EBOLA: THE RACE TO FINDING A VACCINE.

Researchers in Canada, Britain, the US and Mali are testing drugs they hope will stop the humanitarian disaster unfolding in west Africa – and prevent Ebola becoming as prolific as HIV.

In 1959 the French microbiologist René Dubos
gazed into his crystal ball and found reasons to be
concerned. In his lifetime Dubos had witnessed the
steady decline of diseases such as diphtheria,
tuberculosis and polio, but rather than giving him
confidence these medical successes filled him with
foreboding. Though vaccines and therapeutic
drugs had neutralised many of the threats of the
past, he warned that humans could not escape the
microbes that transmitted infectious diseases,
because they were part of the environment and
our ecology.

Complete freedom from infectious disease was a
mirage, he warned. “At some unpredictable time
and in some unforeseeable manner nature will
strike back.”
The Ebola outbreak is arguably just such a riposte,
shattering western dreams of medical utopias.
While the reservoir (the long-term host) of the
virus has yet to be identified (fruit bats and apes
are the leading contenders) there is little doubt
that Ebola is the greatest threat to the world’s
health and security since HIV/Aids or that the fault
lies with man and his insatiable demand for the
world’s natural resources – a demand that puts an
intolerable strain on ecosystems and the parasites
that inhabit them.

No one knows for certain where or when the
decisive “spill- over” event occurred – one theory is
that “patient zero” was a two-year-old boy from
Guéckédou in south-eastern Guinea who contracted
Ebola from contaminated bush meat in December;
another, is that Ebola is continuously emerging
and that there were several simultaneous spill-
overs. Whatever the case, however, the situation in
west Africa is dire and getting worse by the hour –
a humanitarian disaster, according to Oxfam –
which is why infectious-disease experts are
increasingly looking to a vaccine as our next best
hope.

“A vaccine is critical because the truth is we just
don’t know what is going to happen,” says Jeremy
Farrar, the director of the Wellcome Trust and a
veteran of several epidemic scares, including the
2003 Sars outbreak and the wave of bird flu that
swept south-east Asia in 2005. “I’m very much
hoping that we will be able to bring this epidemic
under control using classic public health
containment measures, but if those measures fail
then we need an alternative strategy.”
That strategy is now the responsibility of
researchers at laboratories in Britain, Canada, the
US and Mali, where scientists are in a race to
develop vaccines that could be shipped to west
Africa as early as December, with more doses to
follow next year if trials demonstrate that they are
safe and effective. The frontrunner is a vaccine
known as ChAd3, developed jointly by the
biowarfare arm of the US National Institute of
Allergy and Infectious Diseases (NIAID) and
Okairos, a Swiss-Italian biotechnology company
that is now part of the pharmaceutical firm
GlaxoSmithKline. Trials of different versions of the
ChAd3 vaccine are under way at the Jenner
Institute in Oxford, the National Institutes of
Health (NIH) clinical centre in Bethesda, Maryland,
and the centre for vaccine development in Mali.
About 140 volunteers are being enrolled across the
three trial sites between now and the end of the
year.

In addition, a fortnight ago the Canadian government announced that it and the Walter Reed Army Institute of Research in the US would trial yet another experimental vaccine, known as VSV- EBOV. Such is the concern about Ebola, however, that even before that trial began Canada announced that it was donating 800 vials of its
vaccine to the World Health Organisation in
Geneva (this is a vaccine which, so far, has only
been tested on non-human primates). Last week
Johnson & Johnson also announced it was investing
$200m in developing a two-step Ebola vaccine
together with Denmark-based biotechnology
company Bavarian Nordic. Like GSK’s vaccine, the
vaccine has performed well in animal trials. The
difference is it involves taking two shots, the first
to prime the immune system and the second to
boost it. J&J is planning to begin human trials in
January and says it could have 250,000 doses
available by May. Separately, the WHO says it
hopes to make a serum vaccine using antibodies
from the blood of Ebola survivors available in
Liberia within two weeks.

Meanwhile, China’s Academy of Military Medical
Sciences has donated several thousand doses of an
experimental drug, JK-05, for emergency use by
Chinese aid workers in west Africa, while Peter
Horby, a tropical disease specialist from Oxford, is
in the process of testing several other promising
drug candidates, including ZMapp, the drug used to
successfully treat two American missionaries and
the British nurse Will Pooley, at clinics in Liberia
operated by Médecins Sans Frontières (MSF).
Whether these efforts will bear fruit quickly
enough to halt the tide of human infections
depends on two factors: how quickly the world can
ramp up its response to the epidemic and what the
virus decides to do next. While the first is in our
hands, the second is not. Ebola, like all viruses, is
constantly mutating and could theoretically become
even more virulent or, conversely, evolve so as to
become less virulent and more widely infective. It
is this second scenario that keeps disease experts
awake at night.

