Learn about the evolving Ebola epidemic and its various aspects including disease prevention, management and treatment, response to the epidemic, ethical considerations, and the post-Ebola global health landscape.
Ebola Vaccines
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En provenance du cours de Emory University
Ebola Virus Disease: An Evolving Epidemic
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Prevention, Treatment, and Response
Upon completion of this module, learners will be able to: List the different types of therapeutics for Ebola Virus Disease. Recognize the factors critical to the creation of a successful Ebola vaccine. Define plasma and recognize its importance in the Ebola treatment process. Discuss the response of various international actors to the Ebola epidemic. Recognize the role of communications both in terms of community level in West Africa, as well as at Emory University.
Rencontrer les enseignants
Dabney P. Evans, PhD, MPHAssistant Professor
Hubert Department of Global Health. Rollins School of Public Health. Director, Center for Humanitarian Emergencies.
Carlos del Rio, MDChair
Department of Global Health at the Rollins School of Public Health
Welcome everyone, I am Nadine Rouphael an investigator at the Hope Clinic, of
the Emory Vaccine Center, and an Assistant Professor of medicine at Emory University.
My talk today is on Ebola vaccines.
As you probably know by now Ebola virus is associated with high mortality.
And easy transmissibility among close contacts, with no effective treatment or
prevention available.
This is why the development of an Ebola vaccine
is one important strategy to control outbreaks.
Particularly, the largest one to date, that was Africa is experiencing.
With the concerted international efforts coming from industry, academia,
health authorities, and governments, the quest of finding a safe and
effective vaccine seems to be on a fast track path.
In general, vaccines are licensed in humans after rigorous clinical trials.
In the case of Ebola,
it could be difficult to perform these conventional controlled efficacy trial,
because outbreaks in general, are unpredictable and sporadic.
And even during a particular outbreak, it will be unethical to offer
placebo to subject potentially exposed to such a fatal disease.
In 2002, shortly after 9/11,
the FDA promulgated the so-called Animal Rule as the alternative pathway
to license products against highly lethal pathogens, such as Ebola.
For the Ebola vaccine to be licensed under this rule, it should have shown.
Efficacy in animal, with the establishment of an immune correlates of protection,
meaning the identification of a specific immune response to the vaccine
that is closely associated with protection against the pathogen.
Also, the vaccine should have been shown to be safe and
immunogenic in humans, when induction of this predefined immune correlate.
So far no vaccine have been approved under the animal rule.
So what is the best model to study Ebola vaccines?
Many animal models have been used, however,
the gold standard model here is the non-human primate model.
This model closely mimics the clinical symptom of human disease.
Typically, four to five weeks after vaccination
the animals are challenged by receiving a lethal dose of Ebola virus.
The vaccine efficacy studies will assess
the survival rate in vaccinated versus non-vaccinated animals.
A successful Ebola vaccine should contain a product, or the antigen,
that is able to illicit antibody responses for humoral immunity,
as well as a CD4 and CD8 responses, or cellular immunity.
One particular antigen stands out called the glycoprotein, or GP.
The GP allows for several important vital function, and the antibody against GP
could lead to the control of infection, and serve as a correlate of protection.
In the non-human primate model,
a GP antibody level of 1 over 3 southern 700 and above,
allows the animal to always survive any future lethal challenges of Ebola.
However, the non-human primate model has many caveat.
We do not currently know what level of immune response in animals is required for
vaccine approval.
The challenge doses given to the animals are magnitude higher
than those seen in regular human transmission.
Also not all Ebola exposures in humans are fatal,
as compared to the non-human primate challenges.
A vaccine should be safe, immunogenic, and
capable of stimulating the immune response, as well as practical to use.
So, what are the characteristic of a successful Ebola vaccine?
The vaccine could be used in pre as well as post-exposure prophylactic setting.
For pre-exposure prophylaxis, meaning prior to a subject being exposed,
an ideal Ebola vaccine should consist of a single dose regimen for
the prevention of the general population.
That's one shot for mass vaccination.
However, more than one dose might be needed for long-term protection,
particularly in subject at high risk of contracting Ebola,
such as healthcare workers.
For post-exposure prophylaxis,
this is once a subject has been in contact with the virus, in that case
an ideal Ebola vaccine should provide very rapid protection to prevent disease.
Moving to cross protection.
Ebola is the RNA or ribonucleic acid virus with continued evolution and
ability to escape the human immune system.
A universal Ebola vaccine should be protective against
different strains of Ebola.
The most clinically relevant strains are Sudan, Zaire, and Bundibugyo.
Then there is the issue of prior immunity to the vaccine vector.
Current Ebola vaccine candidates are all vector-based.
A vector is a transporter of genetic pieces of Ebola, and
the use of a vector typically induces a better immune response.
But the immune responses blunted if the body has already been
exposed to the vector in the past.
So its important to choose vectors with low antibody set of prevalence and
the target population receiving the vaccine.
Finally, an important consideration for
successful vaccination especially in Africa is related to logistics.
The ideal vaccine will be one without continuous need for
cold chain from production to administration and is easy to produce.
