Shining light on a global killer — in 3D

Efforts to create a malaria vaccine have had limited success. Springer and colleagues solved the 3D structure of a key protein on the parasite -- and found a fragment which they'll soon test as a vaccine. (Photos_by_Angela/Flickr)

From the perspective of a wealthy country, malaria is a problem that is solved. It’s like smallpox. We ask, Who gets it?  Who cares? Isn’t it better to invest in diabetes?

In truth, malaria is more infectious than ever, endemic to 106 nations, threatening half the world’s population and stalling economic development and prosperity.

That’s part of the reason why Timothy A. Springer, PhD, an investigator in the Program in Cellular and Molecular (PCMM) Medicine at Boston Children’s Hospital and the Immune Disease Institute (IDI), took on Plasmodium falciparum, the parasite that causes malaria. Another is that he likes solving problems in immunology – and has made his name discovering molecules that both promote and fight infections, in part by understanding their structures.

One of his discoveries was the ICAM-1 molecule, the door that the most prominent cold viruses (rhinoviruses) use to enter cells. Springer worked with a pharmaceutical company to develop a drug that shuts such doors in the lining of the nose.

Now, again using structural biology techniques, Springer’s team has revealed the three-dimensional architecture of a molecule that protects the malaria parasite’s surface from our immune defense system, and possibly helps it invade. This discovery opens up a more rational approach to malaria vaccines, replacing some of the guesswork used in the past.

A computer reconstruction of the CS protein that studs the surface of the malaria-causing parasite (shown from two angles), and a key portion of that molecule, shown in green. Arrows point to a region that may help the parasite dodge our immune system.

Right now, there are two major anti-malaria approaches, neither of them ideal. One involves subjecting people to bites of about a thousand infected mosquitoes, irradiated to induce sterility and weaken the parasite. While effective for a small population of individuals – like those in the military – the approach is expensive and impossible to scale up.

The other vaccine, dubbed RTS,S/ASO2, is made from pieces of proteins that sit on P. falciparum’s surface. The pieces are supposed to teach the human immune system to recognize and pick off the whole parasite, should it later attack.

But vaccine developers had no idea which protein pieces to pick. So they guessed — by comparing the DNA sequences of different forms of the plasmodium (there are four types that affect humans plus versions that infect mice and macaques) and choosing the components that are common to most.

But the proteins are three-dimensional, and their DNA sequence doesn’t necessarily dictate how they will fold and appear to the immune system. Two amino acids that seem far apart in a linear sequence might actually fold and sit next to each other. It’s not currently known whether the protein in RTS,S is correctly folded or not. We do know that RTS,S/ASO2, now inching through phase III clinical trials, reduces the number of malaria cases by 35 percent – better than nothing, but for a vaccine to command widespread adoption, researchers need to hit closer to 85 percent.

Now, for the first time, Springer’s team can offer vaccine developers a topographical map of the major malaria surface protein, called circumsporozoite (CS) protein. Springer recreated the protein in systems where it would be processed and folded similarly to the way it is in malaria parasites. Next, the team crystallized it and probed it to determine the exact shape that the immune system would see, to determine the best piece to act as a vaccine. They identified a critical segment called αTSR that is unique to Plasmodium, and may be the only part of the CS protein that adopts a unique fold that elicits an immune attack.

Springer now has this correctly-folded segment in his hands — and a way to makes lots of it. He will test it as a novel vaccine and optimize its performance – rationally, not by guessing. A provisional patent has been filed.

In partnership with the Harvard School of Public Health, Springer and colleagues will begin vaccinating mice to see if they can prevent malaria. The team will also test responses in blood samples from people who have already been vaccinated (or survived infection with malaria). By exploiting that information, “we could make a lot of progress towards a vaccine in the next three years,” Springer says.

Indeed, that sort of progress would be welcomed by billions around the world. Until then, malaria offers only one daunting certainty: there will be infected mosquitoes, they will bite and millions will die.