SILVER SPRINGS, MD—On April 25th, malaria activists observed World Malaria Day, a day marked to recognize the global efforts underway to provide effective control of malaria.

According to the World Health Organization, malaria kills more than 1 million people a year around the world. While malaria may not be a problem that many people in the U.S. think about, it is a vexing health issue that U.S. military researchers cannot help but think about.

“The military is called upon to go to very out of the way places, often in tropical countries, often in remote areas,” said Capt. Thomas L. Richie, M.D., Ph.D., MC, USN, a malaria expert who directs the Navy component of the U.S. Military Malaria Vaccine Program (USMMVP). “We often encounter infectious diseases during those travels that most Americans will never be exposed to. It turned out, historically, in many of those expeditions—sometimes for humanitarian work, sometimes conflict or war—the infectious diseases have turned out to be a very significant threat; to the point sometimes where the success of the mission can be compromised because of those diseases. Often, malaria leads the list, particularly in tropical deployments.”

The conundrum for the military is that while malaria has the potential to wreak havoc on troops, there is currently no FDA-licensed vaccine to protect servicemembers from the disease. Currently, troops take antimalarial drugs and use protective measures to prevent the onset of the disease when they are in areas where they are at risk for it.

For this reason, military researchers are keenly interested in developing a malaria vaccine. At the same time, military researchers are involved in the equally important work of continuing to develop new antimalarial drugs, since these drugs can develop resistance over time.

Developing Antimalarial Drugs

The Daniel K. Inouye Building, which serves as the hub of the military’s malaria vaccine and drug development programs, has labs outfitted with an array of scientific gadgets geared for malaria research. It is also chock-full of malaria wonks who have been studying and tracking the disease in all parts of the world for many years.The Walter Reed Army Institute of Research’s Division of Experimental Therapeutics has been involved in the development of important antimalarial drugs used by troops and civilians, including mefloquine. Army Col. Alan Magill, MC, USA, a malaria expert who directs WRAIR’s Division of Experimental Therapeutics, understands that there is a question on some people’s minds as to why the military needs new drugs when there are antimalarial drugs already available. “One of the questions we always get asked is, ‘Why do we need a new drug? What’s wrong with the one you have?’ It is a fair question,” he said.

The reason is that none of the current FDA-approved antimalarial drugs are completely ideal for the military, he explained, pointing out mefloquine as one example of this. This year the Army said it would curtail its use of mefloquine. Mefloquine is not recommended for patients with a recent history of traumatic brain injury or who have symptomatic TBI, depression or anxiety disorders. In some cases, mefloquine has been linked to anxiety, depression, paranoia, hallucination and psychotic behavior. In addition, questions have been raised about whether there is a link between mefloquine and suicide. When used for prophylaxis, the Army says that patients must be properly screened before being given mefloquine.

The Army is now recommending the use of doxycycline instead. “In areas where doxycycline and mefloquine are equally efficacious in preventing malaria, doxycycline is the drug of choice,” Army Surgeon General Lt. Gen. Eric Schoomaker said in a memo dated Feb. 2. The issue with doxycycline, however, is that it is not always well tolerated by everyone, Dr. Magill explained.

“If I give it to 100 people, 5 or 10 will stop taking the drug because it upsets their stomach. At the end of the day, of you take someone who normally feels well and then you force them to take a pill and then they don’t feel well, it is not good. It is also a slow-acting drug and you actually have a window of about 96 hours where parasites are free to replicate in the bloodstream before doxcycline works,” Dr. Magill said. “Most of the time that doesn’t cause a clinical problem but if you miss a day—certainly if you miss two or three days—you get malaria.”

The Army also uses Malarone. According to Dr. Magill, Malarone is well suited for military use because it is safe and well tolerated, but it is also expensive. Resistance is also an issue that could emerge in the future. “The moment it is used for treatment in endemic areas, I think we could lose the drug in a matter of a year or two because of the emergence of resistance,” he said.

His division is trying to stay ahead of the resistance problem that plagues malaria drugs. In addition, one of the major goals of the division is to develop drugs that will prevent Plasmodium vivax malaria, a non-lethal form of the parasite that in recent years has caused more infections in military personnel than Plasmodium falciparum. Malarone does not prevent P. vivax, but if it did it would be an ideal drug, Dr. Magill said. “We spend a lot of time on P. vivax. We are very unlikely to develop a new drug that doesn’t deal with P. vivax,” he said.

