A massive Phase 3 trial of a malaria vaccine is now underway in Africa, with 5,000 children enrolled already out of a target population of 16,000. If results are favorable, marketing approval could be sought as early as 2012, making it the first commercial vaccine available for the disease, researchers said Tuesday in announcing the trial at the 5th Multilateral Initiative on Malaria Pan-African Malaria Conference in Nairobi, Kenya.
"This is a tremendous moment in the fight against malaria and the culmination of more than two decades of research, including 10 years of clinical trials in Africa," said Dr. Joe Cohen, vice president of research and development, vaccines for emerging disease and HIV, at GlaxoSmithKline Biologicals, which is producing the vaccine. Cohen is a co-inventor of the vaccine.
Malaria is a major health problem around the world. It kills more than 1 million people each year, 90% of them in sub-Saharan Africa and 80% of them younger than 5. It makes 300 million people seriously ill each year. Major progress in controlling the disease has been made by the widespread adoption of bed nets to keep mosquitos from attacking children at night and by the use of artemisinin-based therapy, which is the most effective treatment for infections.
But vaccines have historically proved the best technique for controlling infectious diseases, and researchers have high hopes for the new vaccine, called RTS,S/AS2A, or Mosquirix. The first-generation vaccine is unlikley to provide more than 50% protection, but researchers believe that even that level of efficacy could make major inroads against the disease and lay the foundation for the development of more effective vaccines in the future. The goal is to have by 2025 a vaccine that is 80% effective and that lasts for at least four years.
Producing a malaria vaccine has proved difficult because of the complicated life cycle of the mosquito-borne Plasmodium parasites that cause the disease. The cycle begins when infected mosquitos bite humans, injecting them with a form of the parasite called a sporozoite. The sporozoites invade the liver and begin reproducing in a new form called merozoites. Some merozoites can remain dormant in the liver for years, but most escape into the bloodstream and infect red blood cells, where they continue to replicate.
Eventually, the blood cells burst, releasing more of the parasites into the bloodstream. The parasites are then ingested by mosquitos when they bite an infected human. They reproduce in the mosquito's gut and the cycle begins again when the mosquito bites an uninfected person.
The new vaccine uses two genetically engineered proteins from the surface of the Plasmodium sporozoites to induce immunity. It also contains a combination of nonbiological materials called an adjuvant to stimulate the immune system to react more strongly to the proteins. Initial studies of the vaccine in children under the age of 5 have shown that it can produce protection as high as 63%, but more often in the range of 50%. Its effects persist for at least a year.
The new trial, the largest clinical trial ever in Africa, is being conducted in seven countries: Burkina Faso, Gabon, Ghana, Kenya, Malawi, Mozambique and Tanzania. The idea is to provide as broad a cross-section of different environments as possible to provide the best test of the vaccine. In some sites, for example, there is a year-round threat of malaria, while in others there is only a seasonal threat linked to rain. Two groups are being studied, infants ages 6 to 12 weeks and children ages 5 to 17 months.
GlaxoSmithKline has not said how much the vaccine will sell for, but company chief executive Andrew Witty said last week that price would be no hurdle if the vaccine works. "We are not going to let price get in the way of access for malaria vaccines," he said at a news conference. The company has already invested $300 million in the vaccine and expects to invest an additional $100 million before completion of the project. The Bill & Melinda Gates Foundation has invested another $200 million. Researchers project that controlling malaria will require an annual investment of $4.2 billion.
Meanwhile, researchers are at work on second-generation vaccines. Sanaria, a Rockville, Md., company, has been working on a massively labor-intensive project to manually dissect infected mosquitos to isolate sporozoites, which are then irradiated to make them impotent. A Phase 1 safety and efficacy trial of a vaccine containing the attenuated sporozoites began in April.
Other researchers sponsored by the PATH Malaria Vaccine Initiative are working on vaccines that block transmission. These vaccines generate antibodies to the stage of the Plasmodium that replicates in the mosquito's gut. The vaccine would provide no proteciton to the immunized person. But when a mosquito draws blood from a vaccinated individual, the antibodies would block replication of the parasite and prevent transmission to other people. Pilot studies in humans show that the vaccines sharply reduce the number of infected mosquitos.
Officials at the Malaria Vaccine Initiative hope that combining one of these new vaccines with the RTS,S vaccine will provide much stronger protection, and the group said that it will fund only such combined trials in the future.
-- Thomas H. Maugh II
Photo (top): A trial participant is vaccinated in Kisumu-Siaya, Kenya. Credit: John-Michael Maas / Darby Communications
Photo (bottom): A trial participant's mother uses bed netting to protect the child from mosquitos. Credit: John-Michael Maas / Darby Communications