Why one after another new malaria vaccine tests well in the laboratory but fails in field trials has frustrated legions of malaria researchers, and has been the main stumbling block to malaria eradication. Now, a research team from Germany has unraveled that puzzle and shown that the problem is all about the skin and how it controls the immune system. The implications are profound.
Publishing in the current issue of PloSONE (http://dx.plos.org/10.1371/journal.pone.0010685) the researchers show that a suppressive immune response to live malaria parasites in the skin is the unavoidable result of a malaria-infected mosquito bite. People who have already had live parasites in the skin will have a ready-made suppressive response to any vaccine antigen.
"In these people, vaccination induces further tolerance, not immunity," explains D. Lys Guilbride, PhD, the study's lead author.
How did Dr. Guilbride and her co-investigators, Pawel Gawlinksi, PhD and Patrick D.L. Guilbride, MRCVS, reach this conclusion?
"While doing research on malaria, I was reading literature about cancer immunology and regulatory T cells which shut down the immune response," she recalls. "I saw that these mechanisms applied well to malaria vaccine problems, but couldn't see exactly how the parasite made it happen."
When attending a cellular biology seminar on parasites in the skin, it suddenly dawned on her where - and exactly how - the malaria parasite must be switching off or subverting the immune system by making regulatory T cells. It was in the skin and the skin-draining lymph nodes.
"To prove my hypothesis of parasite-triggered, skin-initiated blocking of immune responses to malaria, we needed to isolate the regulatory T cells involved," she explains. "Then we needed to test the model with bigger experiments in animals and people to confirm that these cells acted via the skin to block vaccines, the way the model predicted."
After identifying the cells involved, the research team compared their model with the results of hundreds of previously published experiments investigating vaccine protectivity. This procedure was more stringent than comparing it to only one experiment of their own.
Out of 1,916 malarial immunization studies carried out between 1965 and April 2010, a careful meta-analysis of all 177 experiments that showed complete protection proved their hypothesis perfectly - that live malaria parasites in the skin shut down immune responses and block vaccine function.
"Since malaria is transmitted by mosquito bite, this means that malaria vaccines are inevitably thwarted by an immunosuppressive response set off by the pre-existing effects of an early malaria infection in the skin," she notes.
Most laboratory-based experimental infections, however, bypass the skin entirely. In this case, responses to malaria antigens do not get shut off, and so behave protectively in the lab tests.
As a result, these antigens get selected as vaccine candidates, but fail in field trials, because there - unlike in the lab - most people already have the parasites in the skin.
"This also explains why vaccines that are partly effective in those who are malaria-naïve - such as infants - do not work in those who have already been infected with malaria. These pre-infected people already have set up a skin-initiated suppressive immune response to vaccines," concludes Dr. Guilbride.
According to Dr. Guilbride, the critical immune effects of the skin stage have been overlooked until now because that stage of infection is very rapid, does not involve parasite amplification, and does not create clinical symptoms.
The findings force a reassessment of the precepts for malaria vaccine development.
"Since we now know why vaccines keep failing, we can redirect our efforts in a totally new direction to make a vaccine that will work well in the field," she explains. "This knowledge, this new understanding of what was preventing vaccines from working, resolves the logjam and lets us address the problem specifically."
Malaria remains a killer of children and adults worldwide. According to the April, 2010 report from the World Health Organization for World Malaria Day, 2010, the most endemic area of the world for malaria continues to be sub-Saharan Africa. The disease has an especially high mortality rate for children (http://rbm.who.int/worldmalariaday).
Malaria statistics are stunning. World wide, one million babies die of malaria annually. Nearly three billion people are at-risk for getting malaria. In Africa, 20 percent of childhood deaths are from malaria.
What are the immediate benefits of this research?
Changes in vaccination protocols and trials - such as vaccination before infection and avoiding induction of skin-stage immunosuppression - will save countless lives because it will optimize current vaccine function in the short term.
Two, the realization that discarded vaccines may find new usefulness when used to vaccinate uninfected individuals (particularly newborns) since even if in the past vaccines failed in adults in endemic areas they should work better in infants who are protected against mosquito bites from birth.
Third, it will reveal an important new use for chloroquine: to block the immunosuppression triggered by the parasites in the skin. This allows vaccines to work better. Since chloroquine is well tolerated and can be transmitted to babies via the mother's milk, it is easy to give, well tolerated, and provides further strong protection against skin-initiated immunosuppression, allowing protective immunity to develop, especially when given along with vaccines. Additionally, chloroquine is inexpensive, so it is realistically accessible to those who need it long-term.
These findings will also redirect the rational focus of malaria vaccine research to prioritize specific and more productive avenues away from unproductive paths.
Where to go from here? According to Simon Pinniger, director of the Malaria Research Foundation which sponsored the research, "Explaining this conundrum should make the hundreds of millions being spent each year by the U.S. government, the Gates Foundations and many others, much more effective. It will bring the eradication of malaria a big step closer."
Argonne receives $21.7 million to advance cancer and vaccine discoveries