Front lines in the nano war
April 25, 2011
The enemy is stealthy. The enemy is lethal. The enemy is among us.
Invading its host, it employs every subversive strategy-evading surveillance, blending in. It travels swiftly and undetected, replicates by the thousands and eventually overwhelms its target. The enemy does not respect age or position. Smaller than bacteria, larger than a cell membrane, it is measured in nanometers, yet it can cripple a Soldier. It can destroy a body. It can hobble a nation.
It is a war as old as humanity. Infectious diseases account for one in every four deaths worldwide, taking their greatest toll in the overcrowded, unsanitary Third-World megacities. Among the host of microscopic man-killers, HIV, malaria and dengue claim the most lives. They destroy families and communities and devour precious resources.
Historically, the world\'s armies have been both the primary carriers and victims. The 430 B.C. Plague of Athens killed 30,000 of that city's residents-including Pericles, its leading statesman and general-and contributed to Athens' ultimate defeat in the Peloponnesian War. During World War I deploying Soldiers carried the Spanish flu to the very ends of the earth-the disease killed 50 to 100 million people. Malaria was the No. 1 cause of medical disability in Vietnam. More recently, up to 100 military personnel contracted malaria each year between 1995 and 2002. From June to September 2002 alone, 38 of 725 Army Rangers deployed to eastern Afghanistan contracted malaria.
Drawing on such lessons, military researchers have long sought to treat and/or prevent infectious disease. The Department of Defense continues its work to develop vaccines against these virulent viruses, bacteria and parasites.
Human immunodeficiency virus targets immune system cells. As it spreads, the immune system weakens, making the host more vulnerable to infection. An HIV-positive person can develop AIDS up to 15 years after contracting the virus. HIV is transmitted through unprotected sex, contaminated blood transfusions, contaminated needles or from mother to child during pregnancy, birth or breastfeeding. HIV affects more than 33 million people worldwide, posing a serious threat to deployed Soldiers and entire nations' stability.
The U.S. Military HIV Research Program at the Walter Reed Army Institute of Research in Silver Spring, Md., is on the front line of Army-based HIV research. Working with affiliated researchers in Nigeria, Kenya, Uganda, Tanzania and Thailand, MHRP seeks to develop an HIV vaccine, as well as preventions, diagnostics, treatments and monitoring to protect U.S. troops and reduce the impact of HIV infection worldwide.
"I know many people living, or who had lived, with HIV/AIDS," said Col. Nelson L. Michael, director of MHRP and WRAIR's Division of Retrovirology. "Prior to 1995, there was little we could do for our patients, and this was heart-wrenching, watching them ultimately succumb to rare infections and cancers. While HIV/AIDS remains an incurable disease, we can do much more for our patients and extend their lives for many years. In our programs in Africa we are just beginning to see the positive effects of more effective therapy, but we have a very long road ahead of us."
Michael points to HIV/AIDS and malarial research program successes in Tanzania, where MHRP leaders meet regularly with President Jakaya Kikwete.
"Our clinical research sites have become model programs for successful international collaborations and sustainable capacity building. President Kikwete has visited our site in Mbeya, and he visited WRAIR in 2009," said Michael.
In Thailand, from 2003 to 2006, more than 16,000 men and women participated in the RV144 Phase III clinical trial of the HIV investigational vaccine, a promising multinational research effort. "RV144 showed for the first time that a vaccine is able to reduce the risk of HIV infection in humans," explained Michael. "Although our results were modest, they are providing a great deal of information to inform the field. For example, the protection appeared highest at six to 12 months, based on post-hoc analysis. If we can sustain or increase this effect, that would be a great accomplishment."
MHRP is also working with the National Institutes of Health and Harvard researchers, respectively, on two other promising HIV vaccine candidates. Michael remains optimistic.
"This is a very long fight," he said. "Nobody had ever made a vaccine against a chronic viral illness, let alone a retrovirus that incorporates itself into our genes. It took nearly 25 years to see the first success in Thailand. The history of all vaccine research is typified by such a long and expensive development period, but initial success is usually followed by a much more accelerated pace of development."
Each year, malaria infects more than 500 million people, killing between 1 and 3 million, mostly children. Found in nearly half the world's countries, the mosquito-borne disease is especially prevalent in tropical and subtropical climates, with Sub-Saharan Africa alone accounting for 90 percent of all cases. From initial infection, symptoms progress from shaking and chills to high fever and severe headache; latter stages are marked by a drop in body temperature, profuse sweating, coma and death.
Now in cooperation with the Navy, WRAIR's U.S. Military Malaria Vaccine Program has been spearheading malarial research for the past quarter century, though the threat to U.S. Soldiers stretches back to the Revolutionary War.
