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Vaccines for the World's Poorest

Michael GoodMichael Good

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Tim Thwaites:

Welcome to another La Trobe University podcast, this time on the challenges of developing vaccines for the world's poorest. My name is Tim Thwaites and I'm from the faculty of science, technology and engineering at La Trobe University. With me today is the director of the Queensland Institute of Medical Research and chair of the National Health and Medical Research Council, Professor Michael Good.

Professor Good is about to deliver the Nancy Millis Public Lecture on a topic of "The Challenges of Developing Vaccines For The World's Poorest -- Do Hidden Molecules Hold The Key?" And that suggests to me that there may be some new ways around those challenges. But let's start at the beginning.

Professor Good, what sorts of vaccines are the world's poorest people in most need of? I mean, can't they just use the vaccines we already have?

Michael Good:

Thanks very much, Tim. There are a number of vaccines already available, as you know. But interestingly, many of the vaccines that had been developed had not been taken up in the world's poorest countries. About 10 million children die every year due to infectious agents. And a third of those deaths are due to diseases which could be prevented had the child been vaccinated.

Tim Thwaites:

What sort of diseases are we talking about?

Michael Good:

Well, if you take for example, hepatitis. There's a vaccine to hepatitis. It's not really available in the developing world because of the price and so on. There are a number of other vaccines as well. I think the really important challenge, though, is to develop vaccines for some of the infections agents, which have been very difficult and which claim virtually millions of lives. We're talking about diseases such as HIV, malaria, tuberculosis, rheumatic heart disease, two of those diseases are diseases that my laboratory works on.

Tim Thwaites:

And is the economic barrier the most important or are there some real physical barriers as well?

Michael Good:

There are certainly economic barriers. So, any vaccine that is developed will have to be able to be produced at a price which is affordable; that's a given. But there are scientific hurdles that we have to conquer for some of these vaccines. Diseases like malaria, diseases like streptococcus which causes rheumatic heart disease, and HIV.

The biggest barrier in terms of science, I believe, is that these organisms have learned how to evade immunity. And they can evade immunity very, very quickly. So, a vaccine which is developed against one strain might be very effective against a particular strain but will not have the coverage to cover the multiple strains, sometimes hundreds if not thousands of different strains out there in the population.

Tim Thwaites:

So, are there ways around this?

Michael Good:

I believe there are ways around it. But I believe the underlying principle is that a vaccine for organisms which have learned to evade immunity by changing their code, so to speak, there's no point targeting molecules which are presenting themselves to the immune system by the organism. The organism throws up these molecules as a decoy. The immune response focuses on those molecules which might be suitable to eliminate one particular strain. But no sooner than that strain eliminated, then another strain pops up.

So, we have to look at what I call non-natural immunity, mechanisms of immunity which don't normally follow exposure to an infectious agent but which if we could induce them, they might be, the word is "might be" very effective.

So, these are often what I refer to as cryptic or hidden epitopes. They're origins of the proteins sometimes on the surface but buried deep in the capsular membrane, sometimes internal molecules of the parasite or the bacteria or whatever which are not readily available to the immune system. If you would use them as a vaccine, they might nevertheless induce immunity which could knock out all strains.

Tim Thwaites:

So, these are the hidden molecules in your title?

Michael Good:

Correct. They are the hidden molecules in the title. And because they're hidden and they're not under normal immune pressure, what we find is that they're hardly conserved; in other words, different strains. Multiple strains have exactly the same sequence in these proteins or these molecules. So, a vaccine if it's effective against one strain will be effective against multiple strains.

Tim Thwaites:

So, how do we expose them? How do we flush them out?

Michael Good:

That's an important question. I think you have to start by thinking about them. You have to realize that that is the approach to follow. Once you can do that, it's often a case of simply sifting through a large number of potential molecules or a large number of potential epitopes in a screening procedure and seeing what comes up.

Tim Thwaites:

What's an epitope again?

Michael Good:

An epitope is a region of a molecule or a protein which is recognized by the immune system, whether it be an antibody or the cellular components of the immune system such as T-cells. They recognize sequences of amino acids, often only a small number, and that's called an epitope.

Tim Thwaites:

So, it's like a marker on the side of the protein to which the vaccine or the immune system responds?

Michael Good:

Exactly. It's the marker which targets immunity.

Tim Thwaites:

What's the next process? How are we going to do this and how are we going to do it economically?

