01/06/2017

Genetically Modified Parasite Shows Promise for Malaria Vaccine

11:37 minutes

Mosquitoes used for hosting and transmitting the malaria vaccine. Credit: Stefan Kappe
Mosquitoes used for hosting and transmitting the malaria vaccine. Credit: Stefan Kappe

What’s the best way to immunize the human body against the malaria parasite? One approach is to use the parasite itself as a vaccine, as long as it’s been disabled somehow from fully infecting the human body.

A group in Seattle has completed early human testing on one such whole-organism vaccine, entailing a genetically modified version of the parasite that’s hobbled from reproducing and infecting the bloodstream. In a trial with 10 volunteers, they say the vaccine proved safe, and is ready to advance to further tests.

Stefan Kappe, a professor and Director for Translational Science at the Center for Infectious Disease Research, explains how it works and why it’s so challenging to develop a vaccine for malaria.

Segment Guests

Stefan Kappe

Stefan Kappe is director for Translational Science at the Center for Infectious Disease Research in Seattle, Washington.

Segment Transcript

IRA FLATOW: This is Science Friday. I’m Ira Flatow. Malaria. It’s one of our oldest and most widely-spread diseases. It strikes as many as 200 million people per year. And science has been searching for a cure for malaria for countless generations, always hoping that some new discovery might be useful in the search.

And that brings us to the work of one group of scientists in Seattle. That group has genetically modified the malaria parasite itself to train the human immune system to fight back. The researchers knocked out three genes in the parasite to create a parasite that cannot reproduce in the body, thus letting the immune system respond and attack it.

And the first human trial has wrapped up, and it appears to have been a success. No one actually became ill. No one suffered any side effects, except some itching from the mosquito bites used to administer the vaccine. But none of the people have been tested with real malaria yet, so we don’t have that real test coming up yet. That’s in the future.

What’s next for this approach? How close are we to a highly-effective vaccine against malaria? My guest is the principal investigator on this test. Stefan Kappe is a professor and director of Translational Science at the Center for Infectious Disease research in Seattle. Welcome to the program.

STEFAN KAPPE: Thank you for having me.

IRA FLATOW: Malaria has been around for a long time. Why don’t we have a vaccine yet?

STEFAN KAPPE: I would say that the main reason why we don’t have an effective malaria vaccine is the complexity of the parasitic organisms that cause malaria. It’s plasmodium. It’s a cellular parasite that is as complex as a human cell, nearly as complex as a human cell. And it undergoes these many changes when it moves from the mosquito vector to a human host.

And within the human host, it has different stages of infection. It first infects your liver, and you don’t feel the infection. And then it comes out of your liver after it multiplies, and it affects your heart cells. And that is what causes disease and potentially kills you.

But every time the parasite changes. It’s kind of a turncoat parasite. It changes every time. And so it has been extremely difficult to devise strategies to come up with an effective vaccine to prevent infection or prevent illness.

IRA FLATOW: Now, what made your strategy successful where others have failed?

STEFAN KAPPE: I think the overall strategy is to fight fire with fire, so to speak. And the parasite itself stimulates the immune system in a great way. But if you disable the parasite so it cannot fool the immune system, it cannot trick the immune system. And it cannot make you sick if you weaken it to a degree that it lacks all these capabilities. But it still stimulates the immune response appropriately. That’s the way to make the most efficacious malaria vaccine.

Other strategies that have used individual proteins of the parasite, for example– just to point out, the parasite has over 5,000 proteins. And people, in the past, have tried to take individual proteins and develop them as vaccines, and that has not been very successful.

IRA FLATOW: So your strategy sounds to me like what we do with a virus, like polio or something else like that. To make a vaccine, you just use a weakened version of it, and the body responds.

STEFAN KAPPE: That’s exactly right. A virus, however, is a much less complex organism. So really, the difficult task for us was to find a way to weaken the parasite appropriately. And also, traditionally, these attenuated organisms, such as polio viruses, have been attenuated by approaches that weren’t really very controlled. They were passed through tissue culture, for example, or through animals, and were just weakened in the process. And then they were used as vaccines.

