After an infected mosquito bite, malaria parasites travel from the bite site to the liver. For that reason, the liver has become the target of numerous efforts to develop a potential vaccine.
Currently there are no approved vaccines for people against any parasitic diseases, including malaria.
Using a novel, liver-targeted vaccination strategy, researchers now have reported the successful testing in mice of a tissue-specific malaria immunization. The results appear in the Journal of Immunology.
Dr. Sean C. Murphy, associate professor of laboratory medicine at the University Of Washington School of Medicine, led the research. The team included Tayla M. Olsen and Brad C. Stone, from UW Medicine, and Vorada ‘Eve’ Chuenchob from the Center for Infectious Disease Research in Seattle. (Visit the Murphy Lab website.)
Malaria parasites take on a number of different forms during their complex life cycle. The parasite first infects people during the so-called sporozoite phase, when it resembles a small, curved whisker in the mouthparts of an infected mosquito.
After a mosquito bite, the sporozoite infects human liver cells. People generally don’t feel ill during the liver infection. About a week later, the parasites vacate liver cells and invade red blood cells. This is when symptoms of malaria appear.
“It’s a race against time,” Murphy said, “We have this seven day window in the liver to kill all the infected cells or we lose.”
Most vaccines tested to date work by virtue of antibodies, he explained. Antibodies are small molecules that recognize pathogens and block their ability to infect human cells.
The Murphy Laboratory is interested in a different arm of the immune system, white blood cells known as T cells. For a potential malaria vaccine, his group found ways to harness a particular type of these infection-fighting cells. Their aim is to have these white blood cells ready and waiting in the liver to squelch an infection before it spreads.
“What we reasoned and what other research has taught us,” Murphy said, “it that we need to get these memory T cells prepositioned in the liver.” The researchers applied a combined approach called “prime-and-trap” to train and recruit these defenders to the proper location.
First, a malarial DNA inoculation primes the immune response and increases the number of desired T cells. A gene gun delivers the DNA. This promising platform technology also is being used by gene gun pioneer and UW Medicine flu vaccine researcher Deb Fuller. To make a gene gun vaccine, DNA from the pathogen is put on tiny gold particles. Next a pulse of helium gas pushes the coated gold particles into the skin, where an immune responses to the DNA-encoded proteins is triggered.
In the “trapping” step, attenuated parasites themselves escort the primed T cells to the liver.
“After all, they’re professionals at going to the liver in the first place,” Murphy said.
Resident memory T cells became abundant in the liver. The treated mice had the strongest immune response amongst the methods tested. They were reliably protected against subsequent challenges from wild-type malaria parasites.
“We had tried some other methods to make this work,” he said. “We used a DNA vaccine that induced a T cell immune response, and low and behold the mouse spleens filled up with the primed T-cells. But those T cells didn’t have any reason to go to the liver. When the mice in that earlier study were exposed to malaria parasites, they were easily infected.”