Michael Good:

Well, in the case of, if I can give an example, streptococcus. This organism is a bacteria. It's called group A streptococcus or Streptococcus pyogenes. It can cause tonsillitis and commonly does so. It causes sores in young children. This particular organism, the body develops an immune response to that. This is very tricky because that immune response can in itself be responsible for some of the diseases which follow that particular infection such as rheumatic fever. Rheumatic fever is an autoimmune disease where aberrant antibody responses or aberrant T-cell responses which have developed in response to the infection, attack the heart, attack the brain, attack the skin, attack the joints to cause this symptom complex called "rheumatic fever".

So, in the case of streptococcus we have to do two things. We have to, one, identify the dangerous type of immune response and avoid that. And then, we have to identify a safe type of immune response and then we then have to make sure that that safe type of immune response can recognize all the different strain of the organism. So, the approach we've taken in the laboratory is to look at epitopes or these origins of the protein recognized by antibody in this case which are buried well deep within the surface membrane of the organism. So, they're not normally exposed to the immune system. And because of their location, we found they're hardly conserved.

So, the approach that we undertook was to simply screen a large number of potential or possible epitopes made synthetically in the laboratory to ask, could we use those to induce some antibody response which would attack the organism? And the answer to that question was, we were able to find one. Then, of course, the important thing was to demonstrate that the immune response that we induced did not cause or could not cause the potentially deleterious side effects which were responsible for the disease.

Having done that, we're now in a position to test these in a clinical trial. That's what we're gearing up to do, to test these in what's called a "phase 1 clinical trial", which is really a trial for the safety. But also, we have to be able to demonstrate some efficacy. In other words, can we induce antibodies in this trial which will target multiple strains of the organism?

Tim Thwaites:

So, how long is all this going to take?

Michael Good:

Well, we've been working on this program for a long while now, the best part of 18 years. So, we think it's probably another few years off. Right now we're in the final stages, leading up to a clinical trial. We've made a vaccine called GMP, which is called "good manufacturing practice" standards, which is highly purified. It has been through tough technology testing for safety and it's about to go into the arm of volunteers.

So, that trial itself once it starts will be over in few months. It's a fairly quick trial and soon can be followed by, obviously, a significant investigation to look at the immune response. And then, hopefully a phase 2 trial involving a much larger number of people. The whole process could from here take another four to five years.

Tim Thwaites:

It seems an awful lot of work for streptococcus. What's the payoff?

Michael Good:

The reason we're working on streptococcus is that it's a very important pathogen worldwide. So, the title of this talk is "Developing Vaccines for the World's Poorest". Probably no disease segregates with poverty more than group A streptococcus. And worldwide it's responsible for about half a million deaths per year.

Within Australia, Aboriginal parts of the population suffered the highest rates of this series of diseases worldwide. Indigenous Australians have rates of rheumatic fever and rheumatic heart disease hundreds of times higher than what's found in the non-indigenous population.

Tim Thwaites:

And do you think that this strategy that you've outlined can be replicated in other cases?

Michael Good:

That will be our hope. We are doing this as a related approach to malaria. Malaria is an organism also. It's a different type of organism. It's a parasite, as many would know. It resides in red blood cells within the body or in liver cells within the body for a short period of time. Again, it induces an antibody response and those antibodies recognized serve as proteins on the parasite. The malaria parasite changes its co-proteins very, very rapidly.

Our approach has been to define a different type of immune response which is targeting the conserved reagents of the parasite. We've been able to demonstrate that T-cells or cellular components of the immune system can recognize conserved agents of parasite proteins. And we're following a similar approach as we are in group A strep, using that approach.

Tim Thwaites:

If the immune system is not normally exposed to these regions, how do you expose them to the immune system to allow this to happen? In other words, if you build up antibodies, how do they find the compounds that they're targeting?

Michael Good:

That's a very good question. So, when the parasite or the bacteria is exposing itself to the immune system, it's a competitive process. So, the most readily available proteins or the most exposed ones win the race. It's a race in terms of inducing an immune response between the readily exposed and the less readily exposed.

Tim Thwaites:

So, the immune system goes for the most obvious targets?

Michael Good:

Goes for the most obvious targets. But if you, however, turn the tables, if you then take that particular protein out of the organism and present it in a different way, then the immune system recognizes something it didn't previously even know existed. And those immune responses are able to recognize the organism.

Tim Thwaites:

Well, thank you very much for explaining all these to us. Thank you for your time and good luck with the lecture.

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