermeasures against ebolaviruses.Listed
are the most advanced countermeasures (based on the authors’ judgment), all of
which show 100% protection in non-human primates (NHPs). Vaccines are shown in
blue and antivirals are shown in green. In the case of vaccines, only those
that require a single vaccination are shown.
Similar progress has been made with vaccines, with several
platforms being highly protective in nonhuman primate models [13].
The furthest developed of these vaccines are based on viral vectors, since
earlier attempts using inactivated vaccines were unsuccessful, and
live-attenuated vaccines are generally considered too dangerous in the case of
ebolaviruses. Viral vector-based vaccines are recombinant vaccines in which
genes encoding proteins of a pathogenic virus such as ebolavirus are inserted
into the genome of another virus that causes mild or no disease. The viruses
mostly used in ebolavirus vaccines are either recombinant,
replication-deficient adenoviruses (Ads) or attenuated vesicular stomatitis
viruses (VSVs), both of which are not known to cause serious side effects in
humans. The ebolavirus genes encode proteins that can be recognized by the
immune system but do not cause disease. The adenovirus platform uses a
non-replicating recombinant adenovirus carrying the genetic information for the
ebolavirus surface glycoprotein (GP) or for both GP and the ebolavirus
nucleoprotein. Vaccination with this virus leads to the production of these
proteins in the vaccinated individual, resulting in the development of an
adaptive immune response. Most studies were performed using the human Ad5
serotype, with which many people have been infected at some point in their
life. While in non-human primate studies this vaccine confers complete
protection if given four weeks prior to challenge, in humans there are
significant problems with preexisting immunity against the Ad5 serotype, so
that individuals who have been previously exposed to Ad5 fail to mount an
immune response to the ebolavirus component of the vaccine. While the Ad5-based
vaccine was safe and immunogenic in a phase I clinical trial, the immune
response was likely insufficient to confer protection [14]. The problem of
preexisting immunity has been addressed by using different serotypes, including
the rare human serotypes Ad26 and Ad35, chimpanzee Ad3, Ad7, and Ad63, as well
as simian Ad21. Limited studies showed 100% protective efficacy in non-human
primates after a single vaccination for the chimpanzee Ad3-based vaccine,
although a booster immunization was required to achieve long-lasting immunity [15].
A phase I clinical trial with this vaccine began in early September 2014.
The VSV platform uses an attenuated replication-competent
recombinant VSV that contains the ebolavirus GP gene instead of its own
glycoprotein gene, leading to the production of virus particles that
incorporate the ebolavirus glycoprotein into the virus envelope, as well as the
production of this protein in vaccinated individuals. In extensive studies this
virus has been shown to protect 100% of non-human primates if given either
three or four weeks prior to challenge [16], and
surprisingly it also showed some potential in post-exposure use, with 50 to
100% survival of non-human primates if the vaccine was administered 20 to
30 minutes after challenge, depending on the species of the challenge
ebolavirus. This vaccine platform has not progressed into clinical trials yet,
but it was shown to be safe in severely immunocompromised non-human primates, and
also did not cause neural pathology even after intrathalamic administration to
non-human primates[17],[18].
This is important because although VSV is non-pathogenic in humans, it can be
neurovirulent in mice, and the possibility of neural pathology in humans must
be ruled out - especially since, in contrast to the adenovirus-based vaccine,
the VSV-based vaccine remains replication-competent. There has been a single
use of this vaccine as a potential post-exposure treatment after a needle-stick
incident in a laboratory worker in Hamburg, Germany, with no side effects other
than a transient fever [19]. A first phase
I clinical trial is planned for fall 2014.
One pressing and extremely difficult question is whether
such experimental treatments and vaccines should be used in the current
outbreak. The recent WHO declaration to ethically approve the use of
experimental drugs and vaccines under certain circumstances is likely to
improve current outbreak response strategies. However, one needs to remain
realistic regarding what can be done during the current outbreak, given both
the extremely limited amount of clinical grade material that is available and
the lack of human safety data for any of the promising experimental drugs and
vaccines. Clearly, improving the chances of survival of an infected patient is
highly desirable. Improved survival might also help to change a perception in
the population that the isolation wards are ‘death traps’ rather than medical
care facilities, which could lead in turn to improved compliance with
conventional outbreak control measures. However, because of the general lack of
human safety and efficacy data for these experimental drugs and vaccines there
is a risk of adverse effects and/or ineffectiveness, which could result in the
perception that developed countries are experimenting on African patients. The
consequent deterioration in the relationship between the affected African
population and foreign health care workers might decrease compliance with
outbreak control measures and may even lead to aggression, ultimately resulting
in further or even complete loss of outbreak control. This risk scenario
applies in particular to the more recent demands for the testing of certain
drugs approved/licensed for other medical applications, which counteract human
host responses that have been implied in the pathogenesis of EHF, but without
preclinical efficacy data for those drugs against EHF. Safety of a drug
targeting a host response mechanism predicted to be relevant during ebolavirus
infection seems too weak as a justification considering the potentially
disastrous consequences of a failure in efficacy on the ground.
