Dr. Amy Hermon-Taylor: The MAP Vaccine

 

 

Video Transcript

So this is something I’m very excited about as well. Will, I’m with you, I’m biased as well. I ran a marathon to raise money for this research. I’m a very unfit person. I was always the last person to be picked at sports in school. I broke my foot after 8 miles in and I still finished. I still ran all the way, and that is how much I believe that this vaccine could be something that changes the world of 4 million people with Crohn’s disease.

So, I’m going talk a little bit about vaccines in general; how they work. Then I’m going to tell you about our vaccine, which is something called a virally vectored vaccine. And I’ll explain what that is and how it works, and then I’ll show you a little bit of the results of the trial of the vaccine in cattle.

So, when I’m talking to patients and their families on social media, one of the most common comments I get is, but vaccines are used to prevent disease, aren’t they? I’ve already got Crohn’s disease so how’s that going to help me? And I tell them, old fashioned vaccines prevent disease, but our vaccine is a modern vaccine. And modern vaccines can be therapeutic. They can treat established infections as well as preventing the onset of disease.

And how do they do that? By stimulating the immune system to recognize and eradicate, in this instance, MAP. So it’s the same sort of thing that Will was talking about; altering the immune system so that the body is more able to deal with the infection.

So, this is our vaccine. It’s called a virally vectored vaccine. That sounds rather complicated. So what exactly is that? And I thought of an analogy to help you understand it. A virally vectored vaccine is a bit like an engagement ring. So an engagement ring has a plain band and that is what does the job. And the job is keeping the ring on the finger. And then within that, you have set gemstones which make the ring unique.

So translating that analogy into our virally vectored vaccine, the vector is like the band on the ring. What it is, is a tiny circle of DNA from a harmless common cold virus. And the instruction on that piece of DNA is, carry me inside your cell. And that is the job of the vector. It carries the MAP DNA inside the cell. So we take that vector, and inside it we put little pieces of MAP DNA. Now, our vaccine has four pieces of MAP DNA. And they’re not any old pieces. They are selected because they are involved in the pathogenicity of the disease. So they’re DNA which is vitally important to MAP and the way is causes disease. And the reason that’s important, is because if you want to kill MAP, you need to strike at the things that it really needs. So if you had a serial killer coming after you, you need to shoot to kill. There’s no point in lopping off a toenail or an earlobe. You need to go for the heart, the brain, the jugular, and that’s what each of these sites represents. Something vitally important to MAP.

So what do we do with this vaccine? We inject it. Two doses spaced six to eight weeks apart. And it enters the bloodstream as you can see up here. Don’t look at me, look up here because this is my; this is the culmination of my lesson in Power Point animation from my fourteen year old step-daughter. So here we have the vaccine, and here we have the immune system; the immune cells. And the vaccine is taken up inside the cell. And once it enters the cell, the cell’s machinery is designed to take those little pieces of DNA and automatically translate them into the corresponding protein. And what is does with those proteins is to put them on the surface of the cell.

So those act as little flags, little signals to other cells of the immune system, specifically T-cells, which come along and recognize those proteins. So there are lots and lots of different T-cells with different matches. When you find a match between your T-cell and your protein, it binds. And what happens then is it makes lots of other T-cells just like itself which seek out and destroy MAP. They also produce substances that are going to switch the immune response from a pathway which makes the disease worse to a pathway which will help to turn around and reverse the infection.

So I need to say a little bit about the immune system here. Will already touched on it. The immune system has; is a bit like a society. So it has; in society we have different people who are specialized to do different jobs. And the immune system is no different. So if you give the wrong job to the wrong person, you may have a disastrous response. So if you say for example, two problems, a patient with a skin rash and a broken toilet. And you had two people to fix them, a doctor and a plumber. Let’s say I’m the doctor. If you send the patient with the skin rash to me, they’ll probably do very well because I’m good at dermatology. If you ask me to fix your toilet, you will have disaster on your hands, I promise you.

Similarly, if you ask a plumber to deal with a patient with a skin rash, they’re not going to have a clue. So the patient will go away and get a lot, lot worse. But if you ask a plumber to fix your toilet, then you’re laughing. So this is; you don’t really need to know what these things are. You just need to know that there are good pathways in the immune system for dealing with MAP infection and there are bad pathways. And what our vaccine does is to push the immune response into the helpful pathway and away from the bad pathway.