“This virus is now in thousands of individuals and
every time that happens it gives a virus the ability
to change and adapt to human beings,” says
Farrar. “Then you don’t know where the virus is
going to go but you run the risk that it will become
a natural endemic human infection.”
In other words, Ebola could become more like HIV,
a virus that, because it does not provoke obvious
symptoms, at least in the early stages of infection,
to date has succeeded in infecting 75 million
people worldwide.

The problem is that what began as a highly
containable outbreak in Guinea last December has
now changed into a conflagration that is
threatening to spill over from Liberia and Sierra
Leone, the two worst affected countries, to Ivory
Coast and Guinea-Bissau, with Mali confirming its
first case last week (though, thankfully, both
Senegal and Nigeria recently declared they were
free of infection). Meanwhile, as the isolation of in
New York last week of a MSF doctor who had
recently returned from Guinea shows, there is an
ongoing risk of health workers introducing Ebola
to countries outside Africa.

And the longer Ebola is allowed to burn in Africa,
the greater the chances that it will set off bush fires
in other parts of the world. It couldn’t happen
here, we are told, because our health systems are
too robust. But as the World Health Organisation
charts the epidemic’s relentless upward curve
(10,000 cases a week by the end of October is the
current prediction; cumulatively, perhaps as many
as 1.4m cases by January) and stories emerge of
elementary errors by hospitals and health
authorities that should know better, many experts
are beginning to worry that the worst could
happen.

In many ways, Ebola is no different from any
other infectious disease, such as influenza, that
originally began life in animals. The difference is
that whereas influenza is now well-established in
human populations, meaning that most people will
have some immunity to it, Ebola outbreaks are
relatively rare.

The first documented outbreak occurred in the
Yambuku district of Zaire (now the Democratic
Republic of Congo) in the summer of 1976. It was
there that Peter Piot, currently director of the
London School of Hygiene and Tropical Medicine
but then a young infectious disease expert, first
encountered the virus and together with colleagues
decided to name it after a river that flowed
through the district. That same year at around the
same time there was another outbreak in Sudan of
a closely related strain, dubbed Sudan Ebolavirus.
In both cases the spread of infection was amplified
by contaminated needles and syringes and many
medical personnel were infected.
Since then three further strains have been
identified: Reston virus, Taï Forest virus (formerly
known as Côte d’Ivoire Ebolavirus) and
Bundibugyo virus. However, the Zaire and Sudan
strains are the two commonest cause of human
infections, with the Zaire strain having the highest
lethality (up to 90% in some outbreaks). Curiously,
Reston is the only Ebola virus not currently known
to be pathogenic in humans, although it is highly
lethal to non-human primates. The reasons why it
has not caused disease among humans are not yet
understood.

Ebola is also closely related to Marburg, another
filovirus (the family of “filament” viruses) that was
first identified in 1967 when it infected laboratory
workers in Germany and Yugoslavia handling
imported primates from Uganda. Like Ebola,
Marburg is extremely virulent, causing a
haemorrhagic fever that frequently proves deadly.
It is for this reason that both Ebola and Marburg
have attracted attention as possible biowarfare
agents and that popular writers such as Richard
Preston, author of the bestselling nonfiction thriller
The Hot Zone , have been drawn to the subject,
describing the viruses in lurid and often
exaggerated terms.

One reason for the fear surrounding Ebola is that
no one knows where the virus goes between
outbreaks. Primates have long been known to
harbour Marburg. Both it and the Ebola virus have
also been found in three species of fruit bat in and
around Gabon. As bats constitute a quarter of all
the mammals on the planet, there is a good chance
they are the main reservoir of the virus and that
the consumption of bats, or chimps infected by
bats, could be the main route towards human
infections, but to date no one has been able to
prove it.

The good news is that humans seem to represent
an end point for the virus, with evidence of only
“stuttering” chains of transmission during
outbreaks and no evidence that humans can
reintroduce the virus back into another animal
(however, there is evidence that fruit bats may
have introduced the Reston strain of the virus into
Asian pig farms). The bad news is that Ebola has
multiple strategies for evading our immune system.
Dr Erica Ollmann Saphire understands Ebola as
well as any scientist alive. A structural biologist at
the Scripps Research Institute in La Jolla,
California, Saphire has been working with
laboratories around the world to map the structure
of the Ebola virus in an effort to pinpoint its weak
spots and identify antibody targets for drugs and
vaccines.

In popular discourses Ebola, which can provoke
internal haemorrhaging and, in some cases, bloody
effusions, has been dubbed the “Hammer horror
virus” and compared to the creature in Alien , but
according to Saphire the metaphor that best
describes Ebola at a molecular level is that of a
“Transformer”.

Like the children’s toy that can be unfolded and
refolded to turn it from a truck to a robot and back
again, Ebola is able to change shape seemingly at
will. According to Saphire, this facility, which is
controlled by a single protein known as VP40,
defies a central dogma of molecular biology:
namely, that gene sequence dictates function.
Although Ebola has seven genes, by rearranging its
protein structure the virus is able to carry out far
more than seven functions.