However, the two current vaccine candidates require
minus 60 to minus 80 Celsius storage and distribution conditions.
And also require sun-based production
which could limit large-scale manufacturing.
To date different vaccines strategies have been used.
These strategies include attenuated and inactivated viral preparation,
which did not protect in non-human primate, and
with the risk of incomplete activation there was a safety concern.
Also, we have genetic and subunit vaccine candidates DNA or
protein, which resulted in incomplete protection in non-human primate.
However, viral vector-based vaccine candidates expressing Ebola genes
did show protection in non-human primate.
Many of these viral vector-based vaccine have been tested.
Some did not move forward as vaccine candidates since they require
multiple doses to induce production are labor-intensive to produce and
have some safety problems, as well as relevant issue due to prior immunity.
However, the leading two candidates vaccines are vector vaccines, in which
the Ebola virus GP is presented either in live recombinant vesicular stomatitis
virus vaccine or replication-incompetent adenoviral vector vaccine.
The first vaccine candidate is a product that contains a variant
of vesicular stomatitis virus or VSV,
a virus that causes a disease in cattle, horses, deer, and pigs.
Humans are rarely exposed to the virus, and very rarely develop infection.
Therefore, the issue of prior immunity to the vector is not a concern,
though more epidemiologic studies are needed to confirm this fact.
VSV is a replication competent vector capable of multiplying within the body.
Hence, some potential safety concerns.
In mismallous, for example, pathology of the nervous system has been identified.
However, in the non-human primate model, no neuro-variance was seen and
limited information in humans exist.
One HIV vaccine study performed in-part at the Emory Hope clinic
showed the first safety human data, which was reassuring.
At the highest dose currently used in Ebola vaccine, almost all subjects had
side-effects, including flu-like syndromes, fever, and moderate chills.
However, no encephalitis was reported.
So the VSV vaccine, when tested as a vector for other vaccines, was safe and
tolerated.
The immunization data, or the immuno response to the vaccine is also promising,
and is mostly mediated by antibodies.
Pre-exposure prophylaxis with one dose in non-human primate provide
the protection against the same virus, however, multiple doses were needed to
ensure cross protection meaning protection against the different Ebola strains.
Long-term protection was studied for Ebola and other models and
in non-human primate for it's likely the different virus called Marburgvirus,
another virus from the Filovirus family, closely related to Ebola.
This experiment showed long-term protection up to 12 to 14 months.
Both exposure prophylaxis,
this is the only vaccine where both exposure prophylaxis data is available.
Immunization should be given in that case shortly after exposure.
However, a bigger interval of 24 to 48 hours after exposure to Marburg,
VSV vaccine was tested.
There is one published data in human on a lab exposure in Germany.
And currently the vaccine is being used under emergent IND for
subject to ebol, exposed to Ebola at our institution.
The second vaccine candidate uses adenovirus vectors.
These vaccines encode for the GP from Zaire and Sudan Ebola species.
Safety data exists on the earlier phase I Ebola vaccine,
as well as other vaccines using adenovirus vectors.
These vaccine induce both antibody response and
boost the immune cellular response.
However, the main issue with these vaccine is the pre-existing immunity,
leading to a decreased immune response.
To overcome this issue, additional doses can be given.
Administration route can be changed, and use of other adenovirus vectors
that human with less likely to have been exposed to such as adenovirus 56,
adenovirus 35, and chimpanzee adenovirus 3 can be used.
Chimpanzee adenovirus 3 vector vaccine
is the leading adenovirus vector vaccine candidate.
A recent study in non-human primate showed good data for short-term protection with
a single vaccine dose protecting against both homologous and heterologous species.
Meaning against the same strains containing the vaccine and
also strains not containing the vaccine.
Long-term protection data was on the other side disappointing with
only 0 to 50% protection at 10 months.
But this improved after a Modified Vaccinia Ankara or MVA boost was given.
As with all adenovirus vectors, no data exists on post-exposure prophylaxis.
Recently published in the New England Journal of Medicine,
data on the first 20 subject receive,
receiving chimp adenovirus 3 vector bivalent vaccine at two doses.
2 times 10 to the 10, and 2 times 10 to the 11.
Both doses were tolerated, with more side effects seen with the high dose.
Fever typically develops 8 to 24 hours after vaccination,
responds to medication well, and resolve within one day.
This implies that if the fever is not resolved within a day, a workup is needed.
A drop in the white count was also noted in the trial, and
vector induced antiphospholipid antibodies were detected in 15% of cases,
and cause a transient elevation of PTT.
All subject had antibodies detected to at least one specie, and
the vita-specific CDAT response was those dependants.
To summarize, from non-human primate and some limited human data,
these vaccines provided pre-exposure protection and
post-exposure protection that was only achieved with the VSV vector vaccine.
Long-term immunity is better seen with this vector as well.
However, cross protection is better achieved with the adenoviral vector.
The adenovirus vector elicit both humoral and cellular responses.
While the VSV vector, it uses mostly a humoral response.
Many trials are currently underway in the US, UK, Germany,
Switzerland, and many African countries,
with the hope to control the Ebola outbreak, a major public health endeavor.
Thank you.
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