Our approach is very, very designed, in that we pick genes that are important for the parasite to grow in the liver, initially. And we delete those genes using genetic engineering, and that renders the parasite unable to replicate after initial infection.

IRA FLATOW: Now I understand that you had 10 human subjects in this, and you, yourself, were part of one of the– were a subject. How did you how did you administer the malaria to these subjects?

STEFAN KAPPE: So just to step back a little bit– so the parasite is transmitted by mosquitoes, and it sits in the salivary glands of the mosquitoes, and that’s the form of the parasite that infects you. And that’s actually the form of the parasite that we try to make into a vaccine by specifically removing genes that then allow the parasite, after it transitions from the mosquito to the human, to infect the liver.

And so in this trial, we administered this attenuated parasite by mosquito bite. And we wanted to prove that this is completely safe, so we gave a very high dose. And in this case, a very high dose means that we gave a lot of mosquito bites.

So each of us volunteers received about 200 mosquito bites carrying this attenuated parasite, weakened parasite, delivering between about 100,000 and 200,000 of those parasites effectively to the human volunteer. But after followup, we found that no one actually developed malaria infection. Therefore, we concluded that this is a safe approach.

IRA FLATOW: Now, I guess to prove it then, you would have to follow up with giving some test subjects real malaria and see if they’re resistant to the real thing.

STEFAN KAPPE: So indeed, and we can do this. So we have what’s called a controlled human malaria infection model in vaccine and drug research for malaria. So we can experimentally infect human volunteers with the real malaria parasite. And if they get the parasite in the bloodstream, we can detect it by microscopy or by polymerase chain reaction, and we can treat the infection with anti-malarial drugs.

So the next step for this vaccine would be to repeatedly immunize volunteers with this vaccine, and then challenge them with the real infectious parasites and see– if they are not developing malaria, they would be protected. And if they are developing malaria, they are not protected, but we can safely treat them.

So this is a very effective way for us to test interventions for malaria– in this case, our attenuated or weakened whole parasite vaccine. And we do this right here in Seattle, in the Westlake neighborhood, at our Center for Infectious Disease research. And we are recruiting volunteers from the Seattle area for these trials.

IRA FLATOW: Is it hard to recruit people?

STEFAN KAPPE: It is actually not very hard. I was personally surprised when we started recruiting volunteers for our effort how many people volunteered. We have a database of over 1,000 volunteers that have already expressed interest in participating in future clinical studies. So there’s a tremendous interest in Seattle to help, to participate.

Many people in Seattle are very globally-oriented. They are outward-looking. They understand the problems, infectious disease problems of the world. Many of them have been traveling and have experienced malaria, for example, before. And if not themselves, then within their families or circle of friends. So a lot of interest, a lot of excitement, actually, for our work, and we really appreciate that.

IRA FLATOW: Let’s say you come up with a successful vaccine, and it works very well. Who’s going to make the vaccine?

STEFAN KAPPE: Yeah, that’s a great question. So traditionally, vaccines, as I said, have been built on individual proteins that can be produced in bacteria. And pharmaceutical companies are very skilled in doing this. But this is kind of a unique approach where we take the whole parasite, so it’s not easy to manufacture such a vaccine.

But there are efforts in small biotech companies to develop methods to, for example, produce this type of vaccine, actually, within mosquitos and then isolate it from mosquitoes and vial it so it can be administered by syringe. Now, this sounds fairly impractical. But when you consider how vaccines have been made in the past– for example, in eggs– it’s actually not so unreasonable to think that we cannot do it in mosquitoes.

And we are also developing cell culture, tissue culture models, where we can actually manufacture this type of vaccine, this whole-parasite vaccine in a culture dish.

