120 Years of Advances for Military and Public Health

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120 Years of Advances FOR

MILITARY AND PUBLIC HEALTH

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ClinicalRM Congratulates The Walter Reed Army Institute of Research on 120 Years of Advances for Military & Public Health!

We are honored to have been a part of your past successes, part of your present ventures, and we look forward to working with you on your future endeavors.

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“The men and women who work at the WRAIR are some of the most passionate researchers I know. Their commitment and dedication to our soldiers and their mission is exceptional. I’m proud that our organization has been chosen to work with them for nearly two decades.”

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WRAIR PHOTO

Congratulations to WRAIR on your 120-year anniversary of providing valuable research and for being a key partner in vaccinology, including HIV, malaria, Shigella, Japanese encephalitis, dengue, meningococcal meningitis, influenza and other new and improved vaccine projects!

120 years of advances for military and public health

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TABLE OF CONTENTS

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A CONVERSATION WITH COL STEVEN E. BRAVERMAN, M.D., COMMANDER, WALTER REED ARMY INSTITUTE OF RESEARCH

By Craig Collins walter reed army institute of research A brief history

By Craig Collins to catch a virus “Fear or Terror on Every Countenance: Yellow Fever”

By John Booss and Marilyn J. August overseas commands

By J.R. Wilson

more on research AND missions

By J.R. Wilson

THE CENTER FOR INFECTIOUS DISEASE RESEARCH Leading the fight against the Army’s – and the world’s – deadliest adversaries By Craig Collins the center FOR MILITARY PSYCHIATRY AND NEUROSCIENCE To protect and promote Soldier resilience, CMPN researchers focus on both body and mind. By Craig Collins partnerships & collaborations

By J.R. Wilson

contents

Celebrating Our Shared Mission

For 120 years, the Walter Reed Army Institute of Research has advanced military medical science to benefit warfighters and the public alike. The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. is proud to serve as a partner in your groundbreaking work. At WRAIR, we support research on a wide range of medical science, including infectious diseases such as HIV/AIDS and malaria, emerging infectious diseases, neuroscience, and psychological health.

Your excellence in serving America’s armed forces and advancing military medicine inspires us in our shared mission. We stand ready to support you for the next 120 years ‌ and beyond.

Advancing Military Medical Research HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE 6720A Rockledge Drive | Suite 100 | Bethesda, Maryland 20817 | 240-694-2000 | HJF.org The Walter Reed Army Institute of Research did not select or approve this advertiser and does not endorse and is not responsible for the views or statements contained in this advertisement.

120 Years of Advances for

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Tampa, FL 33609 Tel: 813.639.1900 www.faircount.com

Cover photo credits: NIAID, Sgt. Eric Provost/U.S. Army, U.S. Navy, and WRAIR

EDITORIAL Editor in Chief: Chuck Oldham Managing Editor: Ana E. Lopez Project Editor: Iwalani Kahikina Editor: Rhonda Carpenter Photo Editor: Steven Hoarn Contributing Writers: Craig Collins and J.R. Wilson DESIGN AND PRODUCTION Art Director: Robin K. McDowall Designers: Daniel Mrgan Lorena Noya, Kenia Y. Perez-Ayala Ad Traffic Manager: Rebecca Laborde ADVERTISING Ad Sales Manager: Ken Meyer Account Executives: Kevin McTernan, Bonnie Schneider, Robert Swartout, Russ Titsch, Geoffrey Weiss OPERATIONS AND ADMINISTRATION Chief Operating Officer: Lawrence Roberts VP, Business Development: Robin Jobson Business Development: Damion Harte, Kevin Higgins Financial Controller: Robert John Thorne Chief Information Officer: John Madden Business Analytics Manager: Colin Davidson Circulation: Alexis Vars Events Manager: Jim Huston FAIRCOUNT MEDIA GROUP Publisher, North America: Ross Jobson Publisher, Europe: Peter Antell

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A special thanks to the Walter Reed Army Institute of Research’s leadership for their time and guidance in the preparation of this publication.

©Copyright Faircount LLC. All rights reserved. Reproduction of editorial content in whole or in part without written permission is prohibited.

Faircount LLC does not assume responsibility for the advertisements, nor any representation made therein, nor the quality or deliverability of the products themselves. Reproduction of articles and photographs, in whole or in part, contained herein is prohibited without expressed written consent of the publisher, with the exception of reprinting for news media use. Printed in the United States of America. Permission to use various images and text in this publication was obtained from the Walter Reed Army Institute of Research or U.S. Department of Defense and its agencies, and in no way is used to imply endorsement by the Walter Reed Army Institute of Research for any claims or representations therein. Contents of this publication are not necessarily the official views of, or endorsed by, the U.S. government, U.S. Department of Defense, Walter Reed Army Institute of Research, or U.S. Army. The appearance of advertising in this publication does not constitute an endorsement by the Walter Reed Army Institute of Research or the contractor of the firms, products, or services advertised. This is not a publication of the U.S. Department of Defense or U.S. government.

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120 YEARS OF ADVANCES FOR MILITARY AND PUBLIC HEALTH

A CONVERSATION WITH COL STEVEN E. BRAVERMAN, M.D., COMMANDER, WALTER REED ARMY INSTITUTE OF RESEARCH

By Craig Collins On June 25, 2013, COL Steven E. Braverman assumed command of the Walter Reed Army Institute of Research (WRAIR). With degrees from the University of Virginia, the National Defense University, and Vanderbilt University, COL Braverman began his medical career at Fort Gordon, Ga., in 1987, moving a year later to the Walter Reed Army Medical Center in Washington, D.C., where he eventually became chief of the Physical Medicine and Rehabilitation (PM&R) Service and director of the PM&R Residency Training Program. In 2000, he became the deputy commander for clinical services at Moncrief Army Community Hospital, Fort Jackson, S.C., followed by an assignment as command surgeon for the National Defense University. After attending the National War College for a year, he commanded the Fort Knox, Ky., U.S. Army Medical Department Activity and Ireland Army Community Hospital from 2005 to 2007.

From 2007 to 2009, COL Braverman served as chief of the Clinical Services Division at the U.S. Army Medical Command, deputy director of Health Policy and Services at the Office of the Surgeon General, and chief consultant to the Army Surgeon General. He deployed to Iraq, from October 2008 to April 2009, as the Multi-National Corps-Iraq Deputy Surgeon for Clinical Operations. After his deployment, from 2009 to 2011, he commanded the Carl R. Darnall Army Medical Center, Fort Hood, Texas. Before taking over leadership of WRAIR, COL Braverman served as the Medical Corps deputy chief and Corps Specific Branch Proponent Officer.

COL Braverman has been awarded the Legion of Merit, Defense Meritorious Service Medal, Meritorious Service Medal, Army Commendation Medal, Army Achievement Medal, and Iraq Campaign Medal. He has received the “A” designator award for professional expertise, the Order of Military Medical Merit, and the General Claire L. Chennault Award for teaching excellence.

Craig Collins: Over the past 120 years, the Army’s Medical Research and Materiel Command has been reorganized and reshuffled multiple times, with laboratories and offices being terminated, recombined, or reshuffled. WRAIR has not merely survived these changes – it’s thrived. It’s as important now as ever. Why has it had such staying power?

COL Steven E. Braverman: I think there are a few things that really distinguish WRAIR. One is its long history. When you have an institution – not just an institute – it earns a reputation over time. And we have a worldwide reputation as an organization that is providing both basic science and clinical research, and translating the research into

COL Steven E. Braverman, M.D., commander, Walter Reed Army Institute of Research. U.S. Army photo

biomedical products – equipment, or medications, or vaccines – valuable not only to the military but also to global health.

And, in fact, several of our OCONUS labs, the labs outside the continental United States, have close ties with academic institutions, and in some cases commercial enterprises, and that has made a difference in building capacity and capability in countries on every continent except Antarctica. The agreements under which we conduct research in those labs require that the work benefits the participating populations – so when we do research in our primary labs in Kenya and Thailand, or in

120 YEARS OF ADVANCES FOR MILITARY AND PUBLIC HEALTH

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The U.S. Military HIV Research Program works closely with the Armed Forces Research Institute of Medical Sciences in Bangkok, Thailand. U.S. Army photo

Tanzania, or Uganda, or Nepal, or any of our other various clinical sites, their people benefit from that work.

In those countries, we’re known as the Walter Reed Program [for malaria work] or [as the Walter Reed] Project [for HIV work], named for MAJ Reed, who established the mosquito as the yellow fever carrier and laid the groundwork for the yellow fever vaccination.

But since Reed’s discovery, the institute has added a few layers to that capacity – to translate research into products with the potential to save lives.

Right, and this really hit home for me when we held ceremonies to observe World AIDS Day. We had a couple of speakers here, one of whom was Dr. Edmund Tramont, who was more or less the founder of WRAIR’s effort in the Military HIV Research Program. Another was Dr. Mary Marovich, who now heads the vaccine research program at the National Institute of Allergy and Infectious Diseases.

Both of them were former WRAIR senior scientists here. One of the things that really stood out was that some of the improvements in the development of treatments or vaccines – including developments that happened outside of WRAIR, or in partnership with federal interagency organizations, commercial or private-sector partners – happened because of the clinical trials networks that we established through WRAIR and our labs in Kenya and Thailand to test these products, some of which were developed at WRAIR, but most of which were developed in collaboration with other organizations.

In some ways, our nation’s ability to participate in this research is reliant on the infrastructure we’ve set up through the military, to do the research necessary to protect our Soldiers. That infrastructure has attracted funding from the President’s Emergency Plan for AIDS Relief, or PEPFAR. We receive support from the Gates Foundation to support research not only with HIV, but also with malaria and dengue fever, which are diseases of great concern to the military because

INTERVIEW

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120 years of advances for military and public health

Top: The Richard G. Lugar Center for Public Health Research is a state-of-the-art medical research facility constructed by the U.S. Department of Defense, Defense Threat Reduction Agency, as part of its collaboration with the Georgian Ministry of Defense. The U.S. Army Medical Research and Materiel Command is establishing a U.S. Army Medical Research Unit as a tenant organization in the Lugar Center at the request of the Georgian government in order to collaborate on public health research. U.S. Army photo by Lt. Col. Jamie Blow Above: Simba Mobagi (right), a lab technician with Kenya’s Rachuonyo District Hospital, works with U.S. Army Maj. (now Lt. Col.) Eric Wagar to accurately diagnose malaria in blood samples. U.S. Army photo by Rick Scavetta

Soldiers go into endemic areas in the Pacific region. Our ability to provide the network to do the clinical trials helps us to partner with these other organizations to make a bigger impact than we could if we were trying to do it alone.

Malaria is a perfect example, actually, of how we’re necessary to this capability, providing both clinical products, such as medications or vaccines, and well as preventive products, such as pesticides, repellents, or netting – or anything else that will keep mosquitoes away from you. We’ve developed products in each of those categories.

Another thing that’s unique to us is our malaria challenge model. We’ve developed a population of mosquitoes that we can infect with the malaria parasite, and then we have people who volunteer to come in and stick their arm over a box to be bitten by five infected mosquitoes. We watch and see what happens – they may have received an experimental treatment or vaccine before becoming infected – to determine whether we might have prevented an infection. We may not have developed all the medications or vaccines being tested, but we developed the model that facilitates the ability to do some of that in-lab testing before it goes to larger clinical trials.

It was through one of our challenge-model trials, incidentally, that we discovered that some people have a genetic mutation that reduces the effectiveness of an important class of malaria medications, because their livers don’t metabolize it as expected. Before, that had been a big unknown – did the medication not work because the malaria parasite developed resistance to the medication, or because the medication didn’t work on the same old parasite? Our continued ability to test and do the bench research proved it was a genetic mutation that caused the medication not to be broken down into a metabolite that kills the malaria parasite.

The next step for those researchers will be to identify ways to make the metabolite, instead of relying on the parent medication. Is there a way for a different body organ to break down the medication into the metabolite, or are there other medicines, in a whole different chemical class, that could work by bypassing the liver? These are questions generated as a direct result of working with our challenge model.

120 YEARS OF ADVANCES FOR MILITARY AND PUBLIC HEALTH

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Laboratory technician and microscopy student Ekanaeli Mshana, from the Tanga region in Tanzania, focuses the lenses of a microscope over a slide with malaria parasite-infected blood cells during the counting pre-test session Nov. 23, 2009, in the lab of the National Reference Laboratory and Quality Assurance Training Center. U.S. Africa Command’s Combined Joint Task Force-Horn of Africa, in cooperation with the U.S. Army Medical Research Unit-Kenya and their Kenyan partners, the Kenya Medical Research Institute, were conducting a medical engagement to provide a two-week basic malaria microscopy training to medical laboratory technologists from the region. Photo by MCC Robert Patrick Gallagher

Does the work of other WRAIR researchers have similar translational benefits? One of the institute’s most talked-about innovations is the creation of the Mental Health Advisory Teams (MHATs), which have been forward deployed to Iraq, Afghanistan, and Africa periodically since 2003.

The methodology used by those researchers – which is aimed at collecting behavioral and mental health information about subjects in real time – is not unique to the military. It’s applicable to many kinds of behavioral studies. What’s distinctive about the MHAT – and the results of our ninth MHAT were just recently reported – is that we can help identify what’s going on with Soldiers in a theater environment, and also in some cases how programs launched in response to earlier findings have made an impact on things like resiliency, family stressors, divorce rates, unit cohesion, multiple deployments, and small unit leadership.

What’s been unique about this opportunity is that as we’ve gone through the years, both in Iraq and Afghanistan, and evolved through the time lines of events in those countries, we’ve been able to connect that work with research unfolding in the states, to get information that can inform policy and programs. The MHATs give us the ability to determine, in real time, how well we’re doing with the prevention and treatment of war-related concerns. We can use those same processes in the United States and take a look at what is happening at units in places like Fort Hood, as well as in places like Germany.

Right now, for example, as we draw down in Europe, we’re looking at a study with some units in Germany on the effect of unit movements and changes in morale, capability, and cohesion. We can study that there, and we can also look into the stressors associated with being located near the DMZ [demilitarized zone] in Korea, where there are constant tensions and family separations.

INTERVIEW

120 YEARS OF ADVANCES FOR MILITARY AND PUBLIC HEALTH

So the MHATs give us an opportunity, and a process, to answer questions that have arisen regarding the effects of war – and some of these questions have never been asked before. Never in our nation’s history have we been at war for 12 years. We’ve never had situations where folks have deployed so many times, and so frequently.

In addition to the psychological toll of multiple deployments over a long period of time, the conflicts in Iraq and Afghanistan also have their signature physical wound – the traumatic brain injury (TBI). How have WRAIR researchers stepped up to help Service Members – either to prevent head trauma or treat an injury?

At our neuroscience branch, much of the research is focused on studies of animal models to identify the effects of concussion and more severe brain injury. Researchers are also working to identify the biomarkers of brain injury, which have implications not only for diagnosis, but also perhaps for treatment of TBI as well.

One of the biggest challenges right now for military medical personnel is that a lot of symptoms associated with PTSD [post-traumatic stress disorder] are similar to the symptoms associated with concussion – and yet treatments for PTSD or depression and treatments for concussion would likely be different if you could tease apart the causes. In some cases, they’re multi-factorial. But if we can get diagnostic tests that can help us more specifically identify the causes of those symptoms, this can lead to better treatments.

We can also demonstrate that treatments are effective by correlating changes in these biomarkers that we can find in the bloodstream, with clinical improvement. We can take that information, share it with our partners who are conducting clinical research on treatment paradigms, and eventually help our military folks – and then ultimately, the civilians as well who get head injuries from accidents and other traumas.

One of the things we’ve learned is that head injuries from blasts are different from head injuries caused by falls, blunt trauma, or the acceleration associated with things like car accidents. It probably took us six to eight years to prove that and agree on that. And that means the research we’ll be doing should be focused on those kinds of injuries – the blast injuries more common to military personnel – but by the same token, it will translate overall to the field of general brain injury research.

It’s interesting to look over the past decade and see how the nature of the conflicts in Iraq and Afghanistan, and their effects on an all-volunteer force fighting for more than a decade, have altered the way WRAIR is organized and operates. We’re headed into a new period of transition – a drawdown, accompanied by a period of certain fiscal constraint. WRAIR has always evolved to meet the Army’s mission – how do you think it will continue to evolve in the coming years?

Well, certainly we’re already evolving in very specific ways. As new priorities come into play, we have to be flexible and adaptable enough to provide research that supports the investigations and/or treatments associated with those priorities. For example, one of the priorities we have now has been established by the Army Surgeon General and also by the Assistant Secretary of Defense for Health Affairs. And that is that our military health care system will focus on the overall health of the Soldier and their Families and not just specific combat-related injuries or disorders.

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The Surgeon General has put together a program to develop a system of health focused on a vision she calls “the Performance Triad,” composed of activity, nutrition, and sleep. The research out there on sleep – much of which has been performed or supported by researchers in our own Behavioral Biology Branch – has demonstrated a clear link between sleep and performance. But there is also research out there that suggests if you sleep more, your risk of becoming obese decreases.

You’ll actually lose weight if you sleep more.

WRAIR fits right into the Surgeon General’s vision. We’re the Army’s primary sleep research facility, investigating the effects of sleep, how to improve sleep, the obstacles to good sleep. We’ve developed a product, a caffeinated gum, used by Service Members to improve alertness and performance and overcome sleep deprivation in the short term. That’s an example of how we adapt to new priorities that arise. We may not ever have thought of the need to develop a product like that if we hadn’t been doing unit-based research, and discovered its importance to the war effort.

Through our MHATs, we’ve also identified small unit leadership as a key determiner not only of the behavioral and mental health of Service Members, but also of the willingness of unit members to seek mental health care. We’ve helped the Army put programs in place to train leaders to avoid stigmatizing unit members who seek help. And so it seems fair to say we’re helping to reduce future barriers to care for Soldiers and their Families who look to improve their overall health, rather than limiting our focus to deployment-related health problems.

Now in terms of fiscal constraints, the future looks challenging. We’re looking at an uncertain environment with sequestration, budgetary restrictions, and personnel drawdowns in a postwar period. But we’ve always worked with partners, both in government and the private sector, who have helped to encourage and support our research through grants, MOUs [memorandums of understanding], or other cooperative agreements. That extramural funding is critical to our effort. We receive a lot of funding to do some of these research programs from our external partners to perform collaborative research. We always make sure that the research that is being done fits within the mission of the WRAIR and what the Army needs. But we partially rely on external funding sources to accomplish the things that we do.

Do you foresee that WRAIR and other military medical researchers will have to rely more on external funding in the future, just to maintain continuity? I know some programs – such as WRAIR’s leishmaniasis laboratory, the only one of its kind – have been scuttled in the past, only to be hurriedly reactivated once personnel were deployed to endemic areas.

Well, if our core appropriated funds are decreased, then there will be a corresponding decrease in the amount of research and productivity we can provide, of course. We’ll then have to make choices as to which research gets higher priority for funding. And in some cases, I suppose we could make up for a funding shortfall through continued work with our external partners – though certainly there are many items in our budget that can only, by statute, be paid with appropriated funds.

In other cases, we would make a deliberate decision to decrease the research effort in one area, and increase it in another, but leave enough of the expertise available so that it could be ramped back up if the prioritization changes.

INTERVIEW

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120 YEARS OF ADVANCES FOR MILITARY AND PUBLIC HEALTH

U.S. Army Soldiers with Company C, 2nd Battalion, 30th Infantry Regiment, from Forward Operating Base Torkham, Nangarhar province, Afghanistan, conduct a dismounted patrol from one of their observation points to an Afghan Border Police checkpoint, Nov. 18, 2013. Mental Health Advisory Teams, which are deployed to Afghanistan, have determined that small unit leadership is a key determiner of the behavioral and mental health of Service Members.

U.S. Army photo by Sgt. Eric Provost

One of the things we really have to look out for is the loss of civilian scientists in our workforce. We need to maintain our scientific expertise in order to sustain our working relationships with those external partners.

So given these challenges, do you think WRAIR’s work – which has been so influential, bringing about historic changes in military medical research and the delivery of care – will continue to be as important to the Army, and to the United States, in the future?