Implementation of any countermeasure needs a well designed
strategy, and this is particularly the case when supplies are limited, as they
are at the moment. In addition, different situations may call for the use of
different countermeasures. For example, foreign health care workers may be best
served by using a safe and effective vaccine approach, whereas confirmed
patients will need a therapeutic approach such as an antiviral (for example
ZMapp or TKM-Ebola). Local health care staff and family members may benefit
from a ring vaccination approach (that is, vaccination of actual or potential
contacts to infected individuals) using a fast-acting vaccine such as the
recombinant VSV, or prophylactic treatment using an antiviral or therapeutic.
If experimental countermeasures are used, clinical safety and efficacy data
should certainly be collected whenever possible. The question, however, is how
that can be integrated with currently ongoing outbreak control measures, and
whether we can ethically justify control groups if the countermeasures have
high prediction values for success. In addition, giving some patients and
health care or aid workers priority for treatment or vaccination will certainly
create discord among the affected population, aid organizations, and
governments, as decisions are unlikely to be seen as politically, ethnically
and ethically correct by all parties. Regardless, targeting of health care
workers with vaccination might be one justified instance for the following
reasons: first, they are at significant risk for acquiring EFH as an inherent
part of their work; second, they are absolutely essential to the on-going
management of the outbreak, and thus for public health; and third, they might
be in a better position to give informed consent to receive an experimental
countermeasure. Despite all of the complications, we should not forget that
using countermeasures could have a tremendous positive impact on the current outbreak,
and provide us with a great chance to gain experiences that can then be applied
during the inevitable future outbreaks.
The decisions regarding whether to deploy experimental
countermeasures, which countermeasure to deploy, and how to do so are extremely
complex and difficult, and will have to involve a careful risk/benefit
evaluation, not only on the level of an individual patient, but also for
overall outbreak management. These decisions should be made jointly with all
affected parties, including scientists and public health experts, the aid
organizations involved in outbreak management, and most importantly
representatives of the people directly affected by the outbreak. As a note of
caution, any use of countermeasures should not affect strengthening the
traditional public health response measures, which have a very successful track
record and are likely to be successful in this outbreak if widely and
rigorously applied.
Research has made significant progress in combating ebolavirus
infections. We now have to translate these scientific advances into tangible
benefits for the people affected by this devastating disease. Events in the
current outbreak are rapidly developing, and it is impossible for the authors
to predict what measures will have been taken by the time this article is
published. However, regardless of whether experimental countermeasures are
eventually used in the current ebolavirus outbreak, it is clear that their use
can only be considered a last resort and that the strengthening of traditional
public health and outbreak response measures are of paramount importance. For
the future, the major challenge lies in advancing the experimental treatments
and vaccines towards licensing for human use. Further, deployment strategies
have to be put into place both for delivering countermeasures into an outbreak
area, and for their administration. It will also be necessary to consider the
possibility that infections will be imported into countries in which infections
with ebolaviruses do not normally occur, and to develop management plans.
Again, overcoming this challenge will require collaboration between scientists,
aid organizations, pharmaceutical companies, local communities, regulatory
bodies, and governments. Noteworthy is the currently increasing interest in
industry as well as in politics in ebolaviruses, something that has to be seen
as a positive development [20]. Finally,
future efforts should not be restricted to ebolaviruses, but also include other
communicable pathogens with the potential to cause devastating outbreaks, such
as the closely related marburgviruses. Even once the current EHF outbreak in
West Africa ceases, it is only a matter of time until the next outbreak
strikes. One should wisely use this opportunity to be proactive.
The authors thank Allison Groseth for critical reading of
the manuscript. This work was supported by the Intramural Research Program of
the NIH, NIAID.
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