A Vaccine for malaria

27th February 2006

Queensland Institute of Medical Research (QIMR) scientists have found that that, in animal studies, an immune response can protect against infections of different strains of the malaria parasite. Malaria vaccine trials in humans are expected to start in Brisbane later this year.

Professor Michael Good from QIMR talks to Carly Johnson about the malaria vaccine trials.

How does this vaccine work?

"The vaccine works by stimulating an immune response that recognises the infection, the real infection when it comes, and destroys it or limits its growth. The real challenge in malaria vaccines is to identify a way to stimulate an immune response which will cover all strains of the parasite and be effective in controlling their growth. Most people are looking at what are called single antigen or subunit vaccines. The difficulties with these approaches are that single antigens are often poorly immunogenic and secondly they're often polymorphic. In other words, the parasite changes its coat.

The approach that we've been pursuing recently is to revisit ways to use the whole parasite. The whole parasite contains all the proteins of the parasite so you limit problems of antigenic variability and typically it's more immunogenic. What we've found is if we use a low dose of the parasite, as opposed to say a large dose, the immune response is even more immunogenic again. It's focused on cell mediated immunity in preference to an antibody focus. Now, that's important because we find that the target antigens in cell mediated immunity are highly conserved where as the target antigens of the antibody are the ones that tend to be polymorphic."

How is this vaccination different from the traditional approach to malaria treatment?

"Malaria treatment is to kill the parasite with a drug once it's in your body and that doesn't in itself induce an immune response which will protect you against subsequent infection. In fact, there's a lot of evidence that when you have a malaria infection your immune response to the parasite is diminished. The infection causes apoptosis of the specific T-cells and memory B-cells and that limits your ability to respond effectively to the parasite next time. So a vaccine, unlike a treatment, aims to stimulate the immune response, rev it up so that the antibody, or the T-cells in our case, will kill the parasite."

How was the idea for the "whole parasite approach" developed?

"We found out that when you get a malaria infection in an animal model the T-cells which were responding to that parasite were apoptosed. The parasite was causing cell death of the T-cells which were supposed to kill the parasite. So we thought that since apoptosis is often associated with a high dose of antigen or parasite that maybe a low dose would prevent apoptosis. We tried a very low dose, so low that you couldn't see the parasites in a blood infection, and we found that that was successful. It didn't cause apoptosis and it stimulated a very potent immune response."

How long has it taken to get to this stage?

"We've been working on this low dose approach for about 7 to 8 years."

How many scientists have been working on this vaccine?

"Not a great number. We've had a student from Thailand (Chakrit Hirunpetcharat), post docs Huji Xu, David Pombo, Salenna Elliott and Alberto Pinzon-Charron. Some research assistants in the lab (Virginia McPhun, Xue Qin Liu). Some are still here, others have come and gone."

What challenges did you face using this approach?

"The biggest challenge in this approach I think is the idea of convincing people that we can make a safe vaccine when you inject whole organisms grown in red blood cells. People are understandably concerned about inducing immune responses to the red blood cells. We have to go to extraordinary lengths to make sure that doesn't happen, and to make sure that the blood that we culture the parasites in isn't infected with other organisms such as viruses. We have to make sure the blood product is safe."

How is this vaccine different from the one that Dr Stephen Hoffmann in the US is producing?

"He and his company Sanaria are looking at a different stage in the lifecycle. The malaria lifecycle starts when the mosquito injects the sporozoites which travel to the liver, then leave the liver and go into the red blood cells. The red blood cells are responsible for all the symptoms and pathology of malaria. Our approach is focused on the red blood cells stage. Steve Hoffman's is focused on the sporozoites that come from the mosquito to the liver."

How will this vaccine be taken?

"We anticipate it will be given by intramuscular injection."

Is this vaccine suitable for children?

"We would hope so. One of the important parts of doing any vaccine trial is to look at safety and immunogenicity. As part of the vaccine trial work up we would be looking initially at safety and immunogenicity initially in adults, and then if it was safe and immunogenic in adults we would look at children."

What are the dangers of vaccinating people with live parasites?

"We probably won't use live parasites. We will use whole parasites which have been killed. With live parasites obviously you would have to be sure they were attenuated and weren't in themselves able to cause disease which is a big problem. But with a dead parasite that won't be an issue."

How stable is the vaccine and what is its shelf life?

"Until we actually test that, we don't know. These are questions we don't have answers for yet."

What sort of issues might there be for using this vaccine in other countries?

"The main ones are showing immunogenicity in different populations and issues of shelf life."

Can you tell us about the human trials process and describe what happens next?

"It's anticipated that human trials should start in about a years time. After that, the next thing to do is grow the Plasmodium falciparum parasites at GMP cells. Obviously we do grow Plasmodium falciparum parasites now, but we don't grow them in a way that would be regulated or allowed by the TGA to inject into people. We would have to use blood which we know is safe and clean and we have to grow these parasites under very stringent, reproducible conditions so that we can do the same thing again and again and again. And we have to produce the adjuvant at GMP."

What is the significance of this vaccine in the fight against malaria?

"There are about 2 million deaths every year from malaria, most are children and mostly in Africa. Any vaccine which could diminish that number would have a big impact on public health."

What is the vision for the development and distribution of this vaccine?

"If this vaccine works as we hope it will, it may be that these processes could be taken up by companies in developing countries around the world and made locally."

What about the future of this vaccine?

"What excites me most is to find a way to get this vaccine, if it works, distributed. So whatever it takes."

Carly Johnson interviewed Professor Michael Good, QIMR, 27 February 2006.