Researchers Continue Military’s Long Battle Against Malaria, Seek to Develop Vaccine

In their efforts to outmaneuver the highly elusive malaria parasite, researchers at the U.S. Military Malaria Vaccine Program (USMMVP) are more than intellectually and professionally committed. Many of them literally have skin in the game.

“Pretty much every principal investigator considers it a badge of honor to participate in a vaccine trial,” said Col. Christian F. Ockenhouse, MD, director for the Division of Malaria Vaccine Development at the Walter Reed Army Institute of Research (WRAIR). He recalled participating in a military malaria trial he led 16 years ago where he subjected himself to malaria-transmitting mosquitoes. “Plus, it is somewhat easier to recruit volunteers if they know the investigators themselves want to participate.”

Fighting malaria has been a long battle for the U.S. military, which began making inroads against the disease at the turn of the 20th century during the occupation of Cuba and the construction of the Panama Canal, according to a CDC history. The U.S. Public Health Service first received funds in 1914 to control malaria inside the United States, including around military bases in the South to allow troops to train year-round, according to CDC. Human vaccines against malaria have been intensely studied since the 1970s.

Ockenhouse, who has been working on malaria-vaccine research for 20 years, said the quest is far from over. “If you think a vaccine is going to come around the corner tomorrow, it is probably better to find another profession,” he said. “On the other hand, I think one of the beauties is that perseverance pays off. Anything worth doing, you have to keep on going back. It is re-engineering and going back and saying, ‘if you had a failure, why did you have a failure’ and improve upon previous results.”

Searching for Military Solution for Malaria

An adept killer responsible for the deaths of between 708,000 to 1,003,000 people in 2008, according to the World Health Organization, the malaria parasite puts both civilians and the military at risk.

malaria-Richie-caption.jpgWithout a vaccine, deployed troops must completely rely on the use of antimalarial drugs, bed nets and other methods to repel potentially infected mosquitoes. While these preventive methods work in theory, compliance can be a problem, and any breakdown in protocol can have dramatic implications.

That happened in 2003 when 80 marines developed malaria, 43 of whom were evacuated to the National Naval Medical Center for care, although all survived. More recently, in December 2009, a Navy Seabee died from malaria complications he had contracted during his deployment to Liberia.

“We do have medications that are very effective for preventing malaria, but it is difficult to achieve good compliance in a combat situation, having to take a pill every day or every week that may cause side-effects,” said Capt. Thomas Richie, MD, research coordinator for the USMMVP and director for the Navy’s Malaria Program. “In the chaos of war, it is not that easy to maintain a medical regimen.”

USMMVP’s goal is to develop a vaccine that protects servicemembers from P. falciparum, and P. vivax. Further, the military does not want to create just any malaria vaccine, but rather one that yields at least an 80% protection rate.

In order to accomplish this task, Army and Navy combined their malaria programs in 2007 to form the USMMVP, bringing together malaria researchers from the Naval Medical Research Center’s malaria program and WRAIR’s malaria program.

Malaria Vaccine Research

The leading malaria vaccine candidate against P. falciparum was developed as a result of work done by WRAIR malaria researchers and GlaxoSmithKline Inc. Known as RTS,S, it is the first malaria vaccine candidate to show that a malaria vaccine could confer a high level of protection from infection.

GlaxoSmithKline and the PATH Malaria Vaccine Initiative, with funding from the Bill & Melinda Gates Foundation, are conducting phase III trials on RTS,S in 11 sites in seven African countries.

Should the vaccine prove effective, it will be on track to becoming a pediatric malaria vaccine in Africa, Ockenhouse explained. “This vaccine has the capability of protecting countless infants if it is taken up by WHO,” he said. “This is a very positive aspect of what the Department of Defense has contributed to world health.”

Still, while RTS,S is the military’s leading malaria vaccine candidate, it only shows about 50% efficacy at best – far short of the military’s goal for a vaccine against P. falciparum. WRAIR scientists are currently working with outside partners to see if they can strengthen RTS,S by using a prime boost approach in which a modified adenovirus vector vaccine is used in combination with RTS,S. This approach will be tested in volunteers in a trial this year.

Other malaria vaccine approaches are being pursued by the USMMVP. Navy researchers collaborated with Sanaria Inc. and the University of Maryland Center for Vaccine Development on an effort to create a vaccine by injecting live-attenuated parasites using sporozoites that have been weakened by radiation. In a clinical trial in 2009-2010, two out 44 volunteers who were injected with this vaccine candidate were protected from malaria. Researchers at the NIH Vaccine Research Center will seek to determine whether administering the vaccine intravenously will boost protection in volunteers.

USMMVP also is pursuing a gene-based vaccine, created by combining two adenovirus vectors, each of which contains the gene for a different malaria protein. In a trial conducted by military researchers in collaboration with GenVec Inc., four of 15 volunteers vaccinated were completely protected from malaria, which is the best result so far for a gene-based vaccine against any human pathogen.

Because researchers do not know what approach will ultimately work, multiple strategies have to be pursued. “There is no vaccine against parasitic diseases,” said Richie. “No one has ever made one successfully and got it licensed, so we don’t know what approach is the best approach.”

In addition to the technical difficulties faced in malaria research, money remains a challenge. The military receives about $8 million from the Military Infectious Diseases Research Program each year to spend on malaria vaccine research and attempts to stretch the limited resources through partnerships with industry and academia.

When the IoM reviewed the military’s malaria vaccine programs in 2006, it recommended that the military invest more into malaria vaccine research, noting in a report that the cost of developing a successful new vaccine ranges upward from a minimum of $300 million, spent over at least 10 years.

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