Among other things, I think the OCONUS labs – which were established out of necessity, because our researchers needed access to the places where these diseases existed in order to do research – will be key to our continued importance. When we made it a requirement that any research we conducted in those areas would also benefit those populations, we enabled our partners to build scientific and medical capability and capacity.

The majority of the people who are working for us now in Thailand, for example, are Thai nationals who have been with us, in some cases, for close to 50 years. They’ve increased their capacity and capability through their universities, and built networks of their own. The same thing happens when we work in Cambodia, or in the Philippines, or in some of the African nations where we do HIV and malaria research.

And it has made a difference. It adds to medical diplomacy – we are closely embedded, in some cases, with the embassies in those countries, and identify the overall diplomatic benefit to participating in some of this research.

The other thing to remember about the relationships we build internationally is that the clinical discoveries we’re hoping to enable not only make a difference to people in that part of the world – they make a difference to U.S. military Service Members. Our Soldiers who are going to get infected if they’re deployed to those parts of the world are going to be infected with the diseases endemic there – malaria and dengue, for example. Dengue virus has four subtypes, and we’ve only been able to develop vaccines specific to a subtype.

If it weren’t for the military relevance of these research programs, some probably wouldn’t have much relevance in the United States at all – for example, malaria isn’t a big threat inside the United States, nor is leishmaniasis, unless someone sick travels back to the U.S. from an endemic area. There wouldn’t be a lot of interest from the big pharmaceutical companies to research medications and vaccines for these diseases, because there’s no market for them. When we – WRAIR and our partners – start to develop products that will help protect our Soldiers, we’re setting in motion events that have the potential to save or improve millions of lives.

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120 YEARS OF ADVANCES FOR MILITARY AND PUBLIC HEALTH

THIS PAGE: Predecessor to the Walter Reed Army Institute of Research, the U.S. Army Medical School was established in 1893. National Library of Medicine photo OPPOSITE: Walter Reed at 26. Reed completed his first M.D. degree at age 18.

Walter Reed Army Institute of Research photo

120 YEARS OF ADVANCES FOR MILITARY AND PUBLIC HEALTH

WALTER REED ARMY INSTITUTE OF RESEARCH A BRIEF HISTORY

By Craig Collins

T

he Walter Reed Army Institute of Research (WRAIR) is today the cornerstone of a research apparatus that, since World War II, has been organized – and reorganized – into a network of distinct installations, each reporting to the U.S. Army Medical Research and Materiel Command’s (USAMRMC’s) commanding general at Fort Detrick, Md. But these lines of command haven’t always been so clearly drawn.

In the late 19th and early 20th centuries, the Army’s medical research was conducted by scientists who reported directly to the Army surgeon general, and who moved fluidly from one assignment to another among units under his command. In January 1893, Brig. Gen. George M. Sternberg, the Army surgeon general – a physician remembered today as the nation’s first bacteriologist – established a new duty station: the Army Medical School.

At the first school of public health and preventive medicine in the United States, Army medical officers were trained in the art and science of military medicine, focusing primarily on the prevention of infectious disease – which was, at the time, the most significant threat to Soldiers’ health.

As its name implies, the Army Medical School was primarily an educational institution, with a research function far subordinate to its teaching mission – though its students learned from the service’s most talented and accomplished medical researchers, many of whom are celebrated today for their work in the laboratory and the field.

When Soldiers were dispatched to the Caribbean and Pacific tropics during the Spanish-American War, for example, Sternberg assigned his Army researchers to investigate the tropical diseases that confronted them.

In 1898, the Typhoid Board, led by the Army Medical School’s first dean, Maj. Walter Reed, established the mechanism of this disease’s transmission and established sanitary protocols that helped prevent outbreaks in Army camps. In 1909, Maj. Frederick F. Russell, an Army Medical School professor of bacteriology, developed America’s first typhoid vaccine. A year later, Army Medical School professor of chemistry Maj. Carl Rogers Darnall invented the liquid chlorine method of water purification now applied to municipal water supplies around the world.

Two years after the Typhoid Board’s discovery, Reed and other members of the Yellow Fever Commission, along with Cuban researcher Carlos J. Finlay, established that this deadly hemorrhagic disease was caused by the

A BRIEF HISTORY

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Maj. Walter Reed was instrumental in defining the concept of mosquitoes transmitting disease, specifically yellow fever, an idea that allowed Col. William C. Gorgas (above) to abate the transmission of yellow fever and malaria during the construction of the Panama Canal. Photo courtesy of National Library of Medicine

first known human virus, and confirmed the mosquito as the infecting agent – a discovery later used by Col. (later Maj. Gen.) William C. Gorgas to control yellow fever and malaria among workers building the Panama Canal.

The Philippine Tropical Disease Boards that began work in 1899, investigated a range of diseases and health problems, many of them in the urban environment of Manila; in 1907, Capt. Percy M. Ashburn and Lt. Charles F. Craig announced one of the most noteworthy discoveries to come from this work: Dengue fever was also caused by a virus. Nearly two decades later, Lt. Col. Joseph F. Siler confirmed the female mosquito as the vector for the dengue virus.

Lt. Col. Edward L. Munson, whose assignments included a stint as a professor of hygiene at the Army Medical School, led the Army Shoe Board, convened at Fort Leavenworth, Kan., in 1908 to design a better military shoe, using an X-ray machine and the feet of the fort’s 4,000 infantrymen. The new design, the “Munson last,” protected and supported the entire foot, and was used exclusively on all military shoes until the late 1960s.

Until 1910, the Army Medical School was housed in the Army Medical Museum and Library building – the “Old Red Brick” – on the National Mall, where the Smithsonian Institute’s Hirshhorn Museum now stands. It moved locations twice more before 1923, when it was renamed the Army Medical Department Professional Service School

(MDPSS) and moved into Building 40, on the campus of the new Walter Reed General Hospital in Washington, D.C., where it would remain for another seven decades.

Between World Wars I and II, the research mission of the MDPSS expanded to include the study of typhus and other rickettsial diseases, malaria, combat stress, chemical weapons countermeasures, battle wound treatment, and military dentistry. In 1933, the Army’s research board in Panama conducted the first American studies on the effectiveness of quinacrine, a synthetic quinine compound, as a prophylactic drug against malaria. During World War II, when Germany’s conquest of the Netherlands and Japan’s control of Indonesia cut Allied powers off from 97 percent of the world’s quinine production, quinacrine became the Army’s standard antimalarial agent, and remained so until the 1950s, when it was slowly replaced by chloroquine.

A RESEARCH INSTITUTE In 1941, with Soldiers and Marines once again fighting in the tropics, the MDPSS offered a 30-day Tropical Medicine Course, including both lecture and laboratory elements, to about 30 officers. This course – one of the institute’s longest-running programs – has evolved over the past 70 years, but remains one of WRAIR’s highest-profile products. The institute’s wartime work in tropical medicine – along with several other Army

A BRIEF HISTORY

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research advances during World War II, including new methods for collecting and shipping blood and refined diagnoses and nomenclature for combat stress-related disorders – helped convince Army leadership to emphasize the school’s research function. In 1947, it was accordingly renamed the Army Medical Department Research and Graduate School.

In the early 20th century, the model for American medical education had been evolving, with the hospital – in the Army’s case, Walter Reed General Hospital – increasingly at the center of a surgical student’s learning experience. Dale C. Smith, Ph.D., a military medical historian at the Uniformed Services University of the Health Sciences, explained that the separation of medical instruction into the “professional” and “graduate” levels compelled the faculty in Building 40 to focus more on research, especially during World War II. “By the mid-50s,” said Smith, “most of the education was taking place over in the hospital, with young physicians in residency. And what was left in the buildings that had been the Army Department Medical Research and Graduate School was now a research institute and reference center for non-routine hospital diagnostics, especially for viral and rickettsial diseases.” This transformation was formalized in 1954, when the institute, its research work consolidated in Building 40, was renamed the Walter Reed Army Institute of Research.

The Korean War – the first armed conflict of the Cold War – had confronted the institute with several new realizations that led to the rapid development of WRAIR research programs in the 1950s and 1960s: First, Soldiers there encountered a new disease called Korean

hemorrhagic fever, one of the first known hantavirus diseases. “It was then that we realized,” said Smith, “that we had to do research on diseases all around the world.”

In many cases – especially among those who had been prisoners of war – Soldiers in Korea also suffered a variety of psychological traumas. WRAIR responded deftly to these new challenges. While expanding its focus on infectious disease research, both stateside and in the U.S. Army Medical Research Unit-Malaysia, the institute also established a Division of Neuropsychiatry to investigate the Army’s ability to deal with Soldiers’ psychological health.

The institute’s singular focus on research freed WRAIR scientists to become more expeditionary. The Armed Forces Research Institute of Medical Sciences (AFRIMS) in Bangkok, Thailand, a joint ThaiAmerican military medical research partnership, was established in 1958 when WRAIR researchers assisted in the response to a cholera outbreak in Southeast Asia. More than a decade later, WRAIR scientists responded to an invitation from the Kenyan government to undertake research into trypanosomiasis, a protozoan parasitic disease afflicting Kenyans in the Lambwe Valley. Both AFRIMS, particularly the U.S. Army Medical Component (USAMC)-AFRIMS to define the American unit, and the U.S. Army Medical Research Unit-Kenya (USAMRU-K) continue to operate today; the USAMCAFRIMS remains an active and productive joint installation, with programs in enteric diseases, malaria vaccine and drug research, viral diseases, entomology, and HIV/AIDS vaccine studies; while

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OPPOSITE: Megan Dowler, Mosquito Lab manager, preparing an assay. Walter Reed Army Institute of Research photo CENTER: The U.S. Military HIV Research Program works closely with the Armed Forces Research Institute of Medical Sciences (AFRIMS) in Bangkok, Thailand.

USAMC-AFRIMS photo ABOVE: U.S. Army medical researcher Maj. Eric Lee (left) and Kenyan lab technician Elizabeth Odundo examine diarrheal specimens at USAMRU-K’s Kericho Field Station laboratory. Photo by Rick Scavetta, U.S. Army Africa

USAMRU-K, the only Department of Defense (DoD) infectious disease research installation in sub-Saharan Africa, investigates a variety of tropical diseases under a cooperative agreement with the Kenya Medical Research Institute.

In 1958, WRAIR opened its Department of Biologics Research (later named the Pilot Production Facility) and began manufacturing vaccines and biological products for use in clinical trials that would result in the protection of Soldiers against diseases they might encounter in areas of deployment. The next few decades were a remarkably fruitful period for WRAIR vaccinologists, including Maurice Hilleman, who led the institute’s respiratory diseases department and developed or improved more than 25 vaccines in his career – including nine of the 14 now recommended for children.

“The work of WRAIR and the pharmaceutical industry, including the forerunner of Glaxo and Merck, for example,” said Smith, “gave us a host of vaccines against childhood diseases, including measles, mumps, rubella [MMR], chickenpox, [as well as] the adenovirus vaccine, hepatitis A and B [vaccines], the first and current Japanese encephalitis vaccine, and early pneumonia vaccine. As for Hilleman, Merck later hired him away to make all those vaccines available to American kids, and by the 1970s, you had a healthy, vaccinated all-volunteer Army that was simply not going to get sick with these diseases – with the glaring exception of malaria.” Dr. Leonard Binn, who worked with Hilleman and still volunteers at WRAIR today, fondly remembers the tremendous successes of the mid to late 20th

century. In 1985, Binn, Dr. Kenneth Eckels, and colleagues tested an effective hepatitis A vaccine formulation, with Col. Bruce Innis and other WRAIR scientists conducting efficacy studies in Thai children in 1991, resulting in the successful 1996 U.S. licensing of the first ever hepatitis A vaccine.

In 1962, the Army, with a goal of coordinating and possibly expanding military medical research laboratories in Southeast and East Asia, sent WRAIR researchers to evaluate the situation. The group’s recommendations led to cooperation with the Institut Pasteur in Saigon, Vietnam, and, in 1965, to the establishment of a WRAIR medical research unit in Saigon whose scientists initially focused on infectious disease, combat surgery, and military psychology. By the team’s third year of operation, individual members were launching their own studies and supporting the research of others, often through the collection of medical information or health data for WRAIR and other Army researchers. Team members also conducted field clinical trials for new disease-fighting drugs, including several antimalarials, coming out of the Army’s research pipeline. The Field Epidemiological Survey Team (FEST), a Special Forces contingent trained by WRAIR researchers in laboratory and epidemiological skills, gathered field data on a variety of diseases, including dengue fever, malaria, tropical sprue, febrile illness, and parasitic diseases such as schistosomiasis and filariasis.

As the Vietnam War escalated, the Army surgeon general, acting on the recommendation of WRAIR’s Saigon team, approved the establishment of a central hospital for malaria patients at Cam

A BRIEF HISTORY

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120 YEARS OF ADVANCES FOR MILITARY AND PUBLIC HEALTH

Ranh Bay. By 1968, the malaria microorganism – which develops drug resistance rapidly – had become the focal point of the largest single program of medical research in the Army’s history. By this time, nearly half the intramural research effort of the Research and Development Command was conducted by WRAIR scientists.

WRAIR’s Vietnam-era research, in addition to its expansive malaria program, covered a broad spectrum. It continued to study the prevention and treatment of other tropical diseases in Southeast Asia, and collaborated on the construction of a plague research laboratory that led to the production of a vaccine. To combat the incidence of bacterial and fungal skin diseases – which afflicted up to half of the men in some rifle companies in the Mekong Delta – WRAIR dispatched a field dermatology research team whose work led to the development of new footgear, protective ointments, and treatments for Soldiers.

In 1966, WRAIR’s Vietnam contingent added a Surgical Research Team that developed improved techniques for the treatment of battlefield trauma and shock, including field-adapted treatments for shock; polymeric tissue adhesives and hemorrhage suppressants; a quickcuring silicone material for stabilizing serious injuries to the mouth before evacuation; an ointment to protect burn victims from infection; and various methods for suppressing the body’s immune response to grafts and transplants. The group also studied innovations such as electrical anesthesia, synthetic blood vessels, plasma expanders, and new blood preservatives.

The minds of Soldiers were of great concern to WRAIR researchers during the Vietnam War. The work of Dr. David Marlowe laid the scientific foundation for future investigations into post-traumatic stress, while psychiatric researchers such as Dr. Harry C. Holloway and Larry H. Ingraham, Ph.D. – who later wrote The Boys in the Barracks, a landmark observation of Army life – investigated the rampant rate of substance abuse among Soldiers. By 1973, the Army estimated that just over a third of the U.S. Soldiers in Southeast Asia had commonly used heroin. After WRAIR scientists provided the DoD with its first valid data on the problem, the Army instituted a drug-screening program and a non-punitive approach aimed at helping users seek treatment, while preserving the Army’s fighting strength and combat effectiveness.

The psychosocial difficulties of Vietnam Soldiers led the Army to establish, in 1977, the U.S. Army Medical Research Unit-Europe (USAMRU-E) in Heidelberg, Germany, which was relocated to Sembach, Germany, with recent installation closures. This WRAIR special foreign activity, initially focused on the causes, cures, and prevention of psychiatric battle casualties, has since expanded its focus to facilitate resilience through investigations of the broad range of stressors acting upon – and the coping capabilities unique to – Soldiers, their Families, and their command units.

TRANSFORMATION The Cold War reached a peak of sorts in the 1980s: While there would be no more drawn-out proxy wars fought by troops in distant lands, there was a massive buildup of U.S. and Soviet nuclear arsenals, and a sustained effort to maintain military readiness as troops engaged in a series of limited, rapid deployments.

This effort required USAMRMC, anchored by WRAIR, to maintain its focus on research into diseases and disorders of military significance.

Dr. Maurice Hilleman (far left) shown with the staff of the Respiratory Disease Department of WRAIR. Walter Reed Army Institute of Research photo

Chief among these research efforts were programs aimed at vaccinations and treatments for infectious diseases, especially in tropical locations.

WRAIR and its overseas installations – USAMC-AFRIMS, USAMRU-K, USAMRU-Brasilia (operational from 1973 to 1999) and USAMRURepublic of Korea (1988 to 1993) – played a leading role in research aimed at a variety of diseases including Japanese encephalitis, malaria, hepatitis A, hantavirus, leptospirosis, typhus, ebola, and leishmaniasis.

The WRAIR/AFRIMS collaboration supported a U.S. Army efficacy trial of the first Japanese encephalitis (JE) vaccine, produced by the Biken Institute (Japan), which was licensed by the U.S. Food and Drug Administration based on this data. When this product was no longer available, a second generation JE vaccine, originating from WRAIR, was licensed in 2010, the product of a series of cooperative research and development agreements between WRAIR and industry partners. It is the only licensed JE vaccine currently available for U.S. citizens.

After the discovery of HIV/AIDS in the early 1980s, the Medical Research and Development Command was named the lead agency for the U.S. Military HIV Research Program (USMHRP), which is conducted

by WRAIR with support from USAMRU-K and AFRIMS. The USMHRP was the first research laboratory to identify HIV-1 heterosexual transmission, and later demonstrated the first efficacy of an HIV vaccine.

The rapid, smaller-scale deployments characteristic of the 1980s exposed troops to a number of stressful occupational and environmental factors, including the lack of sleep and fatigue associated with long-distance air travel. WRAIR was an important element of the Army’s research into occupational and environmental stressors; its sleep and fatigue research, developed over the next few decades, would become world-renowned as researchers measured the performance effects of sustained or continuous operations and abrupt changes in sleep/rest cycles.

120 years of advances for military and public health

A boy in India is immunized against Japanese encephalitis. Photo courtesy of PATH/Julie Jacobson

Meanwhile, the military’s neuropsychiatric casualty terminology continued to evolve. What had been known, at least in part, as “nostalgia” during the Civil War; “shell shock” in World War I, and “combat exhaustion” in World War II was known by the mid-1970s as post-traumatic stress disorder, or PTSD. WRAIR and its associates at USAMRU-E continued to work on ways to maximize post-traumatic growth through coping skills and unit cohesion as troops undertook their most significant post-Vietnam deployments: to Saudi Arabia, Kuwait, and Iraq to fight the Persian Gulf War of 1990-1991.

The abrupt, dramatic, and relatively bloodless end to the Cold War resulted in a massive demobilization of resources that completely reoriented the missions of the DoD. The Base Realignment and Closure (BRAC) process launched in 1988 relocated several WRAIR research programs and resulted in the reorganization of the USAMRDC into the USAMRMC. By the mid-1990s, the command had shed about a third of its research programs.

BRAC, including the “Medical BRAC” of 2005, realigned and focused the work of WRAIR – but it remains the oldest, largest, and most diverse research program in the command, and the largest military medical laboratory in DoD.

A WRAIR for the 21st Century In 2001, WRAIR left its 60-year-old home in Building 40 and moved to newly built quarters on the Forest Glen Annex of the Walter Reed Army Medical Center near Silver Spring, Md. The

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new building, named in honor of the late Sen. Daniel K. Inouye, is co-located with the Naval Medical Research Center.

As transformative as BRAC was for the Army’s military medical research, nothing would refocus the work of WRAIR as powerfully as the Global War on Terrorism that began on Sept. 11, 2001. America’s longest war has been, in the words of Smith, “a funny kind of war.

There are no front lines – to a worse degree than Vietnam, where troops defined post-traumatic stress. We’ve had no choice but to recognize PTSD as a significant problem, now that we have an all-volunteer force who are worried about their careers, and we’re worried about their ability to continue working. We’re beginning to spend some real time and energy on these problems of traumatic stress and what we now call mild traumatic brain injury.”

The influences of the wars in Iraq and Afghanistan are evident in WRAIR’s current organizational structure: Its work is now focused in two new research centers: the Center for Infectious Disease Research (CIDR), which continues to pursue the prevention, diagnosis, care, and treatment of a variety of endemic diseases; and the Center for Military Psychiatry and Neuroscience (CMPN), whose research emphases are post-traumatic stress, sleep management/resilience, and brain injury and neuroprotection.

WRAIR researchers have followed the precedent set by its Vietnam teams, who collocated researchers in the field with warfighters; the institute’s Mental Health Advisory Teams (MHATs) have been instrumental in expanding troops’ access to mental health care and, ultimately, improving outcomes for returning veterans – who have been the first American warfighters to endure multiple yearlong deployments, over a conflict that has lasted more than a decade.

