Breaking Down Science, Step by Step

The Ebola outbreak may be raging on, but at least there is some good news on the horizon. The results from the trial of new Ebola vaccine based on the "Chimpanzee Adenovirus" have come out, and they look promising. Want to know what it all means ? Read on.

Wait.. what the hell is a Chimpanzee Adenovirus ?

Yeah, sorry, I did throw a lot of words at you in that introduction. Adenoviruses are a pretty common form of virus, and is one of the viruses able to cause the common cold. A lot of the time, they can be benign. Adenoviruses tend to specialise in infecting one species.


Which is why there is a specific family of adenoviruses that live in chimpanzees. We call them the Chimpanzee Adenoviruses.

The answer to that is pretty complicated, but delves into one of the most exciting fields of medicine. You see, this Ebola vaccine owes as much to the growing science of Gene Therapy as it does to conventional immunisations.

How does Gene therapy work, and how can that lead to vaccines ?

Let's start with a quick refresher on how viruses work. The whole goal of a virus is to get its genetic material into one of your cells. Once that material is inside your cell, it can trick your cell into reading that genetic material and using it to make more viruses. Adenoviruses insert their DNA, and Ebola uses its RNA to trick the host into making proteins that help the virus and hurt them. In short, viruses have become masters at inserting their genetic code into their hosts, and tricking those hosts into transcribing that code into proteins.


What if these viruses could instead trick the host into transcribing proteins that it needs ?


Genetic disorders such as Sickle Cell disease, Cystic Fibrosis, and Hemophilia are the result of the human bodies inability to produce a specific protein it needs to function. If we can engineer viruses to produce the right protein, in theory these diseases could be cured.

Adenoviruses are ideal for this. They can be engineered to be less virulent and have can carry a lot of DNA, which enables them to safely deliver genes to the malfunctioning cells of a patient.


So how can this technology be used to fight viruses ?

It can help overcome a major hurdle for developing vaccines against viral diseases.


Using a vaccine formulation of dead viruses is good at helping to recognising a virus whilst its floating free in the body. But that isn't where they are doing the most harm. They are causing most of the damage when they are inside a cell, turning it into a virus factory and killing it from the inside. Antibodies just don't cut it. We need to get the T-killer cells* involved.

An infected cell will generally end up presenting chunks of viral protein on its surface, which can be recognised by the immune system. The T-killer cells can recognise these proteins, and in response, they kill off the infected cells.


We want to train these T-killer cells to recognise viral proteins when they are on the surface of an infected cell. So we need to use living viruses.

This is why many viral vaccines are derived from weaker versions of the virus. Viruses that can invade cells, but that don't kill off the host. This is how we got rid of smallpox, by vaccinating people with the less virulent cowpox. It's how we deal with Flu, by taking seasonal flu strains and weakening them for vaccines.


But that wasn't going to work with Ebola. There are no "Weaker" strains of Ebola, and the risks of making one are too high to even attempt. This is where adenoviruses come in.

If they can express human proteins, they can be used to express proteins of other viruses, such as Ebola. When this adenovirus infects a cell, it'll produce Ebola proteins, which will be recognised by the T-killer cells. The T-Killer cells will multiply in response, adapting to become more adept at recognising Ebola.


Why did they use a Chimpanzee Adenovirus ?


The big problem with using human adenoviruses is that a lot of us have already been infected by them. Our immune system knows how to dispatch them very quickly. A human adenovirus wouldn't last very long, and certainly not long enough to get the immune system to recognise a whole new protein.

Which is why the researchers had to use an adenovirus that human immune systems are unlikely to have seen before. Which is why they looked to our closest evolutionary relations, the great apes. Under the right circumstances, their adenoviruses can infect our cells.


Since they are adapted to chimpanzees, immunity to them isn't widespread amongst humans. You are unlikely to have ever contracted a Chimpanzee adenovirus. So when your immune system first encounters it, it will be forced to take its time. Time enough for the virus to express enough of the Ebola protein to elicit an immune response. A response that can prepare the immune system to recognise Ebola inside cells.