“We don’t typically expect molecules in biology to
do that,” says Saphire. “We expect proteins to have
one particular form – just the robot. But Ebola can
unfold from a robot to a truck. It can walk and talk
and shoot, and other times it can carry a lot of
cargo and drive at high speeds along the highway.”
This has important implications for drug design
because it means that you may need to devise
therapies that are effective against both the robot
and truck forms of Ebola in order to be sure of
neutralising the virus.

That is not the end of Ebola’s tricks, however.
Ebola is also a master at evading our immune
system. It does this by employing two other
proteins, known as VP35 and VP24. The first
enables the long filament-like strands of virus to
form a spiral shape that Saphire likens to an
invisibility cloak. Meanwhile, VP24 blocks the
release of interferon, the protein that signals the
presence of a foreign pathogen and tells the body
to ramp up its immune response.

Another factor in Ebola’s favour is that half its
mass is carbohydrate, the compound that provides
energy for human cells, so again our immune
system doesn’t register the virus as foreign. In
addition, the glycoproteins the virus uses to bind to
receptor sites on host cells are arranged along the
main trunk of the virus, where they lie concealed
beneath leafy side branches. It is only when the
virus is sucked into the interior of the cell that it
severs these branches by hijacking enzymes within
the cell and reveals its true nature. But by then it
is too late. Now the virus can use the cell’s
machinery to produce millions of copies of itself.
From then on it’s a race between the virus and our
immune system. Unlike HIV, which only infects
two types of immune cells, Ebola first infects the
leucocytes, the white cells that patrol the blood and
lymph system. Then it attacks nearly every other
type of cell. This process typically takes between
two and 21 days, with death occurring, on average,
six to 16 days after the onset of the illness.

The first symptoms are fever, headache and
fatigue. But as the virus begins to overwhelm more
cells, the cells burst, prompting a chemical release
that leads to inflammation and toxic shock. As the
viral load increases, patients suffer stomach pains,
bloody diarrhoea, severe sore throats, jaundice
and vomiting. Eventually the viral load becomes
too great, prompting the immune system to go into
overdrive and launch an all-out attack known as a
cytokine storm, which causes even more damage.
The final stage comes when cells infected with the
virus attach themselves to the inside of vessels and
arteries, weakening them to the point where they
begin to leak fluids, leading to a dramatic fall in
blood pressure and multiple organ shutdown. In
half of cases, the result is uncontrollable
haemorrhaging. In the most extreme cases of all
these fluids may seep from the nose and mouth
and it may appear as if victims are weeping “tears
of blood”.

For those who have witnessed someone in the
death throes of Ebola at close quarters it is an
unforgettable sight. One moment, victims are
dazed and expressionless. The next they are
doubled up in pain and bringing up haemorrhagic
discharges from their stomachs – a substance
known as “black vomit”. The nearest historical
equivalent are the 18th-century outbreaks of
yellow fever, a disease that also produces a dark
viscous vomit, or the cholera epidemics of the 19th
century. Then, as in Freetown and Monrovia
today, people collapsed on the streets of London,
Liverpool and New York, expiring in pools of fetid
fluids as they were shunned by passers-by.
It is in the hope of saving Africans from further
pain that volunteers are now being enrolled in
trials. The most advanced is the trial at the Jenner
Institute, which uses ChAd3 (chimp adenovirus
type 3, a chimpanzee “cold” virus) as a vector (or
agent) to deliver a small segment of genetic
material from the Zaire strain of the virus. This is
the strain behind the current outbreak in Guinea,
Liberia and Sierra Leone, but unlike the
circulating strain the genetic material in the
vaccine has been neutralised and the virus does
not replicate, so the vaccinated individual cannot
become infected with Ebola. Instead, the idea is
that the Ebola gene will prompt the cells of the
vaccine recipient to manufacture a single protein
on the surface of the Ebola virus and that this will
induce an immune response.

Using the same principle, scientists at the NIH
facilities in Bethesda and Mali are trialling a
vaccine using genetic material from both the Zaire
and Sudan strains of Ebola, while the Canadians
are using another animal virus called vesicular
stomatitis virus (VSV) to deliver genetic material
from Ebola to recipients’ cells.

The GlaxoSmithKline vaccine has already
performed well in animal trials, providing
macaque monkeys with 100% protection against
Ebola for up to 10 months. But our immune system
is very different from that of macaques and, to
date, no vector-based vaccine has been licensed for
any disease in humans. That is why scientists are
proceeding with caution and testing the vaccine in
different concentrations in order to ascertain the
lowest dose that will elicit an immune response.

“The big question is, will the immune responses that we generate with the vaccine be strong enough?” says Professor Adrian Hill, the director of
the Jenner Institute. “That’s always a question with new vaccines.”