“It’s the first time in our history we’ve dealt with this,” said Smith. “It’s really the first time anybody has dealt with it ... it’s a readiness problem, and WRAIR has been tasked to do something about it in the same way they were told to do something about malaria, which was reducing the readiness of the force in Vietnam. The purpose of the Army is to fight – so in Vietnam, WRAIR worked and built new drugs to keep people healthy while they were in a malaria zone. Now, we’ll build something to keep them resilient enough to fight through the kinds of stressors associated with these multiple deployments.”

It’s gratifying when a WRAIR breakthrough proves valuable to the larger world: The vaccines developed or improved by its researchers have likely saved thousands, perhaps millions, of lives, and the solutions being developed today for warfighters – protecting them from disease; helping them become more resilient in the face of unprecedented service-related stress; and keeping them alert and ready to fight – will surely bring lifesaving or life-enhancing discoveries to a multitude of civilians.

But the Army Medical School was established 120 years ago to serve the Army, and its descendant, WRAIR, shares that purpose, a fact that ensures it will continue to evolve as America’s national security concerns change – as they always have, and always will.

“The people of WRAIR, civilians and military,” said Smith, “are not like university scientists, allowed to work on whatever they want to this week; they do what they are funded to do. WRAIR’s history has been made by those research commanders, staff officers to the surgeon general, working with ‘Big Army’ and DoD to shape what’s doable – and what ought to be done – with the medical research funding available, to make the Army as healthy as we can.”

A BRIEF HISTORY

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120 years of advances for military and public health

to catch a virus “Fear or terror on every countenance: YelLow Fever”

By John Booss and Marilyn J. August

By 1900, several pieces of the puzzle were in place that would help to explain the spread of yellow fever. Of principal interest was the mode of transmission; the precedent had been set in 1897 with malaria when mosquitoes were identified as vectors. Walter Reed acknowledged “… the splendid work of Ross, Bignami, and others with regard to the propagation of malarial fever …” (30). Reed also acknowledged the work of J. C. Nott in 1848 in suggesting “… that the spread of yellow fever could not be assumed by the assumption of a diffusible miasm in the atmosphere but required the presence of an intermediate host. …” The specific mosquito, then called Stegomyia fasciata, later called Culex fasciatus and finally Aedes aegypti (19), had been identified by Carlos Finlay in 1886. However, Finlay had failed to convince his colleagues that this mosquito was responsible for disease spread. One of the principal reasons for that failure was ignorance of an extrinsic incubation period, a time during which the virus matures in the mosquito.

Reed recognized the careful work of Henry Rose Carter (8) in two small towns in Mississippi in 1898, “‘demonstrating the interval between the infecting and secondary cases of yellow fever.’” Reed was gracious in declaring, “To Dr. Carlos J. Finlay, of Havana, must be given, however, full credit for the theory of the propagation of yellow fever by means of the mosquito” (30).

Sill missing was a crucial piece of the puzzle: isolation of an agreed-upon etiological agent of yellow fever. Although this was a time of exciting discoveries in medical bacteriology, credit in disproving putative bacterial causes must go to George Miller Sternberg, a pioneer American bacteriologist. An author of early American textbooks of bacteriology in the 1890s, he spent most of his career in the U.S. Army and was largely self-taught in bacteriology.

In 1890, he published Report on the Etiology and Prevention of Yellow Fever, in which he thoroughly disposed of the several candidate bacteria as the cause of yellow fever (36). In 1897, Sternberg appointed Reed and James Carroll to investigate yet another candidate, Bacillus icteroides (Sanarelli) along with his own candidate, Bacillus X. Reed and Carroll, who were joined by Aristedes Agramonte in Cuba in 1898, demonstrated that Bacillus icteroides “bore no relation to the disease” (7).

In 1900, by-then Surgeon General Sternberg appointed Reed, Carroll, Agramonte, and Jesse W. Lazear to a board of army medical officers to investigate yellow fever in Cuba (7). The board first met 25 June 1900 (2).

Astonishingly, within 4 months the board was able to report at the Annual Meeting of the American Public Health Association in October 1900 that Culex fasciatus served as the intermediate host for yellow fever (29). In clearing the field of bacterial contenders and in appointing the U.S. Army Yellow Fever Commission in 1900, Sternberg can be credited as the catalyst of these findings on the transmission and etiology of yellow fever.

Without a bacterial agent identified in culture, the need remained to do studies in human subjects. The use of experimental animals was to come later

The Yellow Fever Commission consisted of (clockwise from upper left) Walter Reed; James Carroll; Aristides Agramonte; and Jesse W. Lazear. In a remarkably brief period of time at the turn of the 20th century, the Commission under Reed demonstrated that the disease was transmitted by mosquitoes and that it could be transmitted by filtered blood, and thus was caused by a virus. Courtesy of the Historical Collections & Services, Claude Moore Health Sciences Library, University of Virginia, except for the image of Walter Reed, courtesy of The National Library of Medicine. doi:10.1128/9781555818586.ch1.f7

(37, 38, 39). Finlay had already used human subjects in his earlier studies (14). Still, the investigators recognized the ethical implications of the studies in humans and offered themselves first. In James Carroll’s words, “Then arose

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LEFT: George Miller Sternberg was Surgeon General of the Army from 1893 to 1902, during which time he appointed the Yellow Fever Commission. Courtesy of the Historical Collections & Services, Claude Moore Health Services Library, University of Virginia. doi:10.1128/9781555818586.ch1.f6 RIGHT: Henry Rose Carter, 1909. As a member of the Marine Hospital Service, he was able to deduce a delay between primary and secondary cases of yellow fever. This extrinsic incubation period implied the need for another, nonhuman, host, later shown to be the mosquito. He was assigned to the Panama Canal Zone in 1904 to work on yellow fever.

Courtesy of Historical Collections & Services, Claude Moore Health Sciences Library, University of Virginia. doi:10.1128/9781555818586.ch1.f6

the question of the tremendous responsibility involved in the use of human beings for experimental purposes. It was concluded that the results, if positive, would be sufficient justification of the undertaking. It was suggested that we subject ourselves to the same risk, and this suggestion was accepted by Dr. Reed and Dr. Lazear” (7). Carroll became the first experimental subject, accepting the risks ahead of other volunteers.

The circumstances to further study yellow fever were propitious. Following the Spanish-American War, yellow fever appeared yet again in Cuba, placing the populace and American troops at risk. Soon after arrival in Cuba, Reed and his Commission colleague, Agramonte, visited an army barracks at Pinar del Rio where an outbreak was occurring. Observations made on that visit “… did not tend to strengthen one’s belief in the theory of the propagation of yellow fever by fomites” (30). A curious story was told of that visit. Only one of nine prisoners, well guarded in jail, had come down with yellow fever.

Speculation was raised that an insect such as a mosquito had bitten the one prisoner. That speculation was buttressed by the observations of Carter of the interval between infecting and secondary cases (9, 21). It was decided to test Finlay’s theory of mosquito transmission of yellow fever.

In Reed’s words, “... the search for the specific agent of yellow fever while not abandoned, should be given secondary consideration, until we had first definitely learned something about the way or ways in which the disease was propagated from the sick to the well” (30). In preliminary experiments by Lazear, mosquito eggs were supplied by Finlay, and mosquitoes were raised in the laboratory, allowed to feed on yellow fever patients, and allowed to bite human subjects. First among the subjects was Carroll, who fell ill and almost perished (21). Lazear, apparently bitten by a stray mosquito in 1900,

was a victim of their research efforts: he contracted yellow fever and died.

The results of the experiments showed that 2 of 11 experimentally infected subjects developed yellow fever. It was concluded that “The mosquito acts as the intermediate host for the parasite of yellow fever, and it is highly probable that the disease is only propagated through the bite of this insect” (italics in the original) (29).

There followed the construction of two small buildings in an open field to compare the transmission of yellow fever by fomites with transmission by the bites of infected mosquitoes or inoculation of infected blood. The “Infected Mosquito Building” was well ventilated and divided into two compartments by a screen. The “Infected Clothing and Bedding Building” was purposely not well ventilated so as to retain any noxious effects of bed clothing, pajamas, and other items from previously infected cases. After some early discouraging results, John R. Kissinger, a soldier who Reed praised for having volunteered “solely in the interest of humanity and the cause of science” and who would accept no payment, came down with experimental yellow fever from the bites of infected mosquitoes (30). In these experiments, six of seven “non-immunes” bitten by infected mosquitoes in the Infected Mosquito Building became ill with yellow fever (32). None of the seven subjects in the Infected Clothing and Bedding Building exposed to fomites from cases of yellow fever became ill, nor did subjects become ill who had remained behind the screen, not bitten by mosquitoes.

The clarity of the design of comparison groups and the results were decisive: 85.71 percent infected by mosquitoes versus 0 percent by fomites. In the definitive publication in JAMA, “The Etiology of Yellow Fever: an Additional Note,” Reed, Carroll, and Agramonte ended with several major conclusions.

TO CATCH A VIRUS

Thank you, WRAIR, for your R&D and clinical research support, which led to FDA licensure of the Japanese encephalitis vaccine, IXIARO.

In Defense Against Japanese Encephalitis

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“We advise and highly recommend JE vaccine for Service members, Department of Defense civilians, and beneficiaries who are, or will be, stationed or visiting for more than 30 days in endemic areas. This includes those who would be based in urban areas, but likely to visit endemic rural or agricultural areas during a high-risk period of JE transmission.”4 — Jonathan Woodson, MD,

Assistant Secretary of Defense for Health Affairs

Japanese encephalitis (JE) is a rare but dangerous and potentially deadly disease.

JE is endemic throughout much of Asia and parts of the western Pacific.5 INDICATIONS AND USAGE IXIARO is a vaccine indicated for active immunization for the prevention of disease caused by Japanese encephalitis virus (JEV). IXIARO is approved for use in individuals 2 months of age and older.

IMPORTANT SAFETY INFORMATION Severe allergic reaction (e.g., anaphylaxis) after a previous dose of IXIARO, any other Japanese encephalitis virus vaccine, or any component of IXIARO, including protamine sulfate, is a contraindication to administration of IXIARO. Alternatively, because of uncertainty as to which component of the vaccine may be responsible, individuals with a history of severe allergic reaction to another Japanese encephalitis vaccine may be referred to an allergist for evaluation if immunization with IXIARO is considered.

IXIARO contains protamine sulfate, a compound known to cause hypersensitivity reactions in some individuals. Appropriate medical care should be readily available in case of anaphylactic reaction.

Vaccination with IXIARO may not protect all individuals.

Immunocompromised individuals may have a diminished immune response to IXIARO. In infants 2 months to <1 year of age, the most common injection-site reaction was redness (>15%); the most common solicited systemic adverse reactions were fever (>20%), irritability (>15%) and diarrhea (>10%). In children 1 to <3 years of age, the most common solicited systemic adverse reaction was fever (>20%). In children 3 to <12 years of age, the most common solicited systemic adverse reaction was fever (>10%). In adolescents 12 to <18 years of age, the most common solicited injectionsite reactions were pain (15%) and tenderness (10%). In adults 18 years of age and older, the most common injection-site reactions were pain (>25%) and tenderness (>25%); the most common solicited systemic adverse reactions were headache (>20%) and myalgia (>10%).

To report inadvertent use in pregnant women, contact Novartis Vaccines at 1.877.683.4732 (1.877.NV-DIRECT).

References: 1. Tauber E, Kollaritsch H, Korinek M, Rendi-Wagner P, Jilma B, Firbas C, et al. Safety and immunogenicity of a Vero-cell-derived, inactivated Japanese encephalitis vaccine: a non-inferiority, phase III, randomized controlled trial. Lancet. 2007;370:1847-1853. 2. Schuller, E, Jilma G, Voicu V, Golor G, Kollaritsch H, Kaltenbock A, et al. Long-term immunogenicity of the new Vero cell-derived, inactivated Japanese encephalitis virus vaccine IC51 six and 12 month results of a multi-center follow-up phase 3 study. Vaccine. 2008;26:4382-4386. 3. Ixiaro [package insert]. Cambridge, MA: Novartis Vaccines and Diagnostics, Inc; 2013. 4. Assistant Secretary of Defense for Health Affairs, Jonathan Woodson, MD. Guidance on the use of Japanese Encephalitis Vaccine, May 7 2013. US Department of Defense, Military Health System Web site. http://www.health.mil/Libraries/HA_Policies_and_Guidelines/Guidance_on_the_use_of_Japanese_Encephalitis_Vaccine.pdf. Accessed June 13, 2013. 5. Fischer M, Lindsey N, Staples JE, Hills S. Japanese encephalitis vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2010;59:1-27.

The Department of Defense did not select or approve this advertiser and does not endorse and is not responsible for the views or statements contained in this advertisement.

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120 YEARS OF ADVANCES FOR MILITARY AND PUBLIC HEALTH

In addition to confirming that “C. fasciatus serves as the intermediate host,” they determined that 12 days or more was required after contamination for the mosquito to transmit the infection. Thus, they determined experimentally what Carter had observed epidemiologically. They found that yellow fever could be transmitted by blood subcutaneously inoculated when taken from a patient on the first 2 days of the illness. They concluded that yellow fever resulting from a mosquito bite “confers immunity” against attempted reinfection with infected blood (32).

In memory of Lazear, the experimental station established by Reed, where the crucial studies were conducted demonstrating the transmission of yellow fever by mosquitoes and not by fomites, was christened Camp Lazear. Ironically, although Carroll recovered from acute yellow fever infection, he tragically died 7 years later of myocarditis attributed to that attack of yellow fever.

An important piece of the puzzle still remained to fall in place. Walter Reed and his colleagues’ final conclusion of their JAMA report was that “. . . the specific cause of this disease remains to be discovered” (32). Having turned away from that goal in their transmission studies, Carroll returned to the project. Initially confronted with local objections to further experimentation, Carroll resumed his studies in September 1901 in Cuba on the nature of the infecting agent (7). In the crucial experiment, six individuals were exposed to the bites of infected mosquitoes (33). Four did not develop yellow fever, but two did. Blood was taken from patients I and II for further transmission study, but due to an accident to the vacuum pump, the blood from patient I could not be used. The blood from patient II was divided into three aliquots of partially defibrinated and diluted serum. The first aliquot, a positive control, was left untreated and successfully transmitted yellow fever to patient III. The second aliquot was heated to 55°C for 10 minutes and failed to transmit disease to patients IV, V, and VI. Based on previous work on heat stability with toxins, Reed and Carroll argued against a toxin. The third aliquot was “slowly filtered through a new Berkefeld laboratory-filter”

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and the filtrate was inoculated into patients VII, VIII, and IX. Patients VII and VIII developed “unmistakable” attacks of yellow fever; patient IX remained well. The scientific data were presented at the annual meeting of the Society of American Bacteriologists, Dec. 31, 1901 and Jan. 1, 1902. Thus, clinical virology can be said to have started in the first years of the 20th century.

Presciently, they noted that the most effective means of controlling the spread of yellow fever was through destruction of mosquito breeding areas and prevention of mosquitoes biting the sick (31). This strategy was employed with extraordinary success by William Crawford Gorgas of the U.S. Army, also present in Havana at that time. A brilliant story unto himself, Gorgas cleared Havana of yellow fever. An interesting connection can be noted here between Gorgas and J. C. Nott, mentioned above, who had suggested that yellow fever transmission required an intermediate host. Nott, coincidentally, was the doctor who delivered the infant Gorgas, whose success in the story of yellow fever eradication was based on Nott’s theory. A few years later, Gorgas also cleared the Canal Zone of yellow fever and malaria, allowing the successful construction of the Panama Canal (17, 18, 25). Thus, the yellow fever-mosquito story was intimately wound into America’s expanding international role (26).

It was clear from the classic studies of the Yellow Fever Commission that transmission experiments had to be performed in human subjects. However, that presented significant ethical issues, not only for potentially lethal viral infections such as yellow fever but also for permanently disabling anterior poliomyelitis.

Although Carroll reported in 1904 that others had also shown that the agent of yellow fever was filterable (7), attempts to identify a bacterial cause continued (2). It was not until a successful experimental animal host, the rhesus monkey, was demonstrated in 1928 (37) and then the successful use of intracerebral inoculation of white mice (38, 39) that large-scale studies of the yellow fever virus could be undertaken and the bacterial candidates dismissed.

This excerpt is taken from Chapter 1 of To Catch a Virus, published by ASM Press.

REFERENCES 2. Agramonte, A. 1928. A review of research in yellow fever. Ann. Intern. Med. 2:138–154.

7. Carroll, J. 1904. A brief review of the etiology of yellow fever. N.Y. Med. J. and Philadelphia Med. J. 79:241–245, 302–310.

8. Carter, H. R. 1898. Communication with a town infected with yellow fever. Med. News 72:546–547.

9. Carter, H. R. 1900. A note on the interval between infecting and secondary cases of yellow fever from the records of the yellow fever at Orwood and Taylor, Miss., in 1898. New Orleans Med. Surg. J. 52:617–636.

14. Finlay, C. 1886. Yellow fever: its transmission by means of the culex mosquito. Am. J. Med. Sci. 92:395–409.

17. Gibson, J. M. 1950. Physician to the World: the Life of General William C. Gorgas. The University of Alabama Press, Tuscaloosa, AL. 18. Gorgas, W. C. 1909. Sanitation of the tropics with special reference to malaria and yellow fever. JAMA 52:1075–1077.

19. Hemmeter, J. C. 1927. Master Minds in Medicine, p. 297–336. Medical Life Press, New York, NY. 21. Kelly, H. A. 1923. Walter Reed and Yellow Fever. Norman, Remington, Baltimore, MD. 25. McCullough, D. 1977. The Path between the Seas: the Creation of the Panama Canal, 1870–1914. Simon & Schuster, New York, NY. 26. Morgan, H. W. 1965. America’s Road to Empire: the War with Spain and Overseas Expansion. John Wiley, New York, NY. 29. Reed, W., J. Carroll, A. Agramonte, and J. W. Lazear. 1900. The etiology of yellow fever. Phila. Med. J. 6:790–796.

30. Reed, W. 1901. The propagation of yellow fever; observations based on recent researches. Med. Rec. 60:201–209.

31. Reed, W., and J. Carroll. 1901. The prevention of yellow fever. Med. Rec. 60:641–649.

32. Reed, W., J. Carroll, and A. Agramonte. 1901. The etiology of yellow fever: an additional note. JAMA 36:431–440.

33. Reed, W., and J. Carroll. 1902. The etiology of yellow fever: a supplemental note. Am. Med. 3:301–305.

36. Sternberg, G. M. 1890. Report on the Etiology and Prevention of Yellow Fever. U.S. Government Printing Office, Washington, DC. 37. Stokes, A., J. H. Bauer, and N. P. Hudson. 1928. Experimental transmission of yellow fever to laboratory animals. Am. J. Trop. Med. 8:103–164.

38. Theiler, M. 1930. Susceptibility of white mice to the virus of yellow fever. Science 71:367.

39. Theiler, M. 1930. Studies on the action of yellow fever virus in mice. Ann. Trop. Med. Parasitol. 24:249–272.

TO CATCH A VIRUS

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120 YEARS OF ADVANCES FOR MILITARY AND PUBLIC HEALTH

USAMRU-Kenyaâ&#x20AC;&#x2122;s public health response efforts include Rift Valley Fever virus, 2006/2007, pandemic influenza in 2009, and dengue outbreak in the northeast region of Kenya in 2011. DoD photo by Tech. Sgt. Daniel St. Pierre

120 years of advances for military and public health

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Overseas Commands

By J.R. Wilson

As

a component of the U.S. Army Medical Research and Materiel Command (USAMRMC), the Walter Reed Army Institute of Research (WRAIR) maintains four special foreign activities: the US Army Medical Research UnitKenya (USAMRU-K) in Nairobi, Kenya; the U.S. Army Medical Component-Armed Forces Research Institute of Medical Sciences (AFRIMS) in Bangkok, Thailand; the U.S. Army Medical Research Unit-Europe (USAMRU-E) in Sembach, Germany; and the newest laboratory, the U.S. Army Medical Research Unit-Georgia (USAMRU-G) in Tbilisi, Georgia.