IRA FLATOW: Is there enough money to be made is this? Drug companies– they want the big victory, the big bucks here. Is there enough money to be made in this vaccine that big drug companies might be interested? Or can you get away with the smaller companies?

STEFAN KAPPE: I think in the end, it is important that large pharmaceutical companies step up to the plate and really help with this development effort. We are talking about a parasitic infection that makes over 200 million people sick each year and kills over half a million people. So I do hope that pharmaceutical companies will carry that responsibility to ultimately help us to produce such a vaccine.

But in terms of economy of this vaccine, I think there is a market there for travelers and people traveling to malaria-endemic areas from Western Europe and from the United States. There’s millions of people traveling to malaria-endemic areas each year. So there’s a market for a vaccine there, for what we call a traveler’s vaccine.

But of course, the vaccine is needed most by those directly affected by malaria every day. And here, it becomes a little bit more difficult to think about the economy and the economy of this vaccine development. And we do hope that, of course, that government and organizations such as the Gates Foundation will step in and participate in developing this vaccine.

IRA FLATOW: Now, I understand there’s already one vaccine that’s advanced through clinical trials and will be used in a pilot program in parts of Africa. How does your vaccine compare to that? Why do we need another one?

STEFAN KAPPE: Yeah, that’s a great question. So this vaccine that you are referring to is a vaccine that is built, as I pointed out before, on these individual proteins. So it’s one protein of the parasite. And this vaccine has undergone extensive clinical testing and has been tested in what we call Phase 3, so these are late-stage clinical trials in Africa. And it has about 30% efficacy.

There’s a lot of debate how this efficacy is calculated, and so on and so forth. But let’s say it’s about 30%. So we and others believe that that is not yet sufficient to really contribute significantly to eradication and elimination, and eradication of malaria via the vaccine. So we have to get better than 30%. And we hope with our approach, we can get to 80% plus. And there is good evidence that we can reach that.

IRA FLATOW: And give us a timeline of how this might play out.

STEFAN KAPPE: Yeah, timeline’s always difficult to predict. But I would say in the best case scenario, with all the funding in place and secured to bring this through clinical development, I would say an 8- to 10-year timeline is realistic.

IRA FLATOW: Is CRISPR going to help you anywhere in this effort?

STEFAN KAPPE: That’s a great question. So this parasite strain that we have engineered by deletion of three genes that cause the parasite to stop development in the liver has been done by traditional methods. And this has taken a long time, and it was very cumbersome. Now with CRISPR, it will be so much accelerated. And we are already creating the next generation of attenuated strains, or weakened strains, using CRISPR technology. It will make a big difference.

IRA FLATOW: And how many bites– your volunteers, you said, got 200 bites? Are you still scratching from this?

STEFAN KAPPE: I am not scratching any longer. It has been a fun experience, actually, sitting there with the volunteers and talking to them about the work. And they were so excited to do it. Of course, they were itching. And I, myself, was itching for a little while after those bites. But it was not as bad as everyone thought. And everyone said they would be happy to come back and participate again. So I think it’s sounds strange, but it’s actually a great experience.

IRA FLATOW: Well, if you’re looking for volunteers, there’s no faster way to get them than come on our show because we have two million listeners. And I hope you’re not flooded– well, I don’t know, actually. Maybe you should be flooded with more phone calls to get volunteers.

STEFAN KAPPE: Yeah, I would appreciate that. Everyone is welcome. And it’s great effort. It’s an important effort.

IRA FLATOW: How do they reach you if they want to volunteer?

STEFAN KAPPE: They can go to our website at cidresearch.org, and they will find a link to our clinical trial center, and they can sign up right there.

IRA FLATOW: All right. There you have it. Our good deed for the weekend. Thank you very much. Good luck to you, Dr. Kappe.

STEFAN KAPPE: Thank you very much. I appreciate it.

IRA FLATOW: Dr. Stefan Kappe, professor and director of Translational Science at the Center for Infectious Disease Research in Seattle, Washington.

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