Podcast transcript
Vaccines to control liverfluke
Professor Terry Spithill
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Transcript
- Matt Smith
Hello, and welcome to a La Trobe University podcast. I'm your host Matt Smith and joining me today is Professor Terry Spithill, Co-Director of AgriBio, the Centre for AgriBioscience. Our topic of discussion is parasites, in particular the liver fluke and the vaccines he has been developing to control parasitic diseases in livestock.
- Terry Spithill
Parasites are organisms that live on another organism, other host, and derive sustenance from that host, so it could be a worm parasite infecting sheep or cattle, it could be malaria infecting humans for example. There’s different types of parasitic disease, what we call protozoan parasites, which are single cell organisms like malaria or babesia which is a parasite of cattle, or they could be more complex organisms like worms, which are large animals that live in different tissues of sheep and cattle in particular. Parasitic diseases can affect a wide range of hosts from wildlife, wallabies, kangaroos, dingoes, to sheep and cattle, deer, goats, sea animals. Parasites have been incredibly successful and as a result of that, they cause significant amount of disease, significant impact on animal health and significant production losses for producers producing milk, meat producers, wool producers, what have you, not only in developed countries such as Australia, Europe and the US, but also insidiously in developing countries like Indonesia, throughout Africa, Asia, China, Cambodia, where subsistence farmers in Indonesia for example, a typical subsistence farmer would have three to four cattle, animals that he uses to work his field. The females provide the milk for his family. In Africa, for example in Sudan, cattle are considered the primary source of wealth. In Sudan, farmers with large cattle herds are considered extremely wealthy and occupy a very prestigious place in the society.
I shouldn’t underestimate the costs these parasitic diseases have in both countries like Australia and in developing countries. The particular parasite I work, which is a worm parasite called liver fluke, is probably one of the most, if not the most successful parasite in terms of the large number of animals it can infect. It also infects humans and it’s a problem on every continent in the world.
- Matt Smith
How is liver fluke caught? How does it get transmitted?
- Terry Spithill
Typically the life cycle would be, an infected animal sheds eggs in the faeces, eggs come out in the faeces, they hatch in the environment and a little infective form invades aquatic snail, a single parasite infecting a snail can produce six hundred to seven hundred thousand infective parasites that are released. They release into the water and on to grass. They then attach themselves to grass, so when animals come down to the water’s edge to drink and eat the grass, they pick up the cysts on the grass. The cysts go through the stomach, they hatch in the small intestine, the parasite goes through the small intestinal wall, into the liver, develops in the liver for about eight weeks, finds the bile ducts, then sits in the bile ducts of animals for years. These parasites can live inside sheep for ten years. In humans, there’s one documented case of a human infected for at least, we know for at least five years with these parasites. So these are very long-lived organisms. Because of the pathology when they migrate through the liver causing damage and fibrosis to the liver, they suck blood, they cause anaemia, and if you’ve got large scale infection, it can cause severe anaemia, severe effects on production, and in some cases, death.
In general, it’s a parasite that doesn’t kill animals or humans, but it debilitates them and so it has what I call insidious effects for producers, where, particularly in countries like Indonesia where farmers cannot afford the drugs that control the disease. The animals live with the disease and the producers live with the disease, and not really aware what the production levels of a healthy animal would be like, because all the animals are affected.
- Matt Smith
It only affects production. It’s not in a parasite’s general interests usually to kill hosts.
- Terry Spithill
No, it’s not.
- Matt Smith
So why are you interested in vaccines for this?
- Terry Spithill
We’re interested in vaccines because we think it’s a sustainable control mechanism, from a long term point of view. We think it’s the best way to control diseases. In humans we now know that smallpox and polio vaccines have been highly successful. Measles vaccine is very highly successful in essentially eliminating these diseases from the population. In contrast, when we try and use drugs to try and control, particularly parasitic diseases, the parasites have mechanisms of resistance, so when you put drug selection on the population, resistant parasites emerge, they get selected for, they take over the population. So every twenty years or so, animal health companies will produce drugs to control the parasite. They’ll be very effective for five years, somewhat effective for ten years, relatively ineffective after that, and after twenty years, essentially the drug has become useless, because all the parasites have developed resistance. So we think that the most sustainable approach is to develop vaccines, mainly because the way vaccines work, it’s very unlikely the parasite would develop resistance to the right vaccine. So once we develop an effective vaccine, we think it could be applied over and over again. One of the advantages of a vaccine is that a producer can vaccinate a small calf or a lamb, with the right vaccine with the right type of immune response, the animal might be protected for life, just like humans are protected for life with polio and hepatitis vaccines. The back up to that would be annual or every two years, the animal might get a booster vaccination. There’s considerable savings for the producer in both the cost of the treatment and also the associated costs of rounding up large numbers of animals to treat them in an effective manner.