The laboratories in Kenya, Thailand, and Georgia are dedicated to research on infectious diseases that both endanger U.S. military personnel overseas and are of concern to the host nation. Each also pursues some research unique to its geographic region, but all focus on research related to stresses and exposures U.S. troops encounter and the performance requirements of a deployed military force.

The laboratory in Germany is focused on behavioral health and resilience of the warfighter. All WRAIR overseas units are located in host-nation facilities except USAMRU-E, which is located on a U.S. military base in Sembach.

“With any overseas site, we’re there with the support of the host nation and the U.S. embassy. There have been other labs, such as Brazil, that no longer exist. There also are places where we don’t have official labs but do have some kind of field operations,” Col. Jamie Blow, military deputy to the principal assistant for Research and Technology-MRMC, explained.

“Our missions are determined by the U.S. Army and the WRAIR commander. We do collaborate with our host nation partners, such as the Georgia National Center for Disease Control [NCDC], and respond to requests for assistance from them – if we can find funding and it fits within our mission scope.” WRAIR’s oldest – and still primary – effort to combat infectious diseases is overseen by the military infectious disease research program and the military operational medicine research program, along with GEIS (Global Emerging Infections Surveillance and Response System) for the labs in Kenya, Thailand, and Georgia.

The work performed by each laboratory typically extends to smaller field sites in neighboring countries, Director of Overseas Operations Lt. Col. Jennifer Chapman added. “We execute PEPFAR [President’s Emergency Plan for AIDS Relief] and biosurveillance activities in Kenya and other areas of Africa, such as Uganda, Tanzania, and Cameroon,” Chapman said. “In each of our labs, we have regional assets and agreements, which we are establishing in Georgia for the Caucasus region, for example.”

WRAIR’s commander, Col. Steven Braverman, said the institute is designed to evolve as mission requirements evolve, such as the higher priority given traumatic brain injury (TBI) research as a result of the wars in Iraq and Afghanistan and relatively new efforts involving behavioral health of the force, intended to help inform commanders about small unit resiliency, for both training and combat operations.

WRAIR’s two primary goals are to advance research and, especially OCONUS (outside the continental United States), to improve the capacity and medical capabilities of the host nation. As a result, he added, studies done in Cambodia or Kenya are designed to ensure they will benefit the people of the host nations and help those nations build their own structures and capacities. That helps build bridges, both medically and diplomatically, with WRAIR’s partner nations.

Behavioral studies in Germany are more directly focused on U.S. and allied Service Members, but still are representative of WRAIR’s global scope.

ARMED FORCES RESEARCH INSTITUTE OF MEDICAL SCIENCES-Thailand AFRIMS-Thailand is the oldest, largest, and most geographically dispersed of the overseas commands. Founded in 1959 as a SEATO (Southeast Asia Treaty Organization) laboratory to help combat a cholera outbreak, it was renamed AFRIMS in 1977 and given a broader mandate in tropical infectious disease research and development.

Since then, it has acquired new disease research missions and been refocused many times to meet new challenges.

The largest component of WR AIR, it comprises about one-quarter of the institute’s 2,000 personnel. The overall command of AFRIMS is held by a Royal Thai Army general officer.

There are two components to AFRIMS; the U.S. Army Medical Component-AFRIMS (USAMC-AFRIMS) works alongside the Royal Thai Army Component AFRIMS. The USAMC-AFRIMS has a relatively small staff of U.S. military personnel and most of the USAMC-AFRIMS employees are local nationals with many of them being M.Ds. or Ph.Ds. “It is a unique relationship because the Royal Thai Army really views us as part of their organization,” said Col. William E. Geesey, the USAMC-AFRIMS’ first commander with a non-science (medical logistics) background. “We do collaborate with them on a number of different projects in different areas, but they have other projects, as well – such as drug tests of their military forces. And about 80 percent of our programs also are independent.

overseas commands

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120 years of advances for military and public health

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The U.S. Army, in conjunction with the Thai Ministry of Public Health, the National Institute of Allergy and Infectious Disease, the National Institutes of Health, Sanofi Pasteur, and Global Solutions for Infectious Diseases, has uncovered successful results for an AIDS vaccination. The study was conducted at the Armed Forces Research Institute of Medical Sciences in Thailand. U.S. Army photo

“All of our activities fall under the purview of WRAIR. We also work under the Chief of Mission authority of the U.S. Embassy Bangkok.

We work with the country team in Thailand and other countries in the region to advance not only the [U.S.] Army’s goals of investigating infectious diseases and disease surveillance, but also to advance overall U.S. government strategy through military-to-military and military-to-civilian relationships that fall within our assigned missions.”

In addition to Thailand, AFRIMS maintains permanent facilities in the Philippines and Nepal, in major metropolitan areas across the region and two permanent field sites in Cambodia, located outside metro areas and run by locals, often without 24/7 power.

“We are also actively engaged with military, government, or university partners in Mongolia and Vietnam, beginning some dialogue with China and, through the Thais to meet with military and civilian officials from Myanmar [Burma],” he added. “Infectious diseases are a major destabilizing issue with many nations. If you back up 50 years, all of the early research done for diseases in Thailand has led to improved public health here so we have expanded to [neighboring nations] where there are still endemic diseases of interest.

“Our primary mission is the development of infectious disease diagnostics, drugs, and vaccines for the military as well as the civilian populations. The first thing we generally do is surveillance, to find out where the diseases are and their prevalence. Based on that, we develop further research studies leading eventually to clinical trials.

The U.S. Army contributed significantly to the development of all of

the currently U.S. FDA-approved malaria drugs and much of that work happened at AFRIMS.” AFRIMS conducts its research on top infectious disease priorities through seven science departments: 1) Enteric Disease – primarily studies the infectious causes of diarrhea.

They partner with many host nation institutions and US agencies such as NIH to conduct preclinical and clinical assessments of vaccine candidates and to understand the epidemiology of diarrheal diseases in the region.

2) Immunology and Medicine – is primarily engaged in the development of drugs and vaccines targeting malaria. With major field sites in Cambodia, they are partnering with the Royal Cambodian Armed Forces and the Cambodian National Malaria Control Program to monitor the emergence of malaria drug resistance and to assess malaria elimination strategies in rural Cambodia.

3) Virology – studies flaviviruses such as dengue and respiratory pathogens such as influenza. Currently, this department is conducting Phase III clinical trials of a dengue vaccine in Thailand and the Philippines.

4) Retrovirology – is focused on developing an HIV vaccine. This department conducted the 16,000 subject Phase III vaccine study called RV144, which was the world’s first HIV vaccine to demonstrate efficacy.

This study changed the entire field of HIV prevention. Currently they work with many collaborators to understand the immunology of protection and to develop the second-generation vaccine with higher levels of efficacy.

5) Entomology – is a support department that manages DoD’s largest insectary, breeding mosquito vectors for use in vector biology

overseas commands

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120 YEARS OF ADVANCES FOR MILITARY AND PUBLIC HEALTH

Check-up exam prior to malaria vaccination in Kisumu-Kombewa, Kenya, as part of a joint GSK/PATH-MVI/KEMRI/WRAIR RTS,S Phase III trial. JohnMichael Maas; Darby Communications

research and animal and human challenge models. They also collaborate with the Department of Agriculture on pesticide effectiveness and safety, vector surveillance, and dispersing equipment.

6) Veterinary Medicine – is another support department that maintains an AAALAC-accredited non-human primate research facility that is used to explore the pathophysiology of diseases and conduct pre-clinical animal studies of products.

7) Epidemiology and Disease Surveillance – is primarily responsible for coordinating infectious disease surveillance activities across 8 different countries in the region funded by DoD-GEIS. Led by a veterinary microbiologist, they also support zoonotic disease field research.

All AFRIMS projects are collaborations with militaries, universities, private institutions, governments, etc., which became more difficult due to travel restrictions under recent budget restrictions.

“That has been frustrating. Building relationships in Asia is extremely important, but slow developing. And if I’m engaging a collaboration running on generator power a few hours a day and can’t actually travel to meet with them personally, it can make things difficult,” he explained.

U.S. ARMY MEDICAL RESEARCH UNIT-KENYA USAMRU-K is composed of 11 U.S. military officers, four locally engaged staff, and approximately 550 locally contracted personnel.

In 1969, WRAIR was invited by the government of Kenya to perform research on trypanosomiasis in western Kenya. The success of this effort led to a cooperative agreement between USAMRU-K and the Kenya Medical Research Institute (KEMRI) in 1979 to conduct militarily and public health relevant infectious disease research

and surveillance. KEMRI is the principal human medical research component of the Kenya government. The expanded mission includes developing and testing improved products for predicting, detecting, treating, and preventing infectious disease threats to deployed U.S. military personnel and the people of Kenya. USAMRU-K also provides HIV prevention, care, and treatment to Kenyan civilians and military through the PEPFAR program. Some other specific areas of USAMRU-K’s research and surveillance activities are: drugs and vaccines for malaria and other tropical diseases; drugs and vaccines for HIV; DoD-GEIS; medical entomology and vector biology; military-to-military medical engagement with the Kenya Ministry of Defense; Malaria Drug Resistance Laboratory; and Malaria Diagnostics Center.

USAMRU-K is headquartered in Nairobi, on the KEMRI campus.

The DoD PEPFAR program for the Kenya Defense Forces and Military to Military Medical Program conducts operations from this location along with the DoD-GEIS program. USAMRU-K operates two field stations located in Kisumu and Kericho, Kenya, and each has well-established clinical research centers, with a high prevalence of HIV and malaria in the surrounding communities. “We are able to do very powerful studies with a lower number of subjects due to the high infection rates. The study sites are the most important aspects of our work, being right in the middle of some of the highest incidence rates in the world for both HIV and malaria,” said Col. Tom Logan, a Ph.D. entomologist in the Medical Service Corps who commands the unit.

“Each of our field stations has its own director and staff. For example, Kericho has 120 personnel, is collocated with a Kenyan district hospital, and has Professor Samuel Sinei and Dr. Fred Sawe as director and senior deputy director, respectively. This facility is part of the global Military HIV Research Program network that is an internationally recognized research leader. This site has nearly 20 active protocols underway, including an early phase HIV vaccine trial. In addition, the Henry Jackson Foundation-Medical Research International agency provides crucial research support activities and is a key part of this unit’s success. The Kericho Field Station is also a major contributor to the successful implementation of the PEPFAR program in Kenya. This site executes and oversees PEPFAR programs with a budget of over $21 million USD in the lower South Rift Valley with a base population of over 10 million people. The program is comprised of 11 primary treatment centers, 88 satellite rural health centers, 353 HIV testing and counseling centers, and 410 prevention of mother-to-child transmission [PMTCT] of HIV centers.

“Kombewa, the site of another clinical research center, sits about 40 kilometers outside Kisumu along with a Kenyan district hospital.

Closer, at about 20 kilometers from the city are two other labs, one for malaria drug-resistance testing and another for entomology, collocated on the KEMRI-CDC [Centers for Disease Control and Prevention] Center for Global Public Health Research campus at Kisian. In Kisumu City we have a Malaria Diagnostics Center and our Basic Sciences Lab/ Administration Center next to the Obama Children’s Hospital.”

120 YEARS OF ADVANCES FOR MILITARY AND PUBLIC HEALTH

The unit, through the Global Emerging Infections Surveillance Program, conducts disease surveillance and associated research activities in Kenya, Cameroon, Uganda, and Tanzania. “These are interesting countries for conducting surveillance for and researching infectious diseases, whether in wildlife or humans,” Logan said. “Samples are brought to our labs to help us stay aware of what is there in terms of infectious diseases, to stay ahead of any outbreaks, and report analyses of those up to the Ministry of Health, DoD-GEIS, U.S. CDC, and to our own headquarters at WRAIR so we can control outbreaks before they spread.

“Right now, we’re heavily engaged in a Phase III malaria vaccine trial, with more than 1,700 infants and toddlers enrolled at our center in Kombewa. This GlaxoSmithKline-led protocol, sponsored

by PATH-MVI, is a three-year study being conducted at 11 sites in seven countries. The study we’re involved with now on the malaria vaccine trial is the largest study we’ve ever done at USAMRU-K and, through successful vaccine development, may possibly protect both military and civilian populations from this deadly disease.

“We also have a number of protocols in place dealing with malaria drug diagnostics, malaria drug resistance testing, new therapeutics, combinations of therapeutics, and dose-ranging studies,” Logan said.

“We also have protocols under way conducting surveillance at the patient level for possible malaria drug treatment resistance.

“In Kericho, our enteric disease research and cohort development for potential vaccine testing is the top funded priority for the medical infectious disease research program. We have protocols in place for evaluation of treatment drugs for traveler’s diarrhea. Malaria and HIV fall closely behind enteric diseases and all three are extremely important risks to deployed Service Members. “What we have with AFRICOM [Africa Command] is not a direct-command relationship, but we are within their AOR [area of responsibility], so we maintain data flow to them when we think it would be useful. We support their commanders’ health-related security cooperation efforts on the continent. We do projects such as training of partner countries at their request on topics such as malaria diagnostics training and external quality assurance assistance visits to their labs.”

As with AFRIMS, USAMRU-K’s primary efforts remain infectious disease research, aimed at developing products and information to protect U.S. Service Members.

U.S. ARMY MEDICAL RESEARCH UNIT-EUROPE USAMRU-E, located at Sembach Kaserne (formerly Sembach Air Base and now an Army installation about 19 miles east of Ramstein Air Base) is the Army’s only behavioral health research asset located with operational units. As such, USAMRU-E is able to send researchers into the field quickly to conduct both randomized trials and survey-based epidemiological studies on emerging behavioral health and resilience issues faced by U.S. Service Members. Initially a forward-deployed research unit, established in 1977 to investigate the high prevalence of drug use in the post-Vietnam Army, the unit now conducts operational behavioral health research. It is the smallest of the overseas commands, with roughly 18 personnel evenly divided between uniformed military, Department of the Army civilians, and contractors.

“I think our size has more to do with the type of research and studies that we do. While the other overseas commands have multisite

31

trials requiring more laboratory capability, USAMRU-E’s research occurs in the field with a given unit, typically a brigade, and generally involves survey-based research leading to validated training and policy recommendations pertaining to behavioral health, so we don’t need as large of a team for our line of research,” noted USAMRU-E Commander Lt. Col. Jeffrey Thomas, a research psychologist with a Ph.D. in applied social psychology.

“Our customers and participants are all operational units and Soldiers. We have fielded human dimension research teams where the Soldiers are – Iraq, Afghanistan, Kosovo – to look at human dimension issues, stressors, and their effects. We have a capability that is somewhat unique, not only within WRAIR, but within the DoD in working with operational units where they are, in order to advance programmatic behavioral health research.”

After more than 35 years in Heidelberg, USAMRU-E was relocated in 2013, along with all U.S. Army medical operations in Germany, to new facilities in southwestern Germany in the Rheinland Pfalz region.

The only WRAIR overseas operation located on a U.S. military base – and in one of the world’s most advanced nations – USAMRU-E’s small contingent nonetheless maintains a significant multination collaboration.

“We have a very nice international presence, taking part in NATO panels, working with Partnership for Peace [former Soviet Bloc] countries, and helping to advance research among partners on behavioral health and deployment support for Soldiers across NATO. And we’ve been very active in consulting with and exchanging behavioral health support ideas and processes with our host nation partner, the Bundeswehr in Germany. We also currently have an active collaborative agreement with the U.K. to examine differences and similarities between U.S. and U.K. Soldiers on mental health issues following deployment to Iraq and Afghanistan.” Thomas said. “We not only have a history of success in Europe, but there are also clear benefits being located in Germany which is at the crossroads of three combatant commands – European Command, Africa Command, and support for the overseas contingency operations in Central Command.” With the expansion of AFRICOM, USAMRU-E has a mental health advisory mission in Africa and recently sent a behavioral health team to Djibouti to conduct a study in the Horn of Africa. “We’ve also supported a few military-to-military requests with some eastern Africa countries of interest to the U.S.,” he added. “Those requests focused on building Army resilience training programs and what they can apply to their own forces.”

With the drawdown in Afghanistan, reduction and consolidation of forces in Europe, and budget constraints, funding continues to ebb and flow, driven by the needs of Soldiers returning from Southwest Asia with PTSD and adjustment problems. “As the problems have manifested, the Army has made more money available to find solutions, and I suspect those efforts will continue in the post-combat era. As long as we continue to answer questions about how to help Soldiers, the funding will be there,” Thomas said, adding that the nature of combat-related mental health concerns has changed with better understanding, new technologies, and faster response and transport.

“We’ve done quite a bit of research on combat Soldier reintegration.

During World War II, Soldiers returning home on ships took up to a month; now they can be home in 12 hours. So part of reintegration has been identifying Soldier expectations. In the past, Soldiers often were

OVERSEAS COMMANDS

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120 YEARS OF ADVANCES FOR MILITARY AND PUBLIC HEALTH

warned of the psychological problems they might have, primarily from an illness perspective, but having reintegration problems when you first get back is common, such as reacting to a car backfiring in a parking lot.

“In studying units just after getting back from Iraq early in the conflict, we found the prevalence of self-reported problems was quite low. But when we checked those same Soldiers a few months later, their problems were much higher. So things were not getting better over time, which runs contrary to the typical clinical perspective.

These data helped inform the launching of the post-deployment [health] reassessment program [PDHRA]. Timing matters in post-deployment reintegration,” he said.”

“In sum, a lot of our work has a strategic reach providing evidencebased data that informs valid training and behavioral health policy.

In this regard, our capability is not uniquely tied to being located in Germany. I know the national military strategic focus is shifting to the Pacific and there will always be a need for the Army to have a flexible forward-located behavioral health research unit ready to respond, regardless of where it is located. From my perspective, USAMRU-E offers a large return on a modest investment for the Army.”

U.S. ARMY MEDICAL RESEARCH-GEORGIA In 2006, Georgia’s prime minister sent a letter to Vice President Richard Cheney asking for help in establishing a modern public health laboratory. The Defense Threat Reduction Agency (DTRA) constructed this laboratory, the Richard G. Lugar Center for Public Health Research (Lugar Center), in Tbilisi, with groundbreaking in 2007 and its opening in March 2011. DTRA continues to fund and operate the facility but the NCDC has moved its laboratories into the Lugar Center and is in the process of taking ownership of the facility.

DTRA is currently working to develop a plan to transition the Lugar Center operation and funding from DTRA to the Georgians and WRAIR by the end of 2017.

WRAIR was tasked in January 2011 by the Deputy Secretary of Defense to establish a medical research unit at the Lugar Center.

WRAIR gained Department of the Army approval of the concept plan for this unit in October 2013 and will station the first permanent personnel at the unit the summer of 2014. The Army was also named the Executive Agent for all DoD activities in the Lugar Center.

WRAIR has laboratory and administrative space within the Lugar Center and will partner with NCDC to maintain and operate the facility and conduct scientific research. We will be tenants in this Georgian facility – essentially their version of the U.S. Centers for Disease Control and Prevention – where WRAIR has been invited to work.

USAMRMC scientists have been working in Georgia in support of DTRA for over 10 years. Since 2011, efforts have been focused on scientific research that is relevant to supporting the warfighter.

Unlike Kenya and Thailand, which are heavily involved in HIV and malaria, Georgia has different endemic diseases and little or no malaria and dengue fever. They are concerned with antimicrobial resistance, disease surveillance, developing capacity for disease surveillance, training for their military, and determining what the disease threats are to their country.

The future of the Georgia facility – and WRAIR’s presence there – will ref lect the global fight against disease, old and new. “By

33

A laboratory in the Richard G. Lugar Center for Public Health Research in Tbilisi, Republic of Georgia. The center was named after Lugar for his special contribution in work directed at decreasing chemical, biological, and nuclear dangers across the world. Republic of Georgia photo

2020, the Lugar Center will be a fully functional research facility with a mixture of research, on pathogens that are endemic as well those that that may move into their borders.”

As to the future and any other new WRAIR special foreign activities or overseas subcommands, Chapman said there is a reason why so few have been established and maintained during the past half-century.