"During pretty much every war, a threat has impacted military operations," said Col. Chris Ockenhouse, MMVP program director. "And even today, depending on where we operate, malaria could be an evolving threat. There's malaria on the Korean Peninsula, up along the DMZ, and we're continually affected with malaria in our operations in Afghanistan."
MMVP researchers are working to develop a vaccine for the two most common forms of malaria-Plasmodium vivax and its more lethal cousin Plasmodium falciparum. The program covers every step in the process, from basic research and identification of vaccine components to the prototype stage and eventual manufacturing at an Food and Drug Administration-approved factory.
"We take those vaccines to our clinical trial center in the WRAIR," explained Ockenhouse. "There we do a Phase I study, usually looking at safety, and a Phase II study, where we actually expose individuals to infected mosquitoes-always under approved clinical protocols that undergo (the) highest ethical review. Then we bring these military and civilian volunteers to a local hotel and monitor them every day for the development of malaria symptoms or the parasite in the blood."
MMVP is currently field testing RTS,S, a vaccine co-developed with GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative, funded through the Bill & Melinda Gates Foundation. "When we started developing this vaccine here about 15 years ago, it gave us about 50 percent efficacy-not high enough for the military, which requires an efficacy of around 80 percent that lasts for one year," said Ockenhouse. "But it's now in a Phase III test with 16,000 infants in Africa, which is the final test before licensure."
Such strides are what motivate Ockenhouse and the MMVP team to continue work toward a vaccine with military applications. "We are very, very dedicated and have a passion about developing a malaria vaccine, not only as a benefit to the U.S. military, but also as a benefit to global public health."
Each year Dengue fever, another mosquito-borne virus, strikes 50 million people worldwide. Mild cases, usually limited to infants and young children, are marked by a nonspecific febrile illness. Older children and adults develop more moderate symptoms, including high fever, severe headaches, rash and muscle and joint pain-hence dengue's nickname, "breakbone fever." Severe cases can downspiral into dengue hemorrhagic fever, with high temperature, hemorrhaging and even circulatory failure.
This year marks the 50th anniversary of the Armed Forces Research Institute of Medical Sciences, a pioneer in dengue research, jointly operated by the U.S. Army and the Royal Thai Army.
"Look at the reports from World War II. They were losing hundreds of guys every day-not dying, but they were just too sick to fight," said Lt. Col. Stephen Thomas, director of Dengue Vaccine Development for AFRIMS. "It's a very significant threat, not just for the military, but also for the United States. We constantly have cases on the Texas border, and we had an outbreak in Hawaii in 2001. Our Southern states and warmer states can support the mosquito, the virus, so this is a big problem. For the military it's the No. 2 infectious disease threat. Malaria's No. 1."
AFRIMS researchers have partnered with Sanofi Pasteur to test ChimeriVax, a tetravalent vaccine against all four strains of dengue. It's a genetically modified organism, which comes up in regulatory scrutiny that's very, very intense. "We're providing two (of several) sites that are involved in the Phase III vaccine trial," explained Thomas.
If the trial is successful, ChimeriVax will be headed for licensure in 5 years.
"It'll probably be the first vaccine that does get licensed," said Thomas, "and it'll be licensed for kids in an endemic country."
Like the other program directors, Thomas points to the tremendous costs and time commitment involved in getting a vaccine to market. But he, too, remains upbeat about their progress. "We've been working a long time on it, we've got a lot of subject matter expertise, and we're at an exciting time in vaccine development.
"It's like a 10,000-piece puzzle," he said. "Over the past seven or eight years I've been watching people find two pieces that belong together, confirming hypotheses and suspicions across different groups and developments. One by one these pieces are being put together. That's exciting, too."
WRAIR and its affiliated programs continue to develop vaccines and other countermeasures, working at the nano level to confront the global threat posed to warfighters and civilians by HIV, malaria, dengue and other infectious diseases. The researchers' strength lies in military rigor, from the preclinical stages through vetted, multiphase clinical trials.
Perhaps no one appreciates the threat and that rigorous response more than Col. Arthur Lyons, chief of the Clinical Research Department in WRAIR's Division of Viral Diseases. "Historically, more military personnel have been taken out of the mission by noncombat threats like diseases," he explained. "Because of the myriad issues that need to be overcome, it takes real commitment to shepherd a vaccine candidate from drawing board to licensure. Regulatory, local, state, federal, DOD and other institutional requirements must be met before any product is approved for general use.
"This has truly been a team effort," Lyons said. "All departments and divisions at WRAIR and the command leadership have been instrumental in the success of these projects."
Jill Lauterborn works for the U.S. Army Medical Research and Materiel Command.