In Western Java for example, every animal is infected. The prevalence of this parasite in cattle is a hundred per cent. Similar numbers occur in Africa and different parts of India and China. It’s a disease that, if we could get on top of it, we estimate we could improve just meat production alone, irrespective of any other positive effects, we could improve meat production by about twenty per cent.
- Matt Smith
Just a question about the vaccine itself. Is it a stop-all measure? Does the vaccine work say on sheep, on goats, on cows? Is it the same vaccine?
- Terry Spithill
That’s an interesting question. The short answer is perhaps. We can’t be sure. Some vaccines are effective in different animals. The issue we have with vaccines is that the efficacy of a vaccine is dependent upon the immune response of the host and the immune response of a sheep, a goat and cattle is not the same. So we may be lucky and the molecules we develop might be highly efficacious in all three hosts for example. It’s more likely that the particular vaccines might be what I call horses for courses, that a particular molecule might work well in sheep but another molecule might work better in cattle. It’s probably too early to say at this stage, because we’re not that close to a vaccine as I sit here today. There are molecules, what we call candidate vaccines, out there, that people are trialling and there are some very particularly interesting molecules currently being evaluated. There’s a molecule from Uruguay which is very successful in sheep now being evaluated in cattle for example. In general we need to evaluate molecules host by host, which is do-able, it’s very do-able but obviously it slows you down, particularly if you have to develop three different molecules for three different hosts. It’s compounding the work required.
- Matt Smith
And there’d be extra hurdles involved if you wanted to develop it for humans as well, or even test it on humans.
- Terry Spithill
That’s also a good question. Obviously molecules that are going to be tested in humans require much further clinical assessment, phase one – safety, phase two – initial evaluation, phase three – large scale evaluation. But in principle a vaccine that worked in cattle may very well work in humans, so if you think of humans as the fourth species after sheep, cattle, goats and humans, it’s possible that a vaccine that works well in sheep and cattle may very well work in humans. So in principle the short answer is yes. It would require much more development.
- Matt Smith
What stage is your research at then? Here at the AgriBio.
- Terry Spithill
We’ve been working on this disease now for probably going on twenty-five years. Over that time we’ve taken different approaches. In the past the approach had been, and this had been a general strategy in the field, we looked at the parasite, we looked at the molecules the parasite made and we thought, oh, molecule A, B or C, that looks like a molecule we could develop as a vaccine. Typically fifty per cent reduction in parasite burdens in vaccinated animals. The problem we have in the case of liver fluke for example, is that there’s a threshold which is the level of parasites below which economic losses are minimal. So if I could explain that. If an animal has one or two parasites in his liver, the effect is minimal. If the animal has twenty to thirty parasites in his liver, the effect is also relatively marginal. But once you get above thirty to forty parasites per animal, particularly a hundred to two hundred parasites per animal, the economic losses can be substantial. So a vaccine that can reduce worm per parasite burdens below that magic threshold, it will be deemed to be economically viable. With few exceptions, most parasite vaccines will never achieve a hundred per cent efficacy like we see with polio and hepatitis, where you get absolute sterilising immunity. Parasites are not viruses, they’re more complex, and they have mechanisms to protect themselves. So typically an animal health company might be targeting an eighty to ninety per cent reduction in parasite burdens, because that will bring the burden down below the threshold such that a producer will get the benefit of using that vaccine.
So what we’ve been doing the last probably three to four years, is adopting a different approach. When you look at a parasite and how it interacts with its host, the parasite induces an immune response, typically it’s ineffective. With a few exceptions, there are breeds of animals which do have a high level of what we call unnatural immunity, they have an immune response which is sufficiently robust to give protection. So what we’ve done, we’ve done some work in a particular breed of sheep in Indonesia, which was highly resistant to liver fluke. We went to Indonesia funded by the Australian government, we spent ten years there studying this parasite-host relationship and we identified an immune mechanism in these sheep which kills the liver fluke. The host in response to the parasite, has an acquired immune response which is highly efficacious. We call that acquired immunity or acquired resistance. We now have a mechanism of acquired resistance. Can we now work out which of the parasite molecules are the target of that acquired resistance? We then make a vaccine for that molecule and vaccinate animals to induce that acquired resistance, the acquired immunity. So the idea is fundamentally different to the previous approach, which I call picking winners. We’re relying on the immune response of the resistant host to lead us to the right molecules.