“With all our labs, everything is tied back to the warfighter; it has to directly impact the U.S. warfighter, whether developing a vaccine, therapeutic, or diagnostic test,” she said.

“The trust and respect we’ve built with the nations in which we operate has led to the very successful relationships we have today.

Of course, the mission and locations also are dependent on political stability and other local factors. It takes many, many years to develop a vaccine. Looking forward, hopefully those we have been working on will reach FDA approval. But we will always be committed to research on endemic diseases around the world wherever our warfighters may deploy.”

What is certain for the future, Blow added, is the continuing battle against malaria, HIV, dengue fever, etc., but diseases that have been militarized or created in labs as weapons are not part of their mandate.

“WRAIR does surveillance of naturally occurring diseases; anything else belongs to DTRA and others,” Blow said. “Working with our partner countries to develop these surveillance efforts, hopefully we can identify and characterize any new [non-manmade] diseases.

That worked with SARS. “We are very capable of adapting to new threats and outbreaks and will continue to do that. We communicate a lot of knowledge through our personnel overseas and they help develop the knowledge and strength of the people of those host nations.”

OVERSEAS COMMANDS

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120 YEARS OF ADVANCES FOR MILITARY AND PUBLIC HEALTH

A scanning electron micrograph revealing the presence of HIV-1 (spherical in appearance), which had been co-cultivated with human lymphocytes. HIV remains an area of research. CDC photo

120 YEARS OF ADVANCES FOR MILITARY AND PUBLIC HEALTH

35

MORE ON RESEARCH AND MISSIONS

By J.R. Wilson

In

one way, little has changed for the Walter Reed Army Institute of Research’s (WRAIR’s) work since its original founding – investigate infectious diseases that threaten U.S. warfighters and seek to develop vaccines and treatments against them. But much has evolved in the ever-changing research and mission landscape.

Ongoing advances in technology and genetics, decades of work with partners and collaborators, major field research at four overseas stations, and increasing requirements from the military have led to more advanced science, methods, and techniques. There also are new areas of focus – HIV, the behavioral health of the force, and traumatic brain injury (TBI), among others – but the original goal of WRAIR namesake Maj. Walter Reed to conquer vector-borne infectious disease remains a top priority.

“WRAIR is famous for a one-of-a-kind malaria challenge model, where we take infected mosquitoes and, in a controlled fashion, have them bite volunteer subjects and give them malaria. The volunteers have either received a vaccine or malaria prophylaxis ahead of time, and we then can see what is effective and fully cure those where prevention didn’t work,” WRAIR Commander Col. Steven Braverman said.

“We have multiple projects related to the HIV vaccine that are follow-ups to the Thai RV144 trial that was shown to be partly efficacious a few years ago. Some look at what did work, what didn’t, how it worked, and so on.

“Then we have several projects working on a vaccine for the dengue virus, including one covering all four subtypes and some in the process of being tested that work through a different mechanism, but all with the same purpose of preventing all types of dengue. So HIV, malaria, and dengue are our most high-profile disease research areas. Another is trying to identify biomarkers in the bloodstream that are associated with TBI, so we can assist with diagnosis and treatment by identifying something in the blood that shows the injury occurred, how severe it is or if it is getting better.”

With respect to another of the more recent areas of concern, military psychology, some research is under way into developing an education or training program to increase resilience. In work centered at its

U.S. Army Medical Research Unit-Europe, WRAIR is also studying Soldiers and, in some cases, Family Members to determine the effects of long-term participation in war, small-unit leadership, effects of sleep and inactivity on performance and well-being, and sleep itself with the Army’s premier sleep lab.

“We have other products that are information and training, so we do research that informs policy or guides military medicine as to whether problems exist and if training can help,” Braverman added. “For example, we research what our Soldiers may be enduring in current combat or the growth of antimicrobial resistance in our health care system. We have the capability to evolve as mission requirements evolve. For example, we’re doing research into TBI at a higher priority than it was before the war, especially developing ways to study concussion or mild TBI rather than penetrating models, such as we had in the past.

“The infectious disease side has more to do with prioritization, looking at known pathogens and threats to our Soldiers in particular countries. As those change, we can change our priorities. For HIV, the subtypes differ between Africa and Asia and the type Americans generally have, so a vaccine that works for one may not work as well for another. If we have to, we could focus our research on one or another.

“Dengue also has different subtypes in Asia than in the Americas.

The type of malaria parasite differs by region and different medications work on different parasites, and infection with those differing parasites causes different symptoms. Some [parasites] also have developed resistance to some of our drugs. There are only a few tools in the malaria prevention and treatment toolbox overall, and if a parasite develops resistance, we could have a real medical problem.”

Research at WRAIR not only looks at infectious diseases and their carriers, but also on methods and technologies used in such research, from new developments to advanced applications of old technologies.

“One of those is real-time polymerase chain reactions [PCRs], which is an old method our people have enabled, doing four or six reactions at a time rather than one at a time,” according to Col. Emil Lesho, founder and director of the Multidrug-resistant Organism Repository

CURRENT MISSIONS

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Chemical attractants to enhance sand fly surveillance, high throughput testing for toxic/behavior modifying chemicals, and risk for domestic transmission of leishmaniasis are a few current major projects being conducted by entomologists studying the sand fly. U.S. Army Africa

and Surveillance Network (MRSN). “We use advanced molecular techniques, taking small amounts of DNA and enhancing it through this reaction to advance understanding of what the bugs are doing, how they affect the health of the individual, and what we can do, including policy changes to prevent infections.

“Microbiology of the future will be more like an applied chemistry and physics lab. For example, we take a chunk of bacteria, blast it apart and get a quick identification – about 200 times faster than a culture.

But that doesn’t tell you what it is susceptible to. We’re also using mass spectrometry, another old technique, in that effort.”

MALARIA AND THE MOSQUITO – THE LONG BATTLE Dr. David E. Lanar, chief of the Malaria Vaccine Branch’s Department of Molecular Engineering, noted thousands of years of evolution within immunologically competent individuals have allowed the malaria parasite to “evolve several exquisite mechanisms to evade detection” by both the human immune system and medical science.

“Once a malaria parasite enters a host, it can shed or change the proteins on its surface, making recognition or binding by antibodies difficult. Also, the parasite can actively penetrate liver cells or red blood

cells where it will completely change into a new cell type and thus present a complete set of new surface proteins,” he explained. “Even more frustrating is that the pathogen’s proteins have evolved to only activate a minimal immune response if they are recognized when the parasite transitions between cells.”

That rapidly changing picture has made the development of an effective malaria vaccine a serious challenge for scientists.

“While there has recently been some success coming from the WRAIR and GSK [GlaxoSmithKline] collaboration to make the RTS,S vaccine, the result is still only a reduction of about 50 percent fewer clinical cases of malaria in children in endemic areas of Africa. The parasites continue to grow and spread throughout the human population, causing much morbidity and mortality,” Lanar added.

“The goal now is to improve on RTS,S. Fortunately, new knowledge of how to activate the immune system with new vaccine constructs may help us succeed in teaching the body how to turn these invaders away.”

Entomology Branch Director Cmdr. Daniel Szumlas (U.S. Navy) said the insectaries at WRAIR house thousands of species of disease-carrying insects from around the world, from sand flies to Anopheles malaria mosquitos to Aedes aegypti mosquitos that transmit yellow fever and dengue, making single-facility research possible in the United States.

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ABOVE: Microbiology lab at the KEMRI/WRAIR trial site in KisumuKombewa, Kenya. Early development and clinical testing of the malaria vaccine RTS,S was part of an ongoing collaboration between GlaxoSmithKline and WRAIR. Malaria very rapidly becomes resistant to new drugs, driving researchers’ efforts to develop new drugs and vaccines. WRAIR has been successful in developing and field testing antimalarial drugs such as halofantrine, mefloquine, and tafenoquine, which provide treatment alternatives for drug-resistant strains. JohnMichael Maas, Darby Communications OPPOSITE: This scanning electron micrograph depicts a couple of clusters of aerobic Gramnegative, non-motile Acinetobacter baumannii bacteria as seen under a magnification of 12,739x. A. baumannii is the etiological agent of nosocomial infections resulting in septicemia, meningitis, endocarditis, pneumonia, and wound and urinary tract infections. MRSN is currently targeting methicillin-resistant Staphylococcus aureus (MRSA), and multidrug-resistant Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. CDC photo by Janice Carr

same way against Aedes aegypti or Anopheles gambiae, which is why we have the overseas labs for field testing with not only the right vector but natural populations.

“Many people can test them in the lab with insectary-reared pests, but a lot of times they have been reared for so many years, they’re not wild type anymore and actually react very differently. So it always has to go from preliminary laboratory testing to the field. And we’re adding a step in there to better control the conditions.”

The Entomology Branch also supports other departments for drug development and the malaria vaccine challenge model, as well as regular basic vector and parasite biology studies to help with any of those.

“That’s probably one of the most important things we do here. Then we have all these other efforts, like octopus arms going in all different directions, depending on what the effort is, but all related to entomology,” Szumlas said.

PRODUCTS AND SERVICES “There are 17 different species of sand flies. Most sand flies don’t even occur in the U.S., but everywhere else in the world, they transmit leishmaniasis and other nasty things,” he said, adding lab research results must be verified in the field. “If you don’t have the important vectors out there, you get good [lab] information, but it might not work the

The Centers of Excellence for Infectious Disease Research (CIDR) and for Military Psychiatry and Neuroscience (CMPN) have a mission focus for the development of products and knowledge that benefit the warfighter. From its mission research, WRAIR and military medical research focus on near-term product development, exemplified

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in other chapters of this publication and also realized, in part for WRAIR, through the Translational Medicine Division that stands in support of the centers and is comprised of the Pilot Bioproduction Facility (PBF), Clinical Trials Center (CTC), and Regulatory Affairs (for Investigational New Drug applications, in-house Food and Drug Administration compliance, and more). The services of the Pilot BPF and CTC are available to outside organizations through cooperative research and development agreements (CRADAs) and similar mechanisms so that others can take advantage of capacity in the conduct of clinical trials or when pilot lots of vaccines and biologics are needed.

Priority follows funding, according to WRAIR Deputy Commander Col. Peter Weina, and future research, beyond continuing pursuit of old and Second Gulf War-related projects, may be in jeopardy.

“New starts are stagnant right now. WRAIR research and missions are funded by ASA-ALT [Assistant Secretary of the Army for Acquisition, Logistics, and Technology], grants, CRADA partners, and many, many other sources,” he said. “[But] new starts are exceedingly difficult, if not impossible, in the current environment.

“We do have educational efforts that have done well recently due to their immediate and direct relevance to the combatant commander’s mission. Major underappreciated or neglected research is what we address when able; MRSN is a good example and our latest ‘new start’ major effort.”

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MULTIDRUG-RESISTANT ORGANISM REPOSITORY AND SURVEILLANCE NETWORK (MRSN) MRSN is a unique program, even among civilian medical agencies, combining basic and applied research with old-fashioned infection control efforts, Lesho said.

“I co-founded it with WRAIR in 2009, at the direction of the Army, as a unique combination of infection preventionists, scientists, microbiologists, laboratorians, and infection disease specialists to collect multidrug-resistant organisms. When a certain organism is isolated, it is sent to us here and we do sequencing and genomapping, then provide a quick report back to the reporting organization,” he said.

“We’re unique from what the CDC [Centers for Disease Control and Prevention] does in that we collect personally identifiable information; the CDC does not. It is both a blessing and a curse, given all the policy and security issues you must have in place. But the military is unique because casualties will pass through four to six hospitals on two continents within weeks of beginning treatment. The second way we’re unique is the CDC has no footprint in highly unstable areas, such as Iraq and Afghanistan. They do get information from Military Health through the National Health Safety Network, which is new, but it is after the fact, while ours is more real time.”

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It’s not in our main mission, but if a hospital asks us for help, we give it.

“Our research priorities are to expedite bioinformatic capabilities so we can annotate whole genomes. Current characterization methods are insufficient, but looking at the whole genome of an organism creates an extremely large data set and complex analysis. You want to detect these superbug and other genes quickly and cheaply, but how you read the spread of a growing line of bacteria is subjective. I would say the lack of available diagnostic methods for these organizations drove the need here.”

VETERINARY SERVICES

The Veterinary Services Program ensures that research complies with the Association for Assessment and Accreditation of Laboratory Animal Care International. Photo by Frank Miller

MRSN was the first to detect the presence of superbug genes, which Lesho said typically come from host-nation patients. When a sample arrives from doctors in another country, MRSN confirms what it is and is not, then alerts the reporting facility and sends a report to policymakers, starting with the Army Surgeon General, who create and enforce policy.

“If you have two patients with the same infection – one identified from blood, the other from urine – the question is which patient gave it to the other. Or is it genetically unrelated? We impact empiric therapy when a clinician is faced with a positive culture but doesn’t have all the details yet. When a patient comes in, the doctor wants to start treatment right away, but it will take awhile to get test results,” he said.

“It’s not uncommon for the reporting group to believe they do not have a resistant organism when they do. After that, they go through a hierarchy of characterizations, based on what it is. If it is from theater or a deadly outbreak, we can move on it quickly, determine what it is resistant to in antibiotics, what it’s related to.”

MRSN also translates basic research into clinical usefulness.

“For example, one hospital had an outbreak resistant to every antibiotic we had, so we used state-of-the-art research methods to determine the mechanism and now have a simple test hospitals can use to test for that bacteria. That also is true of the superbug genes,” Lesho said. “Our big focus is on health care-associated infections, which may change from month to month.

The institute conducts research in areas that might, at first glance, seem unusual for an organization dedicated to the health of deployed U.S. warfighters. One of those is the Veterinary Services Program, headed by Lt. Col. Kenneth E. Despain.

“Our mission, within the larger WRAIR mission, is to provide relevant, professional, and world-class veterinary support that allows the WRAIR and Naval Medical Research Center investigators success in developing and sustaining medical capabilities for the warfighter,” he explained.

“We’ve had Veterinary Services almost from the start of WRAIR, although we were realigned in 2011, taking our existing veterinary pathology and lab animal medicine programs and merging them into one.

“We provide oversight to the animal care and use programs and make sure we comply with the Association for Assessment and Accreditation of Laboratory Animal Care International. We take care of rats, mice, monkeys, any kind of research animal, providing housing, environmental enrichment, and husbandry. We consult with researchers on model use and development.

For example, in most research, investigators are trying to mimic the human condition which, in many species, closely resembles humans.”

The vision for Veterinary Services is to maintain excellence in management and operations of research in WRAIR’s vivarium, where animals are housed and cared for, and support labs for antemortem and postmortem procedures.

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“One thing we do in the vivarium is mimic, as closely as possible, the animals’ natural environment, because sick or stressed animals are not useful for much research,” Despain said. “We also provide comprehensive pathology expertise for animal colony health and development, advanced testing, and evaluation of therapeutic countermeasures. We provide support for the animals rather than conducting research; however, within the services we provide lab animal medical health and enrichment, which can make a tremendous difference in the animals’ general level of contentment.

“That becomes more important as you go up the chain to larger animals. It gets really complicated with primates – giving a lot of interaction with the staff, games to play, group housing, and activities that satisfy the need to forage. Malaria is an area of emphasis for WRAIR and we use primates to determine how a drug or vaccine affects malaria and distributes within the body. Once proof of concept is demonstrated in an animal model, you are ready to pursue work that culminates in clinical trials with humans.”

As part of their recent realignment, Veterinary Services is divided into branches.

The Resource Operations Branch limits access to WRAIR’s primates and research areas, as well as coordinating budgets and facilities. The Large Animal Branch deals with the procurement and care of primates, while the Small Animals Branch takes care of the different requirements of rodents and similar animals.

The Surgery Group has three surgical suites and a number of small animal surgery areas. It provides oversight of both and helps investigators develop surgical procedures, pain management, and both pre-op and post-op care. In the early stages of developing a surgical procedure, the group works with veterinarians to develop the anesthesia and surgical procedures.

The Veterinary Services Pathology Group looks at tissues and gives project investigators a microscopic analysis. They also do clinical pathology, look at blood samples and chemistry, have a bacteriology lab, and use scanning and electron microscopy for ultra-structural work on tissue. The group’s pathologists also formulate publication-quality data, prepare pictures for the investigator’s reports and presentations, do digital imaging of tumors or degraded bone, etc.

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CONCLUSION “Much of the research we do, especially basic science, starts with research in animals.

We may have a condition we want to study, but can’t give it to humans. There are a couple of types we do with animals, such as pharmacokinetics, where we take a medicine we have developed and give it to an appropriate animal model and identify how long it takes to metabolize, how was it metabolized, what were the effects and so on,” Braverman said.

Tight budgets are having an impact on WRAIR’s research future.

“We’ve been trying to do our own ‘Pacific pivot’ for some time, trying to establish a small MRSN in AFRIMS and AFRICOM, which is important to future efforts. But we’re like everybody else – expected to do more for less, including travel restrictions,” Lesho said, adding they nonetheless continue to pursue new areas of research. “Whole genome mapping and whole genome sequencing – clinical applications of those – which have been relative to basic research until now.

“The MRSN also was created for standardization, as a central reference lab. We are not a capacity-building effort. Our goal is to improve turnaround time. We have to focus on the military, which is our priority, but we definitely look more broadly because these infections don’t just affect warfighters.

They affect newborns, people in nursing homes, etc.; these pathogens respect no bounds. But, for now, it’s just a matter of maintain and survive for our group.”

The ongoing efforts of many more branches, departments, and programs and their expanding research efforts and evolving missions are covered elsewhere in this publication. Each has a similar story to tell, of past efforts and successes, of future goals and challenges, each in some way reflecting Braverman’s own conclusions about WRAIR. “My background is health care, and what I’ve learned here is there isn’t really a jump to one product that suddenly works for everything,” he said. “It is very much an incremental approach as we identify what works for some and, from there, try to make incremental improvements to those treatments, so that they work for more people or bring about better immune responses or are better tolerated, can be given more easily or have fewer side effects. Each of those is a separate series of research projects.”

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120 YEARS OF ADVANCES FOR MILITARY AND PUBLIC HEALTH

Infectious diarrhea has historically been a substantial cause of morbidity for deployed U.S. military personnel and continues to the present day in those deployed overseas. Pathogenic bacteria, including Shigella (main image), Campylobacter (inset), and enterotoxigenic Escherichia coli, are principal causative agents. WRAIR and the Navy Medical Research Center are working together on the development of effective countermeasures to prevent or abate bacterial diarrhea, with most efforts aimed at vaccine research and development. CDC photos

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THE CENTER FOR INFECTIOUS DISEASE RESEARCH LEADING THE FIGHT AGAINST THE ARMY’S – AND THE WORLD’S – DEADLIEST ADVERSARIES

By Craig Collins

I

nfectious disease – the problem around which Brig. Gen. George M. Sternberg organized his Army Medical School 120 years ago, and that sent Maj. Walter Reed into the swamps of Cuba to prove where yellow fever came from – has always been one of the Army’s most important concerns.

During the War for American Independence, when smallpox – the disease Gen. George Washington called his “most dangerous foe” – killed more men than musket fire, the disease reduced the troop strength of Washington’s Continental Army by more than half.

In 1777, Washington secretly ordered the inoculation of his entire Army through variolation – the purposeful infection of subjects in a controlled, quarantined environment. The commander in chief ’s decision is now regarded as a decisive factor in winning American independence.

For more than a century, however, diseases continued to be deadlier to Soldiers than combat. Fully two-thirds of the 620,000 Soldiers who died during the Civil War were killed by diseases, including dysentery, typhoid fever, malaria, yellow fever, tuberculosis, smallpox, and pneumonia. In the Spanish-American War, a monthlong conflict in which fewer than 400 U.S. forces were killed in combat, more than 2,500 Soldiers were killed by diseases; by the time it was over, fewer than one-quarter of the U.S. Soldiers who had gone ashore in Cuba remained fit for service, and the entire contingent was evacuated to a makeshift quarantine camp on the eastern tip of Long Island.

Better military medicine – and deadlier weapons – ensured that battle deaths outnumbered those of disease in the ensuing world wars, though infectious diseases still wiped out millions of combatants. In the latter half of the 20th century, as American Soldiers were dispatched to places as varied as Korea, Vietnam, Iraq, Somalia, Haiti, Sudan, and East

Timor, they were exposed to endemic pathogens – bacteria, viruses, and parasites – they’d never before encountered.

