First effective blood-stage vaccine against malaria

Scientists have identified the first effective blood-stage malaria vaccine, according to a New England Journal of Medicine study from University of Maryland School of Medicine researchers, in collaboration with the University of Bamako in Mali, West Africa, and other partners. Development of a blood-stage vaccine has been a major goal of malaria prevention research. Such a vaccine would kill the malaria parasite as it emerges from the liver into the bloodstream, where it causes fevers and other symptoms that can lead to coma and even death. It could potentially save hundreds of thousands of lives and hundreds of millions of cases of malaria illness every year in Africa. There are more than 300 million cases of malaria each year worldwide, and the disease kills more than 800,000 people annually.

In a Phase II trial of an experimental blood-stage vaccine in Mali, the scientists found that the vaccine produced a high level of strain-specific protection. That is, people who received the vaccine were well protected against parasites that had a similar genetic make-up to the malaria strain used in the vaccine. The study was published Sept. 15.

"This trial is the first good news that we have had in a long while for blood-stage vaccines," says senior author Christopher Plowe, M.D., professor of medicine, epidemiology and public health and microbiology and immunology and leader of the Malaria Group at the University of Maryland School of Medicine's Center for Vaccine Development. "The fact that we saw this partial protection against malaria has reinvigorated the entire field. This gives us hope that we could create an effective blood-stage vaccine by using a precise combination of just the right strains to protect against most types of malaria."

A successful blood-stage malaria vaccine could resemble the polio vaccine, which was created by choosing three specific strains of polio to create broad immunity against the disease, explains Dr. Plowe, who is also a Doris Duke Distinguished Clinical Scientist and Howard Hughes Medical Institute investigator.

Though malaria has been eliminated in the U.S. and many parts of the world, in most tropical areas it is common and deadly, particularly to children. In warm climates where mosquitoes thrive, the disease is a major killer of children under the age of five. Malaria is caused by a parasite transmitted through the bite of an infected mosquito. Adults in heavily malaria-infested parts of the world, such as much of Africa, often have had the disease many times over their lifetime and have built immunity to it. Young children in these areas, however, have not yet built such immunity and are particularly vulnerable to the serious and often fatal symptoms of the illness, such as seizures, coma and respiratory failure. Malaria also affects adults who travel to malaria zones from places like the U.S. where the disease is eliminated and where adults do not develop immunity.

The vaccine described in the NEJM study, called FMP2.1/AS02A, is based on a single strain of the Plasmodium falciparum malaria parasite — the most common and deadliest form of the parasite found in Africa. The vaccine consists of a malaria protein from the blood stages of the parasite, and was invented and manufactured by Walter Reed Army Institute of Research. The protein, known as AMA1, is combined with an adjuvant developed and manufactured by GlaxoSmithKline Biologicals. The adjuvant is a compound that boosts the immune response to the vaccine.

For the study, the University of Maryland School of Medicine's CVD team collaborated with scientists from Walter Reed and GlaxoSmithKline and the National Institute of Allergy and Infectious Diseases, as well as with a group of Malian researchers from the Malaria Research and Training Center at the University of Bamako in Mali. The group included lead author Mahamadou Thera, M.D., Ph.D., and Ogobara Doumbo M.D., Ph.D., both professors of parasitology at the University of Bamako. The study was supported by the National Institute of Allergy and Infectious Diseases and the U.S. Agency for International Development.

"Strong partnership, well trained Malian scientists and the trust of the local community were critical for the success of this study," says Dr. Doumbo. "Our team worked hand-in-hand with the University of Maryland, the U.S. Army, the NIH, GlaxoSmithKline and with the community of Bandiagara, a remote rural town in Mali where the Universities of Maryland and Bamako have conducted our malaria research for 14 years."

The study involved 400 Malian children. During the summer of 2007, 200 children received the vaccine, and 200 received a control – a rabies vaccine. The children went back to their lives in Mali, where many mosquitoes carry malaria, and the researchers tracked their rate of malaria illness over the next six months. The scientists initially found that children who got the malaria vaccine had almost as many cases of malaria as those who got the rabies vaccine — the vaccine was only 17 percent protective against all strains of malaria.

The result was particularly disappointing coming on the heels of other blood-stage malaria vaccine trials that have shown no protection. The scientists decided to take a closer look. Using blood samples collected from children during bouts of malaria, the scientists sequenced the parasite gene for the vaccine protein, AMA1. They were excited to find that the vaccine was highly protective against parasites with a similar genetic make-up to the malaria used in the vaccine.

"If children were infected with a parasite with similar AMA1 to that of the parasite used in the vaccine, we saw that it was 64 percent protective," says Dr. Plowe. "No other blood-stage vaccine has shown any detectable efficacy against clinical malaria. This is the first good news that we have had in a long while for blood-stage vaccines."

Targeting the blood stage of the parasite prevents it from multiplying inside red blood cells, where it causes disease and death by sticking to the insides of blood vessels in the brain and other organs. The most advanced malaria vaccine, RTS,S/AS01, attacks an earlier stage of the parasite. The parasite is injected by the bite of an infected mosquito and infects the liver, where it quietly multiplies without causing illness before emerging into the bloodstream to wreak havoc. By combining an "infection-blocking" vaccine like RTS,S/AS01, which has only about 50 percent protective efficacy, with an effective blood stage vaccine, the scientists hope to be able to achieve higher levels of protection that would be needed to eradicate malaria altogether.

"A blood-stage vaccine is incredibly valuable in that it could prevent disease and death, saving many, many lives," says Dr. Thera, the lead author. "Other blood-stage vaccines have been tested but none has shown the ability to prevent malaria disease."

The key to an effective blood-stage vaccine will be to find a precise combination of malaria strains to create the broadest protection, Dr. Plowe adds. The research group is already working on possibilities.

"Our malaria group is world-leading, with state-of-the-art clinical facilities and cutting edge basic science laboratories in Baltimore and throughout the world, including in malaria-ravaged areas of the globe," says E. Albert Reece, M.D., Ph.D., M.B.A., vice president for medical affairs for the University of Maryland and John Z. and Akiko K. Bowers Distinguished Professor and dean, University of Maryland School of Medicine globe. "I have confidence that we are making significant strides toward a solution for this deadly illness that devastates much of the world."