So, to cut a long story short, the immune mechanism we identified involved antibodies in these animals, binding to the surface of this worm parasite, bringing white cells onto the surface of the parasite, bound to the antibodies, and the white cells were killing the parasite.
So, what we’ve started to do now is ask the obvious question. What’s on the surface of the parasite that the antibodies are binding to? So we’ve now got a large group here, three PhD students, two Honours students and a Post Doctoral Fellow, all asking that question, in slightly different ways. We did some very nice work in collaboration with colleagues at the University of York. A paper we published in 2011 was the first definition of the proteins on the surface of the parasite. We identified 239 potential molecules. So we’re now sifting through those molecules to find out is there one, two or three or four of them that might be what we call the lead candidate, which could be the molecule which will induce the acquired immune response to kill the parasite when we vaccinate an animal.
So, as we sit here today, we’ve cloned some of these molecules, we’ve got two of them expressed in the laboratory upstairs. We’re now getting ready to characterise those proteins and then within the next twelve months, some of those proteins will go into vaccine trials to test is our hypothesis correct, that these molecules which are on the surface are very good inducing immune responses which will lead to immunity, which will kill the parasites in the animal. I am optimistic because I think what we’re doing is very logical and it may not be in my career time, that I personally find the molecules. That doesn’t matter, because I've trained a lot of students and PhD students who will be working long after I've retired and maybe one or two of those might come up with the right discovery.
- Matt Smith
So you’ve got, did you say 239 proteins ...
- Terry Spithill
Which we could look at.
- Matt Smith
So you’ve got, I assume, something like a whiteboard up there, with a big list of them, and you’re there going, the answer is on there somewhere, and you’re crossing them off as you go.
- Terry Spithill
Yes, we’re filtering them. We use the term filtering, so you’ve got 239 candidates. We’re looking for molecules that have particular properties. So there’s 239 molecules, but they have different properties, so one of the properties is, is the molecule actually on the surface of the worm? What we did was, we took the surface of the worm, and we analysed all the proteins in it, but we don’t know of those 239, which ones were actually facing out towards the immune system, which ones are in the membrane hidden, and which ones are facing back towards the parasite. So our prediction is that of those 239 proteins, there might be, based on results in other organisms, 25 to 50 proteins on the surface. Let’s say we identify those 25 proteins. The next question is, well, are some of these proteins more reactive with the antibodies with the resistant sheep from Indonesia than other proteins? So we might take those 25 proteins and say, which ones react most strongly with the antibodies from the resistant sheep and the answer might be five or six of them. And they’ll be the five or six that we’ll probably look at in much more detail.
So you’re right. 239 is a big number. We don’t quite have a white board. We have computers, and we have spreadsheets.
- Matt Smith
So that’s on the specific liver fluke. Is there applications for it for other species of liver flukes as well?
- Terry Spithill
Yes, there are. Throughout South East Asia, Asia, Africa, most of the tropical regions, Fasciola gigantica which is the related parasite. But interestingly, in China, Vietnam and Africa, Fasciola hepatica and Fasciola gigantica co-exist and overlap. And so the work we’re doing is focused on the Australian parasite, but I strongly believe it will have very direct benefits to giving lead to compounds that could be evaluated for Fasciola gigantica. The losses in Australia from this disease are estimated to be about sixty to ninety million dollars a year but the losses worldwide due to the tropical and temperate parasite are probably of the order of three to six billion dollars a year. And particularly in developing countries, like in subsistence farmers in Cambodia, Africa, Indonesia, where the cattle are everything to them, if we can improve their productivity of those cattle for subsistence farmers, it will have a very dramatic effect both on their ability to work their fields but also a very dramatic increase in their income.
- Matt Smith
Professor Terry Spithill there, Co-Director of AgriBio, the Centre for AgriBioscience. And that’s all the time we have today for the La Trobe University podcast. If you have any questions, comments or feedback about this particular podcast, or any other in our collection, then send us an email at podcast@latrobe.edu.au.
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