If you have a medical or scientific background, you may be interested in the cell markers I put up there. So the vaccine switches the body into a Th17 and Th1 response, which is programmed to get rid of MAP. And it does that by; one of the ways it does that is by producing the cytokine interferon gamma. If those that we’ll look at in a minute in the trial who didn’t have the vaccine, the immune pathways went the other way. So you saw a lot of these pro-inflammatory cytokines with IL10 and IL-1Beta.

And you also saw something very interesting called FoxP3 T-cells. Now those are a type of T regulator cell, you could call them the immune system’s own immunosuppressant. So they are a cell which specifically switches off parts of the immune system, and in so doing they blind the immune system to MAP infection. When we looked at the study in those animals that received the sham vaccine rather than the live vaccine, they had huge levels of inductions of FoxP3 cells.

I want to talk you briefly through what we saw in the vaccine trial. There were actually two trials. There was an initial trial in mice and then more recently we did a biggest study in cattle. So there were two groups in the study. There was a control group who received the sham vaccine. And that was the vector only without the MAP DNA in it, and then there was the live vaccine. And if we go through what we saw in the results: In those who received the live vaccine, all the immune mediators were pointing the immune system down the good pathway as opposed to those who received the sham vaccine who were sent down the bad pathway with the production of more pro-inflammatory cytokines.

Secondly, we looked at the macrophages and how good they are at killing MAP within them. And in those cattle that were given the live vaccine, they had very high MAP killing capacities. Whereas in the control group the MAP killing capacities were very low. Secondly, thirdly rather, we looked at fecal shedding of MAP. There was MAP present in the feces of the cows. The live vaccine completely abolished fecal shedding whereas in the control group there were many positive results even in the course of the study, which was only 38 weeks long.

Then they looked at several, whether MAP was present in the tissues in the animals, both in blood and in gut tissues and in spleens. And what you saw later in the course of the study, so between 20 to 38 weeks, was in the controls where you haven’t had the vaccine, there were huge levels of MAP progressively worsening, whereas in the vaccine group there were either, their levels were very low or negative. And similarly in the tissues; very high in the controls, very low or negative in the vaccinated group. In none of the animals were there any observed side effects from the live vaccine.

So to finish off, I wanted to just have a look at how we’re doing with Crohn’s, and whether we’re solving the problem of Crohn’s disease. So I put up this slide which shows the incidence of Crohn’s disease across the century, from the 1930’s up to 2007 was the last data that we got. And although you probably can’t see the slide very well, you can see where it’s going. And what that tells us is that we’re not winning with Crohn’s disease at the moment, and therefore we need to do something differently.

Crohn’s disease is a global problem. MAP infection is a global problem. And what we are suggesting between our group is a global solution for that problem. Thank you. Any questions?

Audience: I have a question.

Dr. Hermon-Taylor: Go ahead.

Audience: What kind of viral vector are you using to make the vaccine?

Dr. Hermon-Taylor: What kind of vector?

Audience: Yes.

Dr. Hermon-Taylor: So it’s a prime boost; the priming vector is a new vector which has been made by the Jenner Institute in Oxford who is a leading institute in vaccinology. So the same group that’s building our vaccine as we speak is the group that has made the ebola vaccine. It’s called CHadox2, that’s the priming vector, and then the boosting shot, so the second shot of the vaccine is a MDA vector.

Audience: …you’re not using any adenoviral vector?

Dr. Hermon-Taylor: No. And in the study done in cattle, they did use an adenovirus 5 vector, but that was since, it was not allowed for vaccines. They changed the rules. So we had to find a new vector for the priming shot.

Audience: And the sequence, you say, the DNA you put in the vector, those four genes. Do you have any frame?…

Dr. Hermon-Taylor: Yes, in a single protein.

Audience: What’s the timeline for this?