At the Walter Reed Army Institute of Research (WRAIR), infectious disease continues to be recognized as one of the greatest threats to the strength and readiness of the Army, both in the field and in the garrison. Since its earliest beginnings, its researchers have been focused on preventing naturally occurring diseases through evaluation, control, and treatment; in 2005, this work was placed under the authority of WRAIR’s Center for Infectious Disease Research (CIDR), which encompasses a worldwide network of laboratories and field sites. The center’s work focuses on enteric diseases; wound infections; bacterial and viral diseases, including multidrug-resistant organisms; vector control for malaria and other vector-borne infections; drug and vaccine development for malaria; drug development for leishmaniasis; and research into vaccines and treatments for HIV/AIDS. The work of the CIDR is carried out through several branches, including:

BACTERIAL DISEASES The work of the Bacterial Diseases Branch focuses broadly on the various ways bacterial infections can affect Soldiers. Several programs are devoted to product development and vaccines for enteric pathogens, while other groups – including several being established at WRAIR’s new Richard G. Lugar Center for Public Health Research in Tblisi, Republic of Georgia – are actively tracking emerging bacterial infections and agents around the world.

In its Department of Wound Infections under the command of Lt. Col. Eric Wagar, the branch’s researchers work to engineer and evaluate

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complementary strategies for the prevention, diagnosis, and treatment of wound infections. The focus is primarily on the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species) and the increasing problem of multidrug-resistant bacteria that colonize battle wounds. According to the branch’s acting director, Dr. Edwin Oaks, this department is in the early developmental stages.

“They’re doing basic research and animal model development,” he said, “looking at different ways to evaluate therapeutics for wound infection. These are very complicated systems, because they involve multi-agent infections.” One study, for example, is evaluating the ability of cell-penetrating nanoparticles to deliver anti-inflammatory proteins into mammalian cells. “You can just see, the way they are progressing,” he said, “that they’re going to be developing products probably in the not-too-distant future for wound infection.”

The branch devotes considerable resources to developing vaccines for diarrheal diseases, particularly the primary cause of bacterial dysentery (Shigella flexneri and S. dysenteriae). Its experimental vaccines are generally of two types: live-attenuated vaccines, which contain modified strains of pathogens that can, though weakened, induce a strong immune response; and sub-unit vaccines, which contain very small parts of pathogenic microorganisms, selected for their ability to trigger an immune response.

Because enteric and diarrheal diseases are a major cause of death for children in the developing world, they were recently targeted by the worldwide Global Enteric Multicenter Study (GEMS) led by Dr. Myron Levine of the University of Maryland, a study of more than 20,000 pediatric subjects at seven sites in sub-Saharan Africa and Southeast Asia, the results of which were reported in May 2013. As Dr. Malabi Venkatesan, who leads the branch’s live Shigella vaccine program, pointed out, these areas are, not coincidentally, where WRAIR’s overseas laboratories – the U.S. Army Medical Research Unit-Kenya (USAMRU-K) and the Armed Forces Research Institute of Medical Sciences (AFRIMS, headquartered in Bangkok, Thailand) – conduct several infectious disease research programs. “The GEMS study,” said Venkatesan, “showed that the Shigella bacteria was a leading cause of moderate to severe diarrhea in these areas.” WRAIR researchers are developing both live and sub-unit vaccines for Shigella; both of which were manufactured on site at WRAIR and are currently being evaluated in clinical trials.

While Shigella has been a focus for WRAIR researchers for years, said Oaks, the pathogen comprises one piece of the branch’s broader effort.

“What we are working on,” he said, “is a diarrheal disease vaccine. We’re part of a larger program funded by the Military Infectious Diseases Research Program. That includes work done by the Naval Medical Research Center, and here at WRAIR. We work together. And the ultimate goal is to actually make a diarrheal disease vaccine for Shigella, Campylobacter, and ETEC [enterotoxigenic Escherichia coli].”

The Bacterial Diseases Branch is also responsible for one of WRAIR’s newest initiatives, launched in response to an epidemic of multidrug-resistant organism infections in health care facilities and among wounded warriors. Established in 2009, the Multidrugresistant Organism Repository and Surveillance Network (MRSN), under the leadership of Col. Emil Lesho, collects and characterizes these organisms at medical facilities throughout the Army in order to

inform best clinical practices, influence policy, and enhance infection prevention and control efforts. Currently comprised of a microbiological laboratory, an organism repository containing more than 15,000 isolated pathogens, and seven Army hospitals, the MRSN is available to Navy and Air Force facilities, and is poised to expand to all Army hospitals – and perhaps to all U.S. military hospitals. The network has already helped halt the progress of a fatal outbreak of methicillin-resistant Staphylococcus aureus (MRSA) in a hospital’s neonatal intensive care unit, and promises to be increasingly useful as it matures. “The MRSN is already affecting policy,” said Oaks, “leading to improved infection control in health care facilities.”

The branch’s research outcomes include the development of methods to identify and diagnose infectious agents as rapidly as possible. In partnership with WRAIR’s overseas laboratories, the Bacterial Diseases Branch is developing methods, such as mass spectrometry, that enable technicians to identify infectious agents in a fraction of the time taken by traditional culturing and microscopy, which can take two to three days.

As Venkatesan pointed out, a mass spectrometer – typically about the size of a walk-in closet – isn’t of much use in a wartime theater.

“Our diagnostics people are also working on making kits that can be used by a medic to make a rapid determination of whether a person is suffering from a viral disease or a bacterial disease. It’s a simplified tool, but important, so that field personnel can know not to give an antibiotic to a person who may be suffering from a viral disease. There [is] a whole range of diagnostic kits and equipment being evaluated to fit different settings and circumstances.”

VIRAL DISEASES The recent redevelopment of the adenovirus oral vaccine for serotypes 4 and 7, said acting Viral Disease Branch Laboratory Director Maj. Richard Jarman (Lt. Col. Stephen Thomas, director of Viral Diseases, was deployed during the preparation of this article), illustrates the necessity of the military’s involvement in this research: Diseases that aren’t regarded as a threat by most Americans can have a profound effect on military readiness and end strength.

Adenovirus causes flu-like and respiratory symptoms and, like the flu, it can be fatal – though it usually isn’t. For most Americans, it’s a minor nuisance – but for the Army it can be a back breaker. “The population at risk for adenovirus,” said Jarman, “is one that’s enclosed in a confined space. Students in university dorms and prison inmates, for example, are at risk – but if they’re out of commission for a week, the impact is less significant.” For an Army recruit to miss a week of an eight-week basic training course – which costs more per week than an Ivy League education – is a big deal; every recruit who doesn’t complete the course has to be recycled.

The oral vaccine for the two most predominant types of adenovirus, developed by WRAIR researchers, was discontinued in 1999 after the manufacturer stopped production – and not surprisingly, the rate of infection among Army recruits immediately spiked. When the Army decided to restart production, the manufacturer was no longer interested – “So we had to resubmit the IND [Investigational New Drug application] and do the clinical trials over again, and begin new manufacturing processes,” said Jarman. The second-generation vaccine,

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For the first time in more than a decade, recruits at USS Red Rover take the adenovirus vaccine during their medical in-processing at the Captain James A. Lovell Federal Health Care Center, North Chicago, Ill. U.S. Department of Defense photo by Lt. Cmdr. Mark Herwitz

rolled out in 2011, has massively reduced adenoviral infections among recruits. “It’s a huge success story.”

Another viral disease that causes little concern among temperate-climate-dwelling Americans – dengue fever – is the most common mosquito-borne disease in the world. A Swahili term meaning, literally, “breakbone fever,” dengue incapacitates a patient for seven to 10 days with flu-like symptoms: fever, headaches, and severe muscle and joint pains. There is, as yet, no known antiviral treatment for dengue; patients are typically hydrated while the infection runs its course.

Largely endemic to the humid tropics, the disease took an extreme toll on U.S. Soldiers in World War II’s Pacific Theater and in Vietnam.

As the Asia-Pacific region continues to grow in strategic importance, the Army has renewed its focus on dengue fever, both in developing vaccines and treatments and in gathering contemporary data on the disease’s impact among personnel.

WRAIR’s Viral Disease Branch researchers have been conducting dengue vaccine research for more than 20 years – but, as it has been among all dengue researchers, their progress has been unusually painstaking, complicated by the fact that, for reasons not yet understood, a primary infection by one of the virus’s four disease-causing serotypes increases the risk that a later, secondary infection by another serotype may have more severe symptoms – internal hemorrhaging or shock, which both can be fatal.

Under these circumstances, a vaccine that contains just one dengue serotype will do much more harm than good, Jarman explained. A live attenuated vaccine would need to contain all four serotypes, and it would need to contain them in the proper ratios, because of their different rates of replication. After testing many different formulations,

Army researchers and their research partners at GlaxoSmithKline (GSK) recently shifted focus to a different type of vaccine, developed

by WRAIR’s Viral Disease Branch.

The new platform, said Jarman, is “a purified and inactivated vaccine – which is basically all four types in equal amounts, formulated and inactivated with formalin so you don’t have to worry about the replication. The expectation is that you would get an equal immune response, because it’s not biological anymore. The viruses aren’t competing with each other.”

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

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LEFT: 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 RIGHT: An Anopheles stephensi mosquito, known malarial vector, on a human finger. CDC photo by Jim Gathany

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

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Results of the RTS,S Phase III vaccine trial conducted in Africa were presented at the 6th Multilateral Initiative on Malaria Pan-African Malaria Conference, Oct. 8, 2013, by Dr. Lucas Otieno, principal investigator at U.S. Army Medical Research Unit-Kenya. Perhaps someday, a military-quality vaccine for malaria will be given to Soldiers deploying to malaria endemic areas of the world. U.S. Army photo

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.”

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.

The challenge model is also being used to evaluate an experimental vaccine for another strain of the malaria parasite, P. vivax, which is not as deadly as P. falciparum but, according to Paris, causes most of the cases of malaria in the U.S. military. P. vivax tends to “hibernate” in a person’s liver, causing the disease to recur or “relapse.” “Because of its biology,” Paris said, “P. vivax presents the biggest hurdle for the elimination of malaria.” MMRP investigators today are among only a handful of scientists around the world developing an experimental P. vivax vaccine.

Mild to moderate malaria caused by P. falciparum and P. vivax is treated with oral drugs. When P. falciparum developed resistance to the classic agent chloroquine at the time of the Vietnam War, WRAIR was called on to urgently deliver a new malaria prevention drug to maintain combat readiness of deployed troops and cure those who

needed treatment. WRAIR scientists invented and then co-developed a new drug named mefloquine as a chloroquine replacement. As with all drugs, resistance emerged to mefloquine over time and WRAIR physicians and scientists played an important role in the FDA approval of the next-generation malaria prophylaxis drug malarone in 2000.

There are more cases in the United States of P. vivax than P. falciparum.

WRAIR clinical scientists developed primaquine in the 1940s-1950s to treat the hidden P. vivax parasite in the liver, and it is still used today.

WRAIR invented the potential primaquine replacement, tafenoquine, that is in advanced clinical testing today.

Severe malaria is treated with intravenous drugs. Quinine is used worldwide, whereas quinidine is the only agent approved for use in the United States, although it can cause cardiac damage. For these reasons, WRAIR researchers and others have for some time focused on artemisinins. Artemisinins were widely used more than 2,000 years ago in traditional Chinese medicine, and were redeveloped by the Chinese government to treat North Vietnamese soldiers during the Vietnam War – at about the same time WRAIR researchers were developing mefloquine for U.S. troops. In the 1980s, WRAIR scientists found sweet wormwood growing on the banks of the Potomac River, extracted artemisinins, and began studying them. One of the most promising compounds to be studied by the group, artesunate, is a semi-synthetic artemisinin derivative that is water soluble and deliverable intravenously (IV). A team of WRAIR researchers led by Dr. Qigui Li and Col. Peter J. Weina, M.D., recently published that patients with severe malaria who received IV artesunate were 35 percent less likely

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Sgt. Michael Sandford, a laboratory technician at the Walter Reed Army Institute of Research in Silver Spring, Md., demonstrates how to use the arthropod vector rapid detection device (AV-RDD), May 3, 2012. The AV-RDDs detect pathogens in mosquitoes and sand flies that cause malaria, dengue, and leishmaniasis. Walter Reed Army Institute of Research photo

to die than those treated with quinine. WRAIR and U.S. Army Medical Materiel Development Activity (USAMMDA) have for a decade been engaged in an effort to replace quinidine with IV artesunate in the United States. In 2007, the FDA approved the use of IV artesunate as an investigational new drug to treat severe malaria in the United States, making the compounds available in the United States for the first time.

It is better to prevent malaria than to have to treat it. The three drugs used today as malaria prophylaxis are doxycycline, found to be effective in the 1980s by scientists working at the WRAIR laboratory in Thailand; malarone; and mefloquine. The leading candidate for a new prophylactic agent is the WRAIR drug tafenoquine, now being developed for prevention by the USAMMDA at the U.S. Army Medical Research and Materiel Command.

THE LEISHMANIA DIAGNOSTICS LABORATORY WRAIR is the only institution in the world focused on developing new drugs for the prevention of malaria in healthy adults – and it is home to the only certified laboratory in the United States specializing in another vector-borne parasitic disease: leishmaniasis. Protozoans of the genus Leishmania, delivered by the bite of certain species of sand flies, attack hosts in two ways: The more common cutaneous form of leishmaniasis (CL) creates skin lesions that can be difficult to treat and may cause permanent scarring or damage a patient’s mucous membranes; in the potentially fatal visceral leishmaniasis (VL), the parasite migrates to the internal organs and bone marrow.

Since 2003, when U.S. troops were deployed to Southwest Asia, where sand flies thrive, more than 3,500 troops have been diagnosed with CL. To date, there is no vaccine, prophylaxis, or FDA-approved drug treatment for CL; WRAIR is the only institution in the world with a dedicated CL drug development program. Currently, the treatment for CL involves killing the parasite through the intravenous introduction, or injection, of toxic heavy metals called antimonial salts. However, Phase III trials of antibiotic creams developed by WRAIR researchers, conducted under a U.S./French/Tunisian partnership, demonstrated a greater than 80 percent cure rate, presenting the possibility of a safe, nontoxic, first-line treatment for CL that patients could apply themselves. The results of the study were published in the New England Journal of Medicine in February 2013.

WRAIR’s Leishmania Diagnostics Laboratory specializes in the development of diagnostic assays that will help both military and civilian clinicians diagnose the disease and differentiate between its forms. Investigators have successfully diagnosed suspected leishmaniasis lesions from species all over the globe, from the Middle East to Latin America.

ENTOMOLOGY To better understand the vectors that spread these diseases – Leishmania-carrying sand flies; the Anopheles genus of mosquitoes that carry malaria; Aedes aegypti, the mosquito that carries yellow fever and dengue; the Culex mosquitoes that carry West Nile virus

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120 YEARS OF ADVANCES FOR MILITARY AND PUBLIC HEALTH

The RV144 trial tested the “prime-boost” combination of two vaccines: ALVAC®-HIV vaccine (the prime) and AIDSVAX® B/E vaccine (the boost).

MHRP photo

and encephalitis; and other arthropods – WRAIR investigators study them both in the field and in a global network of insectaries, anchored

by WRAIR’s 964-square-foot facility in Maryland. The facility, which opened its doors – multiple, mosquito-proof doors – in 2000, is the starting point for all of WRAIR’s repellent, drug, and vaccine research for vector-borne diseases. The Anopheles mosquitoes used in WRAIR’s malaria challenge studies are bred, hatched, raised, and fed a blood meal with the Plasmodium parasite in the insectary.

The products most often associated with the Entomology Branch are those that reduce the risk of being bitten by a carrier – either personal protective measures, such as topical repellents, treated uniforms, and bed nets, or vector controls such as pesticides. Topical repellents are too expensive for many people who live in the most mosquito-infested parts of the world, and the most effective one developed to date, DEET, has fallen out of favor among U.S. Service Members, for various reasons.

Out of necessity, WRAIR’s entomologists spend time studying whether people are willing to use a repellent or not – and increasingly, they don’t like DEET. “It’s sticky and it eats plastics,” said Cmdr. Dan Szumlas, director of the Entomology Branch. “Nothing works like topical repellents, but if people don’t want to use them, then obviously they’re not effective at all. So we’re looking at different kinds of spatial repellents, or insecticides, that have that effect that people can use either on their uniforms, or on a device on their body, or in a device you can put in the middle of a group, and protect everyone from bites.”

Branch investigators are developing a new generation of both topical repellents – such as picaridin, which is now available to troops – and spatial repellents.

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The Entomology Branch also conducts basic research into vector and parasite biology, and its field workers assist in worldwide vector surveillance efforts. Increasingly, given the enormity of such a task, this work is performed jointly, in partnership with several agencies, including the U.S. Department of Agriculture, the Naval Medical Research Center – which maintains several laboratories of its own – and the WRAIR’s own Walter Reed Biosystematics Unit (WRBU) headquartered at the Smithsonian Institution’s branch in Suitland, Md. Together, investigators from these institutions are participating in the Mosquito Barcoding Initiative (MBI), led by Dr. Yvonne-Marie Linton, a senior National Research Council fellow on assignment from the Natural History Museum in London.

The MBI represents the first time researchers have collaborated in such a global effort against mosquito-borne diseases. Investigators are creating genetic references to the world’s mosquitoes by collecting specimens in the field or using museum specimens, identifying them to species, and finally sequencing “barcodes” that correlate with specific genes. One of the project’s ultimate goals is to equip field personnel with devices that can identify not only the mosquito species, but what kind of pathogen it might be carrying.

Szumlas pointed out that aside from the obvious benefit to public health, this biosurveillance tool could help protect Soldiers deployed overseas. “In the field, the commander has so many things to worry about,” he said. “Infected bugs infecting people is one of those, but it’s probably a lower priority until the red flag goes up. And that’s what the surveillance is all about: To collect mosquitoes, identify what they are, and then see what’s in them. If there is malaria about to be transmitted, the commander of that unit can say to everyone, ‘If you have not been using your repellent, your prophylactics, your netting, you’d better right now, because we’ve got some hot mosquitoes out and around.’”

Ironically, WRAIR’s entomologists, who continue to spend much of their energy trying to repel these insects, are working on better ways of attracting them – not only to participate in biosurveillance efforts, said Szumlas, but also to provide subjects for vector and parasite studies. “A lot of times,” he said, “they have been reared for so many years they’re not a wild type anymore, and they actually react very differently.” To lure mosquitoes, either in the laboratory setting or from within the huge screen tents erected in the field, WRAIR entomologists are evaluating a new generation of traps: some baited with sugar, which mosquitoes seek when they’re not looking for blood, and some with carbon dioxide, the signature attractant in the respiration of all warm-blooded animals.

THE MILITARY HIV RESEARCH PROGRAM When the United States launched its HIV/AIDS (Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome) research program in the 1980s, the Department of Defense, recognizing the threat the disease posed to end strength and readiness, had already begun developing protective measures – education programs, vaccine development, and innovative anti-viral therapies. In 1986, based on data collected at the Walter Reed Army Medical Center, the military program published evidence of the possibility – which was then a controversial idea – that HIV could be transmitted heterosexually. That same year, the Army also adopted the Walter Reed staging classification

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can be useful diplomatically; for example, if AFRICOM [Africa Command] is trying to build a better relationship with the Nigerian military, we can go in, with established relationships, and help them determine prevalence and what types of HIV are circulating.

The threat assessment group helps to build strategic relationships.”

THE RV144 VACCINE TRIAL: A FIRST SIGN THAT WE MIGHT WIN

Col. Nelson Michael, M.D, Ph.D., director of the U.S. Military HIV Research Program (MHRP) at the Walter Reed Army Institute of Research in Silver Spring, Md., receives the Hero of Military Medicine Award for his excellence as an HIV researcher and leader in global health, May 2, 2013. U.S. Army Medical Research and Materiel Command photo

system for HIV, the first of its kind. The system provided a framework for diagnosing infected military personnel and evaluating patients’ clinical responses to antiviral treatment.