The exception to that is that his division is currently working on developing a replacement for mefloquine, a process that could take several years. “If we can replace mefloquine with a drug that is as good as mefloquine, but didn’t have a psych liability, then that is a step forward,” he said.

Need for a Malaria Vaccine

While developing preventative malaria drugs is a painstakingly long process, so is developing a vaccine. The military has been working on developing a malaria vaccine for servicemembers for many years. USMMVP was created in 2007 when the Naval Medical Research Center’s malaria program and the WRAIR’s malaria program—both of which are located in the Daniel K. Inouye Build-ing—were formally unified.

The goal of USMMVP is to develop a vaccine that protects servicemembers from P. falciparum, the parasite that causes a form of the disease that is responsible for the most malaria deaths worldwide. The military’s goal is for the vaccine that will prevent malaria in at least 80 per cent of servicemembers. As a secondary goal, the USMMVP is developing a vaccine against P. vivax.

Lt. Col. Mark Polhemus, MC, USA, director of the Division of Malaria Vaccine Development at WRAIR, which is the Army component of USMMVP, said that a malaria vaccine is the best way to protect people from the disease. “Really, the best way to protect a large group of people from a disease entity is a vaccine. History has shown that time and time again. What we are trying to do is the same thing that has been done for measles, mumps, hepatitis, etc.,” he said.

One reason why a vaccine would be an optimal way to protect servicemembers is that when servicemembers do not take their preventative medications in malaria-endemic regions, malaria often becomes the defining health event of the mission. That happened in Liberia in 2003 when a U.S. military mission had to be aborted because a number of Marines stationed there developed malaria, due to a lack of complete compliance in taking antimalarial medicine.

Developing a Malaria Vaccine

The Army and Navy both are developing vaccines in hopes of coming up with a suitable one for the military. Currently, an advanced version of a malaria vaccine called RTS,S, that resulted from work at WRAIR by Army researchers in partnership with Glaxo-SmithKline over a 15-year period, could be FDA licensed in the years to come, pending phase III clinical trials. RTS,S, which is considered the most advanced malaria vaccine candidate to date, however, does not meet military standards for a high rate of protection for servicemembers.

“The leading vaccine candidate is called RTS,S and it is going into its phase III trial and it has shown to be 50 percent protective in naive people—children who have not been exposed to malaria. The phase III will probably show the same thing that we have seen in all of the other phase II trials and that means it will be available to go to licensure here and used in all of sub-Saharan Africa in a period of 5 to 10 years,” Dr. Polhemus said.

Because the military needs a vaccine that affords greater protection, the Army is working on developing a second-generation malaria vaccine through several different approaches. “The world recognizes that we have a great first start here with RTS,S, but that not just for the military, but for all of the world, there needs to be a next generation vaccine that has higher protection rates and a little longer duration,” he said.

On the Navy side, researchers are moving forward with work on other vaccines including an attenuated-sporozoite vaccine developed in collaboration with Sanaria Inc. Work on this vaccine has been funded by the Malaria Vaccine Initiative (MVI) at PATH, which is supported by the Bill & Melinda Gates Foundation.

The vaccine was formulated using the sporozoites dissected out of mosquitoes that have been raised and infected in a sterile lab setting. It is currently set to enter a trial in which it is injected in humans. “This is a very exciting trial. We have the IND allowance by the FDA to go forward in people,” Dr. Richie said.

The other vaccine for which his division has a new IND allowance is a genetic-based vaccine developed in collaboration with GenVec, Inc, and Vical, Inc. Funding for this project is provided to the military through USAID, Congressionally Directed Medical Research Program and the Military Infectious Diseases Research Program.

While the USMMVP is in search of a vaccine suitable for the military, its work benefits other malaria researchers. In the early stages of research, the malaria vaccine work done by USMMVP overlaps with the mission of other organizations to develop a malaria vaccine for people living in malarias areas. “Whatever we turn up will be equally applicable to their mission,” Dr. Richie said.

Both the Navy and Army components of the USMMVP could do with more money, Dr. Richie said. The roughly $9 million year that the USMMVP receives from the government is “woefully inadequate,” he said. “We can barely pay our overhead and staff and we are unable to conduct any clinical trials and we are unable to manufacture vaccines on that budget, so we have to get a lot of outside help from donor agencies such as the Bill & Melinda Gates Foundation,” he said.