That is the basic theory behind the Chimpanzee Adenovirus based Ebola Vaccine.

Wait, they've cobbled together two potentially dangerous viruses. Is that safe?

Nine men and Eleven women were recruited in September to find this out. The watchword for this study was safety. They started each person on a low dose. If it looked safe, they would then test another group with a higher dose of vaccine.


The only side effects were two cases of fever from the group given the higher dose of vaccine, but they were treatable, and weren't serious.

Some of the participants looked like they had problems clotting their blood, but the researchers figured out that the study participants were producing an antibody which messed with some of their tests**. Some of the patients had a slight drop in white blood cells in the bloodstream. Which is what you'd hope for, as they should have dropped out of the bloodstream to react to cells infected with the Adenovirus vaccine.


So does this Ebola vaccine work ?

We don't know for sure. This was just a safety trial. It wasn't blinded, there was no placebo group, the participants weren't given live Ebola virus. This study was designed to show the vaccine isn't in itself dangerous.


That isn't to say we haven't got any hints about whether the vaccine could work.

The researchers took blood tests, to see whether the participants were producing antibody against Ebola. Luckily, none of the participants had any prior immunity to the chimp adenovirus, which could have been a major confounding factor.


Turns out, ninety percent of the people in the low dose group, and all the people in the high dose group produced antibodies. But the high dose group produced the most antibody by far.

What's more important is whether the T-killer cells will react to Ebola. So the researchers took blood samples, and extracted any T-cells within them. They could judge how well these T-cells could recognise Ebola by seeing how much they freaked out when exposed to an Ebola protein. When T-cells freak out, they produce chemicals called "cytokines". These cytokines could be measured to work out which T-cells were producing the biggest reaction.


The good news is that all of the T-cells had a reaction to Ebola after immunisation, and the biggest reactions were from those who had received the highest vaccine dose.

So it does look very promising, but remember to manage your expectations, this is just the first safety trial. All this paper set out to be was the start of a much larger conversation in the scientific literature played out through the language of experimental trials and evidence. We'll have to see how that conversation plays out before we can pop the champagne corks and celebrate.


In the mean time, I'll say what I always say. The Ebola outbreak in West Africa will be (and in some place already have been) brought under control by standard infection control. Hygiene, Contact tracing and Containment.

Validity Report- 4/5

In terms of presenting their results, this is pretty much on the spot. They achieved exactly what they set out to do. But this was a safety study, and it is really important to realise that it isn't designed to test whether this vaccine works or not. It's a preliminary study, which is why I can't give full marks, because there is still much work to be done before the results can be taken as read.

The group sizes are small to limit the pool of potential victims should everything go belly up. Both the researchers and the participants knew exactly who was getting what drug, because it would be criminally reckless if they didn't. These are all good things from a practical perspective, but get in the way if you want to make larger assertions about how well the vaccine works. This study needs to be replicated by another lab, using a different population, hopefully one that is more representative of the people who will need this vaccine.


*also known as Cytotoxic T-lymphocytes, and T-helper lymphocytes, which I've lumped together into one group for the purposes of this article. They are both concerned with killing off host cells infected with virus, and how they do it, whilst complex and interesting, probably isn't necessary for understanding the basics.

** I would have liked them to try out a different coagulation test, just to confirm that these individuals could still clot their blood. As it stands, all we can say is that we don't know how well these people could clot their blood because the test broke. But research is messy, and unexpected events like this can crop up and there is no planning for them. Hopefully the next people to test this vaccine will be better prepared.



Chimpanzee Adenovirus Vector Ebola Vaccine — Preliminary Report

Image Credit

September 4, 2014 — A 26-year-old man, the third participant enrolled in VRC 207(The trial described in this study), receives a dose of the investigational NIAID/GSK Ebola vaccine at the NIH Clinical Center in Bethesda, Md. Credit: NIAID


Gene therapy using an Adenovirus vector

A chimpanzee at the Sweetwaters Chimpanzee Sanctuary by Valentina Storti

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