Based in part on these advances, Congress mandated the formation of a military HIV/ AIDS research unit, to be led by the Army. The program that has emerged and evolved over the last quarter-century, centered at WRAIR and known collectively as the U.S. Military HIV Research Program (MHRP), has grown to include research sites in Kenya, Tanzania, Uganda, Mozambique, Nigeria, and Thailand.

The director of the MHRP is currently Col. Nelson Michael, M.D., Ph.D., who was deployed to Jordan during the preparation of this publication.

According to Col. Jerome Kim, M.D., deputy director of the MHRP, an early program focus was on protecting the military’s blood supply.

“The idea at the time – and it’s still true today,” he said, “was that if you’re injured on the battlefield, you don’t always have the luxury of having banked blood available. Sometimes you just have to put out a call for donations.”

MHRP investigators, building on the early HIV tests pioneered by Dr. Robert Gallo, a co-discoverer of the AIDS virus, developed screening protocols for blood units as well

as a total-force HIV screening effort. “At first it was criticized,” Kim said. “People were saying: ‘You’ll have too many falsely diagnosed people, and cause all this stress.’ But the Army’s program was set up to make sure false diagnosis didn’t happen. It was an idea that was way ahead of its time.”

Today this diagnostic group, based at WRAIR, performs all the confirmatory diagnostics for everyone in the Army, anywhere in the world, who tests positive for HIV. In fact, MHRP developed and implemented the most advanced HIV diagnostic algorithm in the United States, which can be used to detect HIV in deployed troops. “They also do what we call viral load testing,” said Kim. “They can tell how much virus there is in people’s blood – and then also provide the service of telling those doctors who is resistant to what drug. So we provide a clinical service as well as diagnostics.”

Another MHRP group is focused on threat assessment. MHRP conducts epidemiologic studies, identifies specific targets for preventive intervention, and prepares specific recommendations for program and policy changes that are intended to decrease HIV transmission among most at-risk populations across the Army. This threat assessment expertise

The work of the MHRP’s immunologists and virologists has advanced the MHRP’s threat assessment capabilities and also laid the groundwork for pursuit of the program’s ambition to eliminate the threat of HIV/ AIDS. In an unusual arrangement, WRAIR’s researchers include both early-stage clinical vaccine researchers, led by Dr. Merlin Robb, and a group that helps plan and conduct large scale efficacy studies, led by Kim. The MHRP has been developing HIV vaccines for nearly 20 years. The program made history in 2003, when it launched a trial among more than 16,000 Thai subjects combining two vaccines. Vaccinated subjects were first given ALVAC-HIV, which uses a canarypox virus to introduce select HIV genes into the body, and then a booster of AIDSVAX B/E, a glycoprotein vaccine used in an earlier Bangkok trial.

When the subjects of this trial, known as RV144 or simply “the Thai trial,” were examined six years later, the results demonstrated that the ALVAC-HIV and AIDSVAX B/E “prime-boost” had lowered the rate of HIV infection by 31.2 percent, compared to those who had been given a placebo. “So there was evidence that the vaccine could actually protect against infections. It was the first time that had ever been seen,” said Kim, “the only clear demonstration of protection in humans.

And that’s important, because, at the time, we were thinking protection might not even be possible. We were thinking that, at best, the vaccine might decrease the amount of virus in your blood if you got infected.”

After the RV144 trial, the most important question became: How did the vaccine work?

A series of follow-on collaborations, involving 150 researchers from 27 institutes around the world, combed through RV144 results to generate hypotheses. The effort culminated in a study led by scientists from WRAIR and

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Duke University, who in 2012, reported the vaccine was triggering an immune response that targeted a vulnerable site on the virus’s protein coat, a site known as V2.

The methodical, deliberate pace of these collaborative events may obscure what likely will be regarded, when the final history of the HIV/ AIDS vaccine is written, as a historic milestone: In the span of a decade, MHRP researchers and their partners have proven that protecting humans with an HIV vaccine is possible, and identified a point of attack for future vaccines and therapies. Already, clinical trials have been launched to build on these findings.

MHRP has developed a promising next-generation MVA vaccine in collaboration with the National Institutes of Allergy and Infectious Diseases (NIAID) Laboratory of Viral Diseases that is aimed at global protection (one whose efficacy is not limited to a regional subtype). The MVA vaccine is already being tested in combination with several vaccine candidates in the United States, Sweden, and East Africa. This MVA vaccine will be used in combination with an Ad26 vaccine in the United States in 2014 through a private-public collaboration.

Since 2004, the MHRP has provided prevention, care, and treatment services in the African communities in which research is conducted. These activities were undertaken at the insistence of former MHRP Director Debbi Birx, M.D., who put forth the idea – an unusually forward-thinking idea, at the time – that the program was ethically obligated to treat people who participated in clinical trials and later became infected with HIV. This eliminated potential coercion by offering treatment to all regardless of participation in HIV vaccine trials. At around the same time, the White House launched the President’s Emergency Plan for AIDS Relief (PEPFAR), which continues to fund MHRP’s effort to provide these services both in civilian communities and with militaries.

“By setting up PEPFAR programs at each of our sites,” said Kim, “we now have the ability to offer treatment to everyone in the region.”

In Tanzania, for example – where the military has had battalions decimated by HIV – MHRP partners have been invited to set up care and treatment programs at military hospitals. “That kind of relationship is a critical part of our engagement with foreign militaries,” Kim said. “It has strategic importance.”

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Established 55 years ago, the Armed Forces Research Institute of Medical Sciences (AFRIMS) is a model collaborative program between U.S. and Thai military and civilian scientists. AFRIMS played a critical role in RV144 and the follow-on study on the RV144 correlates of risk. U.S. Army photo

As it continues to work toward an effective vaccine, MHRP’s research has turned its attention to another future goal: curing infected patients. This research, explained Kim, focuses on the early stages of infection – an emphasis for which MHRP’s vaccine work has laid the groundwork. “If you stop an invader on the beaches,” he said, “it’s a lot better than letting it land, set up camp, and establish itself. We were studying early infection in order to understand what we need to do to prevent the initial landing, or to contain it just after landing – but it turns out some of the research we were doing is ideally suited for the cure agenda.”

In one study, researchers initiated anti-retrovirals within the first days of infection and then intensively studied them. “These people now have no detectable virus at the limit that we can detect in their blood,” said Kim. In collaboration with other scientists from universities and the National Institutes of Health (NIH), MHRP researchers are designing interventions aimed at eradicating HIV before it can take hold. “All of these different efforts are ongoing,” he said, “and really exciting cutting-edge research has been done in the last year.”

Despite sharp reductions in infection rates – according to a United Nations 2012 report, HIV infections have fallen by 50 percent or more in 25 countries, with an additional 14 countries having achieved declines of 25 to 49 percent – HIV still infects 34 million people annually, posing a significant threat not only to military readiness and force protection, but also to the stability and security of many already struggling nations.

In June 2001, before a United Nations General Assembly special session on HIV/ AIDS, Gen. Colin Powell, the former secretary of state and U.S. Army chief of staff, echoed the anxieties of his predecessors – Washington’s dread of smallpox, and MacArthur’s fear of malaria – when he said: “No war on the face of the Earth is more destructive than the AIDS pandemic.” A dozen years later, and 120 years after Army Surgeon General Brig. Gen. George M. Sternberg established an Army Medical School whose researchers ventured out to study the world’s most virulent diseases, there are, at last, signs that WRAIR’s Center for Infectious Disease Research may someday make these diseases – like smallpox, which WHO declared eradicated in 1979 – a thing of the past.

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THE CENTER FOR MILITARY PSYCHIATRY AND NEUROSCIENCE TO PROTECT AND PROMOTE SOLDIER RESILIENCE, CMPN RESEARCHERS FOCUS ON BOTH BODY AND MIND.

By Craig Collins

U.S. Army photo

W

hen renowned psychiatrist and neuroanatomist David McKenzie Rioch established a Division of Neuropsychiatry within the Army Medical Service Graduate School in 1951, it was the launch of a golden age. His research group, which had helped to establish a new terminology for situational behavior disorders during World War II, was a historically significant prototype for the modern neuroscience laboratory: It was a wide-open scientific think tank where the boundaries of departments and research disciplines were deliberately blurred.

Neuroscientist Robert Galambos, a member of this founding group, later recalled: “The Rioch organization came into being because the Army wanted to solve a pressing practical problem. The commandant of the Walter Reed Army Institute of Research [WRAIR], Col. William Stone, defined it when he interviewed me for the job. He said, in effect, psychiatric casualties had reached the top of the Army’s list of medical problems, and Rioch’s mission was to supervise the basic research effort that would drop it to the bottom.”1 It was to this organization that an Army draftee, the 29-year-old neurobiologist David Hubel, reported for duty in 1955. “One then had little of the feeling of frenetic competition that is found in graduate students today,” Hubel later wrote. “It was possible to take more long-shots without becoming panic stricken if things didn’t work out brilliantly in the first few months. … Scientifically, I could hardly have chosen a better place than Walter Reed.”2 In 1957, Hubel launched his main research project at the WRAIR, an electrophysiological study of

axonal neurons in the brains of cats. This study laid the groundwork for later discoveries Hubel and research partner Torsten Wiesel would make about information processing in the visual system – discoveries that would earn the pair a share of the 1981 Nobel Prize in Physiology or Medicine.

The experiences of American warfighters in Vietnam shifted the division’s objectives. Rather than broad-based studies of the entire nervous system, the group took on a more mission-focused research program. In the 1960s and 1970s, it dispatched the Army’s first expeditionary psychological research teams – precursors to today’s Mental Health Advisory Teams, or MHATs – to observe, study, and document substance abuse by young Soldiers. The group’s “jet lag” studies in the late 1970s helped the Army develop simple countermeasures to reduce fatigue and improve performance after long-distance air deployments.

Renamed the Center for Military Psychiatry and Neuroscience (CMPN) in 2009, this group at the WRAIR continues to pursue a vision much like that of Rioch – a vision that: focuses on issues critical to the psychological and neurological health of Service Members; attracts and develops world-class researchers; fosters a creative, innovative, and collaborative culture; and moves products from the bench to the field to promote Service Member wellness.

For more than 60 years, from World War II to the Global War on Terrorism, WRAIR’s psychiatry and neuroscience program has been remarkably productive; its research innovations have yielded more than 30 patents for scientific contributions. Today, research-based solutions

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U.S. Army Pfc. Shawn Williams of the 1st Stryker Brigade Combat Team, 25th Infantry Division, based in Fort Wainwright, Alaska, gives the thumbs-up to members of his unit as he is evacuated after being injured by a roadside bomb, June 17, 2011, in the Kandahar province of Afghanistan. The proliferation of explosive devices in Iraq and Afghanistan has led to increased numbers of traumatic brain injuries. U.S. Department of Defense photo by Lt. j.g. Haraz Ghanbari, U.S. Navy

delivered by CMPN scientists are aimed at the different types of challenges facing contemporary Service Members, embodied in the center’s organizational structure. The center’s four research directorates, housed within WRAIR, are: • Brain Trauma Neuroprotection and Neurorestoration • Blast-Induced Neurotrauma • Behavioral Biology • Military Psychiatry Brain injury has always been one of the leading causes of military casualties – probably even more so over the last decade. Up to 30 percent of combat trauma suffered by Service Members in Iraq and Afghanistan has occurred in the head and neck region. The vast majority of this trauma has been caused by the enemy explosive devices common to these conflicts: improvised explosive devices (IEDs), mines, mortars, bombs, and rocket-propelled grenades. A 2003-2008 study revealed that more than half of the military’s evacuated neurosurgical patients had sustained a traumatic brain injury (TBI) caused by a blast event, and that 71 percent of these victims also suffered a penetrating traumatic brain injury, or PTBI. Advances in armor and battlefield medicine have rendered these injuries less deadly – but have also increased the number of patients who, as a consequence, confront a lifetime of cognitive and physical disabilities. TBI victims, in general, have a shorter life expectancy, and are more likely to suffer from seizure disorders, neurodegenerative

diseases, neuroendocrine disorders, and psychiatric diseases. One such long-term consequence of TBI, chronic traumatic encephalopathy (CTE), has recently gained attention as a potentially devastating outcome for people who suffer from multiple mild TBIs. Under the leadership of Dr. Frank Tortella, senior scientist and TBI subject matter expert for WRAIR and its command, WRAIR’s Brain Trauma Neuroprotection and Neurorestoration (BTNN) Branch aims to protect Service Members from these outcomes, with investigations that have two ultimate objectives: a means of diagnosing mild to moderate TBI promptly, in the field; and identifying new treatments to protect brain tissue, decrease the short- and long-term neurological damage associated with TBI, and increase the likelihood that brain tissue will recover and heal.

Currently, mild TBI or concussion is hard to diagnose beyond the obvious symptoms: a loss or alteration of consciousness, post-traumatic amnesia, headache, dizziness, blurred vision, ringing ears, cognitive problems, and sleep disturbance. As such, the mTBI has been called the “invisible” injury of war since many, if not most, cases of mild TBI are under-diagnosed and go undetected by traditional brain imaging approaches. Consequently, it remains difficult, if not impossible, to tell how severe a mild TBI really is, or how the injury changes over time.

Researchers in the Brain Trauma Neuroprotection and Neuroplasticity Branch have contributed substantially to the growing body of work

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Ongoing studies conducted by the Center for Military Psychiatry and Neuroscience have sought to further the understanding of how TBI affects the brain.

that continues to show TBI-specific biomarkers – higher- or lowerthan-normal levels of proteins and enzymes associated with specific neurological mechanisms – in brain tissue and/or cerebrospinal fluid (CSF) and serum. These biomarkers have been detected and measured in animal models, and increasingly in human subjects in clinical trials, and they show great promise – but the science is still too young to link the presence of specific biomarkers to an indication for certain drugs.

“Their studies have identified some pretty good TBI-related biomarkers – biomarkers that have sensitivity and specificity,” said Col. Paul Bliese, director of the CMPN. “This has a lot of applicability to places like Iraq or Afghanistan, where someone may encounter many other kinds of injuries, but where one isn’t necessarily sure whether they’ve suffered a traumatic brain injury as well.”

There is no drug therapy currently approved as a standard of care for TBI. The directorate’s approach to discovering and developing effective TBI drugs is via cooperative research and development agreements (CRADAs) with pharmaceutical companies, as well as collaborative efforts with the Army’s Operation Brain Trauma Therapy (OBTT) program, a multicenter pre-clinical drug-screening consortium. Using animal models of severe TBI, the efforts of the BTNN research team have demonstrated what drugs are highly neuroprotective and anticonvulsant and therefore suitable for the launch of Phase I clinical trials to demonstrate safety and bioavailability in normal volunteers. With Phase I trials complete for one such drug, the next

step is already under way – a Phase II trial, with cost sharing between private industry and the DoD, of the drug’s safety and efficacy in moderate and severe TBI patients.

TBI-related brain physiology is still not completely understood, and two decades’ worth of clinical trials have not produced a single drug capable of reliably protecting the brain from TBI-related harm. Singledrug “monotherapies,” which target individual or simple brain mechanisms, simply haven’t proven adequate to address the complexities of the injured brain, and BTNN researchers are among those turning increased attention to combination drug therapies that achieve efficacy through synergistic drug-pair interactions.

The center’s neuroprotection and neurorestoration researchers have also contributed to research in non-pharmacological TBI treatments, such as therapies in which human amnion-derived stem cells, transplanted into injured brain tissue, have demonstrated an ability to protect against neural tissue damage and motor deficits. BTNN Branch researchers have also conducted pre-clinical investigations, in animal models, into an innovative method for selectively cooling the brain post-trauma. The use of a cooling cuff placed around the common carotid artery can achieve rapid and sustained reductions in brain temperatures – which in turn reduces intracranial pressure, inflammation of damaged tissues, brain edema, and the permeability of the protective blood/brain barrier (BBB) – without adversely influencing core body temperature.

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device that can identify TBI biomarkers, and drugs that can help protect brain tissue from post-traumatic damage, these will indeed be historic breakthroughs.

BLAST-INDUCED NEUROTRAUMA

Staff Sgt. Guadalupe Jaramillo (left) adjusts the advanced combat helmet on a Soldier in her unit at Manas Air Base, Kyrgyzstan, on Aug. 9, 2013. It is hoped that CMPN research will lead to a better understanding of TBI and therefore therapeutics, techniques, and equipment – such as helmets or body armor – to protect Service Members from it. U.S. Army photo by Staff Sgt. Raymond Kokel

“They’ve been able to show that if you can just reduce the temperature of the brain one or two degrees,” said Bliese, “you can actually alter the outcome – very similar to the idea of putting ice on your knee.” The group’s isolation of the carotid artery has been an important evolutionary step from earlier interventions involving whole-body cooling, which actually increases the risk of several adverse outcomes, including blood clotting, hypotension, and infectious pneumonia, particularly prevalent in polytrauma patients. The selective technique of isolating the common carotid artery, however, also limits the therapy’s applicability, making an excellent tool but far less feasible as a clinical therapy in forward-deployed medical facilities.

Of course, the majority of the world’s TBIs are suffered not in battle, but in car accidents, and by the military’s own estimate (epidemiological data released in 2013 by the Defense and Veterans Brain Injury Center and the Armed Forces Health Surveillance Center), 80 percent of military service-related TBI occurs in non-deployed environments. The work of this research team has also led to the development of a head injury model causing true mTBI/concussive syndromes to examine changes that occur in the brain after single and repetitive concussions, and explore those changes over time to understand the link between mTBI and potential chronic illnesses such as CTE. The work of the center’s Brain Trauma Neuroprotection and Neurorestoration Branch, said Bliese, is, “despite being one of our newer programs, one that has been particularly successful, over the last few years, in rolling out some potentially very useful products.

And if a group like BTNN is able to identify and develop serum diagnostics and therapies that would be useful following a traumatic brain injury, the application of that goes well beyond the military: These are products that would change the landscape of medicine and could be rolled out in emergency rooms in hospitals around the world.” Collectively, when the work of the center’s Neurotrauma and Neurorestoration Branch helps to produce a field-deployable

Severe TBI has represented the most significant life-threatening trauma to Service Members in Iraq and Afghanistan, but the vast majority of traumatic brain injuries suffered by Service Members since 2000 have been mTBI, consisting of closed-head injuries without penetration of the skull. More than three-quarters of the TBI suffered in this time period have been caused by blasts.

A critical difference between explosive blast injuries and other brain trauma, Bliese pointed out, is that a blast consists of several potentially injurious events; in air, the most distinctive feature of a blast is the supersonic shock front, through which there is a nearly instantaneous “step” increase in pressure. Extreme stresses can be induced by shockwave exposure and the process of the loading by shockwave reflection and diffraction around the skull, and consequently how, where, and what stresses are imparted within the brain, remain critical unresolved phenomena. It is largely unknown whether or how these events (e.g., skull deformation, compression and shearing waves, cavitation, and impact acceleration) interact to damage the brain or impair its function and whether or how the incidence of multiple blasts or concussive events can interact to worsen subsequent injuries. Another complicating factor is that blast is a whole-body insult resulting in polytrauma, and the injuries to other parts of the body can greatly influence the evolution and extent of blast injuries to the brain.

“There’s so much we don’t know yet about either the biomechanics or the neurobiology of blast TBI,” said Bliese. “To further complicate matters, most concussions actually don’t happen on the battlefield.

They occur because of things like airborne training, combatives [hand-to-hand combat training], or just playing sports. And as we’re discovering with athletes, prior concussions can adversely affect the severity of a subsequent concussion. Many of our Soldiers can literally be playing touch football or basketball in their downtime, take a concussion, and then go out and encounter a blast the next day, followed by another mechanical injury immediately after. We don’t understand the interplay among these combinations: If you had a concussion from one form of injury and then you had a subsequent blast exposure, we don’t really understand the time interval needed to recover, and the factors that determine that heightened vulnerability.

We also don’t really understand the mechanism of injury. Is age an associated factor? If you’re a 45-year-old sergeant first class versus an 18-year-old private, and you encounter the same blast, do you feel better or worse? We actually don’t know the answer to that. These are the kinds of issues this group is looking at.”

