Future of Malaria Research Focus of Half-Day Symposium at HSPH, May 25, 2007, Harvard Public Health NOW

Dyann Wirth presented at the symposium.

In 2003, a contingent of U.S. Marines docked off the coast of the West African nation of Liberia. Of the 157 people who went ashore - some briefly - 69 Marines contracted malaria. In all, 44 Marines became ill enough to be evacuated to Europe or to the United States, and five of them developed life-threatening malaria infections.

"It was all preventable if they had taken anti-malarial drugs properly and if they were treated when they first [became ill]," said Stephen Hoffman, who is a former director of the Navy's malaria program, at an April 25 symposium at HSPH dedicated to the future of malaria research.

Now, Hoffman is the chief executive and scientific officer of Sanaria, Inc., a Maryland-based company with the single purpose of developing a malaria vaccine.

Stephen Hoffman

His presentation was one of several given at a half-day symposium that discussed the genomic tools, vaccine and drug discoveries, and public-private partnerships that have reinvigorated the fight against malaria. The symposium was co-sponsored by the HSPH Office of the Dean, Broad Institute of MIT and Harvard, and the Global Infectious Diseases Program - a University-wide program formed last year under the auspices of the Harvard Initiative for Global Health.

The event was held on Africa Malaria Day, which marks a 10-year pledge of African leaders to cut malaria deaths by half by the year 2010. Coincidentally, the symposium fell on DNA Day, which commemorates both the publication of the double helix structure of DNA and, 50 years later, the completion of the Human Genome Project. Fittingly, Eric Lander, one of the leaders of the Human Genome Project and founding director of the Broad Institute, was one of the speakers.

Most of the world's malaria burden falls on the poorest people who do not have access to anti-malaria drugs or to health care. The disease has escaped decades of major public health efforts to control it. The global risk of malaria has risen, infecting 500 million people annually and killing an estimated one million, mostly children under age five and pregnant women.

"This disease represents a challenge to public health," said Dyann Wirth, chair of the HSPH Department of Immunology and Infectious Diseases and director of the Harvard Malaria Initiative. "There is more malaria now than at the time when the 1950s malaria eradication campaign began. Why is it that we don't have a cure?"

One of the problems is rapid drug resistance in the malaria parasite, Wirth said. Chloroquine, the best antimalaria drug so far, worked for 16 years before widespread resistance developed. In the 1990s, the parasite dodged the new drug, atovaquone, so quickly that it failed in clinical trials. Adding a second plant-derived anti-malaria drug, artemisinin, to other antimalarials can sustain the effectiveness of new drugs, but it doubles their cost. Making matters more difficult, mosquitoes - which host the malaria pathogen - have developed resistance to insecticides.

"Incomplete scientific knowledge is the first and foremost reason we don't have malaria vaccines yet," said John McNeil, scientific director of the PATH Malaria Vaccine Initiative, which maintains a portfolio of vaccines at all stages of development, including two in clinical trials this year. "Basic science forms the underpinnings that translate into effective interventions," he said.

The new genomic tools encompass people, the parasite, and mosquito hosts. "Malaria is one of the most powerful shaping forces of the human genome," said Pardis Sabeti, a postdoctoral fellow at the Broad Institute who recently began working with Wirth. The illness is estimated to be at least 100,000 years old, she said, and it's not going away. "It's continuing to develop methods to evade the immune system and drugs," said Sebeti.

Lander offered hope for a vaccine based on his experiences slogging away at unraveling the human genome. "Students might not have a sense for how rapidly progress might be made if everyone works together," noted Lander. The Human Genome Project was all about setting a measurable goal and working methodically toward it, despite major obstacles and objections. "One should have appropriate scientific skepticism because plans need to overcome the barriers," Lander said, but "even in the face of perfectly rational skepticism, one should dream big."

Already, an international team led by researchers at the Broad Institute, Cheikh Anta Diop University in Senegal, and Harvard University have completed a genome-wide map of genetic variability of the parasite that causes the most severe malaria, Plasmodium falciparum, noted HSPH research scientist Sarah Volkman, who was co-author on a recent paper announcing the group's findings. Using methods based on principles of natural selection and pioneered in humans, the team is working to identify hundreds of genetic variations crucial to pathogenicity, drug resistance, and disease severity in the parasite.

Sarah Volkman (left) and Pardis Sabeti

They are also preparing for association studies to match clinical phenotypes to genetic variations. The researchers hope to identify potential vaccine and drug targets, as well as an early warning system to detect drug resistance and vaccine escapes.

Other sessions at the symposium addressed vaccine and drug research and the public-private funding structures needed for testing, clinical trials, and delivery.

"There has been a sea change in funding and the excitement around global health," said Michael Gottlieb of the Grand Challenges in Global Health Initiative at the Foundation for the National Institutes of Health. "I don't think in my lifetime we've seen such enthusiasm about trying to make a difference in global health as now."

From left to right, Michael Gottlieb,John McNeil, J. Carl Craft, and Jay Keasling

The cost of manufacturing the malaria drug artemisinin can be greatly reduced by harnessing microbes to make the raw precursor chemical, said Jay Keasling, who is in the final stages of engineering E. coli and yeast to accomplish that goal. Keasling is conducting the research through a triad of the University of California, Berkeley; a company he co-founded called Amyris Biotechnologies; and a nonprofit drug company named OneWorld Health.

Keasling's product will be used with proven products in the pipeline of Medicines for Malaria Venture (MMV), a nonprofit foundation. The MMV has assembled the largest portfolio of antimalarial drugs ever, said the foundation's chief scientific officer

J. Carl Craft. MMV is merciless about pruning candidates that fail key testing along the way and has four drugs in phase-three clinical testing, including a lead candidate identified in a Broad/Harvard/Genzyme collaboration.

Even as the latest cutting-edge science peppers the development pipeline with possibilities, the first vaccine to come to fruition may be based on a 40-year-old discovery and on 23 years of continuous research, said Ripley Ballou, vice president of clinical development at GlaxoSmithKline Biologicals. His team is preparing for phase-three efficacy trials of a vaccine targeted to one of the earliest genes cloned from the parasite, a surface protein known as the circumsporozoite protein, or CS.

The speakers emphasized the wide range of opportunities available to students who wanted to follow their interest into careers ranging from research to public policy and regulation to the ethical, cultural, and social skills required for deployment in the field. "There is enormous job satisfaction," Ballou said. "It's very fulfilling."

—CM