Download Black Plague Claims Researcher

Is there hope for containment
by drugs and vaccines?
Current Research
on Ebola Treatments
E
A
bola continues to
plague West Africa as
it infringes upon the USA.
Meanwhile, there is a
scramble to develop and
approve new treatment
options for this deadly
disease.
By Christopher Massey
November, 2014
Christopher Massey is the
Research and Development
Manager at Hardy
Diagnostics.
He earned his degree in
microbiology at Cal Poly in
San Luis Obispo, California.
HardyDiagnostics.com
Several promising
vaccinations and therapies
have been developed over the
last couple of decades, but
they have yet to be thoroughly
tested for use in humans.
Some treatments have been
tried on human subjects in
emergency situations, but
their safety and efficacy are
still unknown.
ZMAPP
The most widely publicized
proposed treatment is
ZMAPP. This therapeutic
agent, developed by MAPP
Biopharmaceutical, is a
chimera of three separate
monoclonal antibodies
Under a magnification of 25,000X, this
digitally-colorized scanning electron
micrograph (SEM) depicts numerous
filamentous Ebola virus particles (red)
budding from a chronically-infected
VERO E6 cell (blue). From the NIAID.
specific to the proteins of
Ebola. The antibodies are
designed to
bind and neutralize the Ebola
virus. ZMAPP has been used
on an emergency basis to treat
some victims of Ebola.
However, due to the limited
number of doses produced,
the safety and efficacy of
ZMAPP has not been fully
determined. ZMAPP is
produced in genetically
engineered tobacco plants,
which makes the production
of new doses a slow process.
Phase 1 trials are being
planned and are expected to
start soon.
TEKMIRA
Tekmira has answered with a
cocktail of three siRNAs
(Small Interfering RNAs)
against Ebola packaged as
lipid nanoparticles. These
lipid nanoparticles
encapsulate the siRNAs and
deliver them through the
bloodstream to target cells,
where they are then
transported into the cell. Once
inside the cell, siRNA’s bind
with viral RNA and signal its
degradation.
Tekmira began Phase 1 trials
early this year, and the drug
has been used on patients on
an emergency basis. The drug
has been shown to be 100%
effective in monkeys infected
with a 1995 strain of the
Ebola Zaire virus.
BCX-4430
BioCryst has gone the route of
a broad spectrum antiretroviral. BCX-4430 is an
RNA polymerase inhibitor,
which binds to the active site
used by the viral polymerase
and becomes incorporated
into transcripts, thus
disrupting transcription via
chain termination. A Nature
paper released in March of
this year showed that BCX4430 injected intramuscularly
after infection with Ebola and
Marburg virus protected
rodents. Macaques infected
with Marburg virus were also
protected when BCX-4430
was administered up to 48
hours after infection. This
would make this therapy an
option for people accidentally
exposed to the virus. Aside
from filoviruses, BCX-4430
supposedly has demonstrated
broad-spectrum activity
against more than 20 RNA
viruses in nine different
families, including filoviruses,
togaviruses, bunyaviruses,
arenaviruses,
paramyxoviruses,
coronaviruses and
flaviviruses. Phase 1 trials are
expected to be underway
soon.
BRINCIDOFIVIR
Chimerix’s Brincidofivir is
similar, a broad-spectrum
antiviral which selectively
disrupts the viral DNA
polymerase complex. This
drug has shown effectivity
against dsDNA viruses like
cytomegalovirus, adenovirus,
BK virus, smallpox,
and herpes simplex virus and
it is in phase III trials against
cytomegalovirus and
adenovirus. The drug has also
been shown effective in vitro
against Ebola (even though
the virus is an RNA virus) and
has been administered to
some patients on an
emergency basis. The FDA
has approved Phase II trials
against Ebola to begin in
infected patients. One
significant benefit of
Brincidofovir is that it can be
taken orally as a tablet and is
shelf-stable at room
temperature, making this a
choice therapy for
introduction to the third world
if proven effective.
FAVIPIRAVIR
Toyama Chemical’s
Favipiravir was primarily
developed as a stockpiled
therapeutic drug against
influenza outbreaks. The drug,
with a broad spectrum of
activity against RNA viruses,
has been proposed for use in
treating Ebola. Its mechanism
of action is through selective
inhibition of viral RNAdependant RNA polymerase.
Unlike Brincidofovir, there is
no evidence to indicate that
Favipiravir has any effect on
eukaryotic polymerases. Mice
studies have shown 100%
recovery of mice infected
with Ebola if treated with
Favipiravir within six days of
infection. Favipiravir is in
Phase III trials in the U.S. for
influenza treatment, and
Toyama Chemicals states that
they have over 20,000 doses
of the drug stockpiled for use.
PLASMA TRANSFUSION
For a more traditional
treatment, blood plasma
transfusion from recovered
Ebola victims to infected
patients has been proposed as
a course of action. A paper
released in 1999 described the
administration of plasma from
convalescent Ebola victims to
eight infected Ebola patients.
Only one of the eight patients
died, showing that plasma
transfusion may be a possible
method of treatment.
Antibodies from the
convalescent victim would be
transferred to the patient,
which would then fight the
virus in the patient. The
effectiveness of this treatment
is largely unknown, but it may
serve as a stop-gap treatment
until other therapies can be
properly developed and
approved.
VACCINES
While some are developing
treatments for those already
infected, some are working on
vaccines to stop the disease
altogether.
NIAID/GSK is working on
two versions of the same
vaccination which uses a nonreplicating chimpanzee
adenovirus to deliver one or
two Ebola glycoproteins into
human cells. One is for the
Zaire strain of Ebola; the
other is for the Sudan strain as
well as the Zaire strain.
The adenovirus injection is
boosted with a modified
vaccinia virus for immediate
and lasting protection. Once
the virus enters the cell, the
sequence for glycoprotein
recombines into the host
DNA, and the cell begins
producing it.
Another potential option uses
Vesicular Stomatitis Virus as
a vector to deliver Ebola
glycoprotein genes to target
cells. A major difference
between this vaccination and
the NIAID/GSK vaccination
is that VSV-EBOV is
replication-competent. Studies
on macaques show that
vaccination may be effective
after a single treatment and
that the vaccine may be
administered orally or intranasally, greatly aiding in the
deployment of the vaccine to
target areas of low resources.
When the immune system
recognizes the Ebola
glycoprotein, it responds with
antibody production and Bcell proliferation, generating
immunity against the virus.
The use of a human
adenovirus was not utilized
due to natural immunity in
some of the population to the
adenovirus itself, rendering
the vaccination ineffective for
some recipients.
In a challenge study, all four
macaques given the
vaccination showed robust
protection against Ebola virus.
The vaccination is currently in
Phase 1 trials for safety which
are expected to complete in
December of 2014.
Similar to the NIAID/GSK
vaccine, Crucell
Biopharmaceuticals is
developing a recombinant
adenovirus to deliver
multiple-vector protection
against Ebola and Marburg
virus. Marburg virus is a
similar filovirus which causes
intermittent outbreaks of
hemorrhagic disease in
humans. Testing is currently
being conducted to determine
the most effective construct.
This vaccination is planned
for clinical trials in late
2015/early 2016.
While these treatments and
vaccines are still in their early
stages, it is encouraging that
there are several options in
development to combat this
devastating disease.
Chris Massey
Santa Maria, CA