While WRAIR and its partners at GSK conduct Phase I clinical trials in the United States and Puerto Rico, aimed at determining the safety of the new vaccine, the institute is also partnering with the French vaccine research company Sanofi Pasteur. The Sanofi vaccine, based on a chimeric of the attenuated yellow fever virus backbone with its antigenic structural genes replaced with each of the four dengue serotypes structural genes, is being evaluated at WRAIR-established field sites in Thailand and the Philippines.
“The Army wants a vaccine against dengue,” said Jarman. “It doesn’t matter if it’s an Army-developed one or not.” The Viral Disease Branch has launched partnerships with other companies – with virtually every major developer of dengue vaccines – in various stages of development, including several in the pre-clinical phase, and WRAIR plans to conduct Phase II trials, through its AFRIMS in Thailand, of a promising vaccine developed by the National Institute of Allergy and Infectious Diseases (NIAID).
A safe and effective vaccine for dengue would have profound implications for the U.S. military and the rest of the world. “If you lose seven to 10 days in a theater of operation,” said Jarman, “it’s a big deal. And if a soldier is diagnosed with dengue, he or she is evacuated. They’re not kept in theater. If you’re losing people like that, you become combat-ineffective pretty rapidly. There have also been a number of studies about the economic burden of this disease in Asia, and it’s huge – second only to malaria. And one of the greatest things about working in the Center for Infectious Disease Research is that, while the target for our products is the soldier, everything we do can really improve public health. That’s really important.”
The Military Malaria Research Program
The historical influence of malaria – the disease caused by a mosquito-borne parasite of the genus Plasmodium – on the U.S. military is literally etched in stone on the walls of the administrative headquarters WRAIR shares with the Naval Medical Research Center in Forest Glen, Md. The wall commemorates Lt. Gen. Douglas MacArthur’s apprehensions about sending soldiers into World War II’s Pacific Theater: “This will be a long war, if for every division I have facing the enemy, I must count on a second division in the hospital with malaria, and a third division convalescing from this debilitating disease.”
It was 1775, when Washington spent scant funds on quinine to treat malaria among Continental Army troops, that the U.S. military began its fight against malaria. By the time of the Vietnam War, when the disease – particularly the virulent drug-resistant strain P. falciparum – had incapacitated 10 percent of the Army, it had become the focus of the largest single medical research program in the Army’s history.
While the disease is not now a major cause of concern in North America, it is still deadly in warm, tropical endemic regions; P. falciparum kills about 650,000 annually, mostly sub-Saharan African children under the age of 5. One of the Military Malaria Research Program’s (MMRP) main research initiatives – the development of antimalarial vaccines and drugs – has remained stubbornly elusive due to the parasite’s ability to replicate rapidly and develop drug resistance.
In partnership with the pharmaceutical company GSK, scientists with WRAIR’s MMRP helped develop the world’s most promising malaria vaccine, RTS,S – the first experimental vaccine to establish that protection from the malaria parasite is possible. Results of the vaccine’s Phase III trial, reported in October 2013 at the 6th MIM (Multilateral Initiative on Malaria) Pan-African Malaria Conference, revealed that the vaccine, administered to 16,000 children, the population most at risk for malaria, at 11 sites across Africa, demonstrated about a 30-50 percent efficacy depending on the age at vaccination. The rate is not yet good enough as a vaccine for the military, but the vaccine’s potential has introduced the possibility that RTS,S may be used as part of malaria-control efforts.
According to Col. Robert Paris, director of the MMRP, the RTS,S vaccine, like many before it, builds immunity to weaken the parasite to the point where it does not cause disease. WRAIR researchers hope to develop a vaccine that provides sterile immunity – in other words, a vaccine that trains the immune system to kill the malaria parasite before it reaches the blood stage, which causes the symptoms and complications of malaria. “What we’re looking for in a military vaccine,” he said, “is to achieve complete protection from infection.”
Colorized scanning electron micrograph of red blood cell infected with malaria parasites, which are colorized in blue. To the left are uninfected cells with a smooth red surface. NIAID photo
The safety and efficacy of the RTS,S vaccine was initially established at the WRAIR’s own laboratories using the malaria challenge model, a protocol developed by WRAIR investigators that involves the intentional infection of study subjects with the parasite, followed by a period of close observation and treatment. To date, the malaria challenge model has been used to assess candidate malaria vaccines and drugs in more than a thousand volunteer subjects.