Dr. Hermon-Taylor: So the study was done over 38 weeks that they followed the cows up, for  38 weeks and then they were euthanized so that they could look at the tissues…Oh, that timeline. OK, thank you for the clarification. So manufacture is happening now, and that takes a year. After the manufacture is completed, then they’ll be a Phase I trial which will be done at the Jenner Institute where the manufacture is taking place. And then we’ll go on to do a Phase II trial in 20 patients with Crohn’s disease based at St. Thomas’ Hospital in London and that’s estimated to start in the first quarter of 2017. The trial will also run for one year, but it’s intended that we’ll analyze the results in real time and that once we start to see evidence of safety and efficacy, we’ll make it available on a named patient or compassionate use basis.

Audience: …MAP in Crohn’s infections 100%…

Dr. Hermon-Taylor: In the numbers that we’ve tested so far, which is about 70, the test has found MAP in 100% of Crohn’s disease. But I don’t really; the important thing about the test is that it’s 100% specific and 100% sensitive. We haven’t got that data yet, but the way the test is designed and what we’ve seen so far, we believe that it will be very sensitive and very specific. Sir.

Audience: In the vaccine trial…at 38 weeks was there any clinical response?

Dr. Hermon-Taylor: No, there was no clinical disease.

Audience: There was no clinical disease or clinical response?

Dr. Hermon-Taylor: Oh, so in MAP infection in animals, although you get huge amounts of MAP in the tissues and in the bloodstream, that doesn’t necessarily translate into clinical disease until much later in the course of the infection. So it could be years before they show any signs of clinical disease. And in the 38 weeks, no animal showed clinical signs although they were heavily infected with MAP.

Audience: Can you also vaccinate cattle to reduce it at the front end?

Dr. Hermon-Taylor: That would certainly be a very good idea, and we’ve proven it in cattle. The important thing in cattle is that is abolishes fecal shedding entirely. So if you vaccinated the cattle, you would hugely reduce the amount of MAP that humans are exposed to in the environment. The problem is, that the economics don’t work out as well for the veterinary sector as they do for the human market. So the vaccine is estimated to be going to cost around 2000 pounds per shot, so 4000 pounds for the entire course. And if you compared that to the cost of the current drugs, that’s a huge reduction in cost even before you consider the economic burden of the disease. If you look at the U.K., I don’t know the U.S. figures, we have 250,000 patients with Crohn’s in the U.K. And on those 250,000, we spend 1 billion dollars a year, every year, on treatments that manage, but do not cure the disease. So there’s a huge economic burden. So if you could cure the disease with one of these treatments or another treatment we develop in the future, then as well as making a lot of people better, you’ll also offer huge cost savings to health systems across the world.

So your question was about could it be used in animals. The veterinary market is different in that you wouldn’t support a price tag of 4000 pounds for the cost because the animal’s life is not worth the same as a human’s life. But potentially, over time, these things are always more expensive when they’re made because of the huge cost to make it, but they’re very likely to come down over time. And if it is indeed proven to be a human pathogen, then the equation may well change somewhat.

Audience: …How can you achieve a MAP viral titer with no adenoviral vector, and make sure that vaccine is working? Because one of the problems  of vaccines is that you have to have the viral priming. Otherwise, you lose the ability to target specific cells. How do you do it with no adenoviral vector?

Dr. Hermon-Taylor: In all honesty, I don’t know the answer to that question, but the guys at the Jenner Institute are kind of the top experts in the world on that sort of thing. So I think they’re on the case.

Audience: OK.

Audience: I may have gotten it wrong, but isn’t one of the hypotheses that MAP actually triggers an autoimmune disease that is by its presence. And isn’t there some risk that if you introduce MAP in this way that it could make it worse?

Dr. Hermon-Taylor: It’s not the whole of MAP that you’re introducing with the vaccine. So, it’s just tiny pieces of DNA that you’ve taken out. It’s not the whole organism. It doesn’t

Audience 1: It stimulates an immune response, right?

Audience 2: Yes, but…it does it in a …system, so it doesn’t really affect the immune system. They’re building pieces, small pieces,

Audience 1: But it’s designed to stimulate an immune response.

Audience 2: But it’s not the same thing…

Dr. Hermon-Taylor: I’m going to have to hand it over to my colleague. He’s waiting. Thank you. Come and find me afterwards.

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