The center’s Blast-Induced Neurotrauma Branch, led by Dr. Joseph Long and charged with unraveling the complexities of blast injuries – and ultimately with discovering and advancing therapies or policy changes that will help to improve survival and functional outcomes following blast injuries – is facing an additional glaring obstacle: Because of the unique physics of the insult and the currently limited understanding of the parameters underlying blast TBI, the only way to study how and whether a brain has been hurt by blast is to expose it to blast. Consequently,

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Spc. Wesley A. Coble and Sgt. Victor Alcantar, combat engineers assigned to 1st Platoon, 43rd Engineer Company, 2nd Squadron “Sabre,” 3rd Cavalry Regiment, take cover behind a “blast blanket” after detonating an entryway with explosives July 31, 2013, at a subterranean tunnel complex on Fort Hood, Texas. The Soldiers were taking part in a training event designed to develop tactics, techniques, and procedures for emerging battlefields. CMPN’s Blast-Induced Neurotrauma Branch has been seeking to understand how the brain reacts to blasts. U.S. Army photo by Pfc. Erik Warren

center researchers have pioneered the development of a compressed gas-driven shock tube, in which, in a controlled manner, high pressure gas is used to generate and drive a shock wave to produce a scaleable simulation of the types of blast waves likely to be confronted by troops.

While the work is still fairly young, this research group has achieved interesting and promising results in the past several years, demonstrating that: • blast exposure, either from explosions or shock tube simulations, can cause axonal injury; • blast exposure causes changes in brain cells’ energy metabolism and DNA fragmentation, along with neurobehavioral disruptions that to a large extent parallel those described in injured warfighters; • whole-body blast exposure is followed by the rapid release of tissue enzymes, the levels of which may someday be used to determine a blast’s severity; • repeated blast exposure causes macrophage activation and the sustained increased circulation of inflammatory mediators, which along with the acute activation of platelets and leukocytes, can worsen the effects of brain injury – suggesting future inflammation-targeted therapies that may help to mitigate acute blast-induced neurotrauma; • blast-induced brain injuries are appreciably exacerbated by

preceding blast exposure; and • in addition to protecting lungs and enhancing survival, the use of a thoracic Kevlar® vest provides protection to the brain from the overpressure experienced in whole-body blast exposures.

To build on these productive studies to date, the Blast-Induced Neurotrauma Branch has identified several immediate goals and areas of focus for future work. In particular, since human brain injury from blast is likely governed by the particular scale, anatomy, and physiology of the human, it is critical to devise means to translate or scale blast induced stress conditions and outcomes from a test species, such as the rat, to human injuries. While establishing these biomechanical and anatomical parameters, branch investigators are also collaboratively evaluating and comparing preclinical animal neuropathological outcomes with human injuries using high-resolution magnetic resonance imaging (MRI), from which notable parallels have become apparent.

Ongoing exploration of the neurobiological underpinnings of blast TBI is driven by the goal of identifying pharmacotherapeutic targets to improve outcome, or recognizing countermeasures to the many factors, such as stressors or nutritional deficiencies, that may increase blast TBI vulnerability. Since blast is the leading cause of auditory and visual impairments among warfighters, blast studies include assessments of

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ABOVE: Dr. Lauren Waggoner, from the Naval Postgraduate School, prepares actigraphs and smartphones for issue to Sailors as part of a sleep study conducted aboard the guided-missile destroyer USS Jason Dunham (DDG 109), Dec. 3, 2012. U.S. Navy photo by Mass Communication Specialist 2nd Class Deven B. King CENTER: One area of study for Behavioral Biology researchers focuses on sleep banking. Here, Soldiers from the 505th Parachute Infantry Regiment catch a few winks before jumping over North Carolina during a training exercise. U.S. Army photo by Sgt. Christopher Harper OPPOSITE: A Soldier receives information on signs and symptoms of a concussion during a consultation at the traumatic brain injury clinic at Fort Belvoir Community Hospital, Jan. 9, 2013. The Defense and Veterans Brain Injury Center team assigned to the TBI clinic assists with the evaluation of Service Members who are suspected of suffering from traumatic brain injuries. U.S. Navy photo by Carlson Gray

these neurosensory functions and injuries to underlying structures.

Finally, since neuropathological features of CTE have been recently identified in blast-exposed military veterans, attempts are under way to discern whether multiple blast exposures yield similar brain changes (e.g., tau protein hyperphosphorylation and myelinated axonopathy) in rats, which, with a much shorter life-span than humans or larger species, may be well suited for studies of this chronic nature.

BEHAVIORAL BIOLOGY For all the technology applied to warfare today, the outcomes of armed conflicts continue to be largely determined by the mental acuity and alertness of warfighters, many of whom are confronted with limited opportunities for adequate sleep and rest.

Under the leadership of Thomas Balkin, Ph.D, a past chairman of the board of the National Sleep Foundation, the Behavioral Biology branch investigates and develops methods for optimizing warfighter alertness,

performance, and resilience. Its primary research mission – using data gathered at the center’s specially designed sleep laboratories, in the field, and from sophisticated models and simulation tools – is to identify the role of sleep in facilitating resilience to, and recovery from, exposure to sleep loss and other combat-related stressors.

The center has been renowned for its sleep research since the early 1960s, when WRAIR scientists were the first to demonstrate that microsleeps (0.5-2.0 second lapses in wakefulness) account for some, but not all, of the cognitive performance deficits that characterize sleep deprivation; that a wide variety of mental abilities are affected by sleep loss; and that mental processing “speed” is generally affected more than “accuracy” by sleep loss. In the 1970s, recognizing the need for a wear-and-forget objective measure of sleepiness that could be used to measure sleep in the military operational environment, WRAIR sleep researchers invented the wrist actigraph – a wristwatch-like device that provides sleep/wake data based on wrist movement measurements.

(Wrist actigraphs are now commercially available from a number of manufacturers, and widely used by sleep researchers and clinicians across the world.) In the 1980s and early 1990s, emphasis was placed on determining the sleep and performance effects of a variety of pharmacological agents – both sleep inducers (benzodiazepine agonists) and vigilance enhancers (e.g., modafinil, caffeine) – studies with implications for fatigue management in military operational environments.

One result of this work was development of a caffeinated chewing gum product, which is currently provided as part of the military’s “First Strike Rations.” With the advent of advanced functional brain imaging technologies in the 1990s and 2000s, WRAIR sleep researchers (with collaborators from NIH and John Hopkins University) performed groundbreaking research that characterized the changes in regional brain activity during sleep loss and sleep, showing that (a) sleep deprivation primarily affects prefrontal cortical regions (constituting the physiological basis of cognitive deficits manifested during sleep loss);

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(b) although REM (dreaming) sleep is generally characterized by brain activity levels comparable to those seen during wakefulness, activity in the prefrontal cortex is depressed during REM (thus explaining the bizarre nature of dreams); and (c) reestablishment of conscious awareness after sleep is primarily a function of subcortical activation – full reactivation of the prefrontal cortex takes 10 to 20 minutes of continuous wakefulness.

“WRAIR sleep researchers were the ones to show,” said Bliese, “that physiologically, the parts of the brain that were really shutting down after sleep loss were the parts in the prefrontal cortex that had to do with a lot of the higher-order decision making. This is common knowledge today, but practically speaking it was an important innovation, because we could show these images to senior leaders within the military and others, and say: ‘This isn’t an issue of motivation or effort. The vigilance and performance deficits that result from sleep loss have a physiological basis: the part of the brain that performs higher-order mental tasks like decision-making literally “shuts down” with sleep loss. So if you deprive Soldiers of sleep, you’re going to have a lot of negative consequences.’”

Building on these findings, the center’s Behavioral Biology researchers have developed algorithmic models that predict a Soldier’s ability to perform cognitive tasks, based on their recent sleep history and their internal, circadian rhythm. “Being able to quantify the relationship between sleep deprivation and cognitive performance is a significant step,” said Bliese. “They’ve developed a series of models. If individuals go into the laboratory and are restricted to three to five hours of sleep a night, and they do this repeatedly, building cumulative sleep restriction, our researchers can accurately model the decline in performance.”

This algorithm has now been approved by the FAA and adopted by commercial airlines and others for use as a decision aid for developing optimal work/rest schedules (e.g., of aircrew, shiftworkers, and others). Commercial entities have also licensed the government patents generated by Behavioral Biology scientists to incorporate the algorithm

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directly into wrist actigraphs, to optimize the utility of these devices for fatigue management at the level of the individual Service Member.

“I could see something like this having a huge cultural impact in the Army, or in other work organizations,” said Bliese, “because if you’re in a highly demanding organization and you go to your boss and say: ‘Hey, I’m tired,’ your boss may say: ‘Just suck it up.’ But if you say to your boss: ‘Listen, I’m tired – and look, here’s my estimated cognitive performance,’ and you press the button and show him it’s at 58 percent, that’s going to have a much bigger impact.”

Of course, Service Members are among several occupational groups for whom some periods of sleep deprivation are unavoidable, and another goal of the Behavioral Biology directorate is to help them through these periods without impairment. The center’s three-pronged fatigue management system (FMS) includes, in addition to monitoring sleep and alertness and modeling performance, the use of effective interventions – both pharmacological and non-pharmacological – to facilitate sleep and alertness as needed.

These interventions can be as simple as the targeted use of stimulants such as caffeine, which, if ingested, typically takes effect in 20 minutes, allowing time for a restorative nap before waking alert. The center has also tested a caffeinated chewing gum known as Stay Alert (now Military Energy Gum) that served as a quick and safe method of improving alertness and performance on mental and physical tasks, such as marksmanship.

A recent and ongoing area of research conducted by the directorate’s researchers is in the area of “sleep banking” – i.e., the finding that individuals can reduce sleep-related performance impairments during sleep loss by previously extending their time in bed. “In our group’s study,” said Bliese, “one group of subjects came to our lab for a week and extended their nightly time in bed to 10 hours. They weren’t sleeping that whole time, of course, but it did extend their sleep time – and another group stayed on their typical sleep schedule [i.e., about 7-7.5

CMPN

Leading,

a dvoc at ing & collaborating

to improve child health, here and around the world. www.cincinnatichildrens.org

congratulations to

Walter Reed Army Institute of Research

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Chief Warrant Officer 2 Brian Boase, the brigade master resiliency trainer for 3rd Brigade Combat Team “Rakkasans,” 101st Airborne Division (Air Assault), leads a refresher course on ways to cope with stress while deployed during a two-day resiliency course at Forward Operating Base Salerno, Afghanistan, Dec. 5, 2012.

U.S. Army photo

hours time in bed].” Both groups then went through a weeklong period of sleep restriction, sleeping only three hours per night, followed by a series of tasks of varying complexity.

“The results were like night and day,” Bliese said, “Those who’d ‘banked’ some sleep prior to sleep restriction were better able to maintain cognitive performance – and perhaps just as importantly, they also recovered from the sleep restriction much faster when subsequently allowed to resume their normal sleeping schedule.”

“Until recently, the scientific sleep community dismissed the notion that there was any benefit whatsoever to extending nightly sleep duration beyond eight hours. Such ‘extra’ sleep was considered a waste – sort of like consuming more calories than are needed to satisfy daily energy requirements,” said Balkin. “But it turns out that this ‘extra’ sleep is stored and ‘released’ when it is needed during subsequent sleep restriction – just like the energy from extra calories is stored as fat and released during subsequent food restriction.” The study – which earned its lead investigator, Dr. Tracy Rupp, the National Sleep Foundation Young Investigator Award – suggests that if people can fill up their sleep coffers, they will be better equipped to deal with the challenges of sleep loss when they need to.

Currently, this group is focused on determining how sleep banking works, the potential benefits of non-pharmacological “slow wave sleep enhancement” – interventions that might increase the recuperative

efficiency of sleep; and sleep-related strategies to enhance resilience to, and recovery from, mTBI events and psychological stress.

MILITARY PSYCHIATRY The wars in Afghanistan and Iraq are historically significant for many reasons; most conspicuously, this marks the longest war in U.S. history. Its duration, and the nature of combat in the Iraqi and Afghan theaters, have subjected the nation’s all-volunteer military to its biggest test. Often called upon for multiple deployments for more than a decade, Service Members and their Families have been challenged by the deployment related stress.

Early studies and surveys of warfighters in Iraq and Afghanistan revealed that about 5-9 percent had mental health symptoms before deploying; after deploying, this percentage increased to as much as 20 percent. Many have suffered from symptoms of post-traumatic stress and/or depression, and in recent years, young veterans returning from the Middle East are more likely to commit suicide than the civilian population, according to a 2011 study.

Over the past two decades, the Military Psychiatry Branch has emphasized research to improve Service Member psychological functioning, to reduce the impact of mental disorders, and to enhance psychological resilience.

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Over the course of much of the Iraq and Afghanistan conflicts, studies led by Dr. Charles Hoge, (Col., U.S. Army, Ret.), revealed that symptomatically, “post-concussive syndrome” following an mTBI and PTSD were much alike – so much so that it was possible, even likely, that a person suffering from PTSD and depression might be diagnosed with “post-concussive syndrome.” This was an important observation for tens of thousands of Service Members with mTBI diagnoses, as there was not – and still is not – a known evidence-based treatment for mTBI. Hoge’s studies suggested that Service Members with a “post-concussive syndrome” diagnosis could benefit from proven cognitive therapies for PTSD and depression.

The Center for Military Psychiatry and Neuroscience’s most widely cited epidemiological study of the mental health impact of the wars in Iraq and Afghanistan is the WRAIR Land Combat Study conducted by the Military Psychiatry Branch. Since its inception in 2003, approximately 100,000 Service Members have been studied across the deployment cycle as part of the Land Combat Study. One of the most visible components of the Land Combat Study is the Mental Health Advisory Team missions. The first MHAT was conducted in 2003, in response to the concerns of Lt. Gen. James Peake, the Surgeon General of the Army, about the mental health and increasing suicide rate of Soldiers.

The first MHAT deployed in 2003 to Iraq and included Lt. Col. Carl Castro and Lt. Col. Tony Cox, who were then WRAIR’s chief and deputy chief of military psychiatry.

The MHATs, which have deployed periodically to Iraq and Afghanistan over the past decade, constitute the first comprehensive effort to collect behavioral health care data from and about Soldiers in a theater of operations. Rather than rely on limited focus groups, they are a systematic attempt to survey Soldiers about their behavioral health needs – and just as important, to assess the obstacles Soldiers face in seeking and receiving quality mental health care.

The emphasis on these comprehensive surveys, said Bliese, evolved rapidly. By 2006, when MHAT IV was deployed to Iraq, WRAIR had become the lead organization for the teams. “That was just the right time, in terms of technology,” he said, “to allow us to deploy in theater with scanners, so that we could go in and collect the data, scan the data, run the statistical analyses, conduct an outreach to commanders, and write the entire report within a short period of time. This became a way of providing behavioral health information back to operational commanders in near real time.” Since 2009, the teams have applied greater scientific rigor to their sampling methods, achieving a randomized sample that allows valid comparisons of results from survey to survey.

The MHATs have become a milestone in military medicine: They have been critically important in collecting information about troops’ anxiety, depression, and post-traumatic stress symptoms, and have documented the challenges Soldiers face in seeking and receiving mental health care – including the warrior’s stigma against seeking help, a shortage of clinicians, and the influence of leaders at different command levels.

The teams have also helped shape operational doctrine and policy, according to Bliese. “The teams have brought about some very concrete results,” he said. “For instance, back in 2009, when the team went into theater, they estimated the rate of the mental health problems, and they also evaluated the number of behavioral health providers in theater. And they found, essentially, that there weren’t enough providers, given the

A team of military medical doctors holds a news briefing at the Pentagon, May 4, 2007, to review some of the findings and recommendations of the Mental Health Advisory Team survey. This study – the fourth since 2003, assessed the mental health and well-being of deployed U.S. Army and Marine Corps troops serving in Iraq. Pictured are (from left) Marine Corps Col. William P. Nash, Army Col. Carl Castro, Navy Rear Adm. Richard Jeffries, Army Maj. Dennis McGurk, and Army Maj. Gen. Gale S. Pollock, commander, U.S. Army Medical Command and acting Army surgeon general. Photo by R.D. Ward

rate of mental health problems they were seeing on the surveys. So we made a recommendation to go to what we call the dual provider model: We said each brigade combat team should have, organic to that combat team, two behavioral health providers, because this would allow one to go out and kind of do rounds for the units that might be spread out, and another one could stay there, at these large forward operating bases.

The MHAT survey wasn’t the only piece of information to lead to the implementation of the dual provider model – others were saying similar things – but it was a key piece of information.”

In addition to the MHATs, the Land Combat Study has collected data across the deployment cycle and has made important contributions that have informed policy and programs. For example, the development of Battlemind Training was informed by findings from the Land Combat Study. Battlemind training is, essentially, the Army’s version of cognitive reframing: First, it recognizes the courage, leadership, camaraderie, mental toughness, and maturity it takes to succeed in theater, and then teaches Soldiers how to reapply those skills to Family and workaday life – and perhaps to apply them to resolving problems with anxiety, depression, or PTSD. “Carl [Castro]’s idea,” said Bliese, “was to help Soldiers who had been over there for a year, who were having trouble with the transition, to reframe the way they thought about it, in a more positive way.”

Battlemind, typically consisting of succinct post-deployment debriefing and training sessions, seems like a common-sense idea, but it has also proven repeatedly to be an intervention that works for returning Soldiers. The first randomized trials to assess the efficacy of post-deployment Battlemind training, an element now integrated into the Army’s Comprehensive Soldier Fitness resilience training program, were conducted by USAMRU-E and WRAIR researchers in 2007. In a

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2009 study, Bliese and other WRAIR researchers surveyed more than 1,000 Soldiers; those who received Battlemind debriefing and training reported, four months afterward, fewer symptoms of post-traumatic stress, lower levels of help-seeking stigma, fewer depression systems, and fewer sleep problems.

“It sounds easy, and there is nothing scientifically complicated about the idea of validating a training program,” said Bliese. “But it’s complicated to actually pull it off. The group working with the Soldiers has been very good at designing and conducting randomized trials of intervention programs, with the idea that if we can develop and deliver this low-cost, simple intervention to Soldiers returning from combat, and if we can show efficacy with this program three or four months later, then that’s a real win. And that group has had a number of real wins.”

The Military Psychiatry Branch has continued to leverage the skills required to conduct group randomized trials of intervention programs and most recently launched a group randomized trial, “Social Fitness Training Strategies at Post-Deployment” with members of the California National Guard in 2013. This longitudinal study assessed social fitness training, defined as the existence of healthy social networks that support optimal performance and well being, at the platoon level for post-deployment behavioral health and resilience across four different phases.

Today, the Military Psychiatry Branch has expanded its perspectives to include examination of the Army’s behavioral healthcare system. This work has provided a snapshot of routine challenges faced in the delivery of behavioral health care to include access to care, stigma, and provider use of best clinical practices. In addition, the Military Psychiatry Branch has started to examine neurocognitive assessments of anxiety and anger in order to compliment the survey based methodology in hopes of developing computer-based tools to mitigate the effects of combat in Service Members.

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achieved, especially for the Military Psychiatry branch. “We’ve always had this issue: How do we translate this science into something the Army can act upon?” Bliese said. “For a lot of what we develop here – say, with the Mental Health Advisory Teams – it’s not always clear how to turn those information products into actionable information for the Army. Unlike, say, the neuroprotection group, where at the end of the day they might have a device you can put into the field that assesses biomarkers for PTSD, or looks for TBI in a blood sample, or a pill to treat a traumatic brain injury, a lot of what we do appears in the form of a journal article – and feeding that scientific literature back into the Army system has been the mission for this Research Transition Office.”

Whether they are investigating the physical or the psychological dimensions of mental and behavioral health, Bliese believes the scientists in the Center for Military Psychiatry and Neuroscience are proactive, mission focused, and innovative. “I think we’ve been very adaptive to the issues the Army defines as relevant,” he said, “and we’ve been good at applying science to those issues to help provide solutions.”

The History of Neuroscience in Autobiography. Volume 1, Editor Larry R. Squire [Society for Neuroscience], Washington, D.C., 1996.

2. From Les Prix Nobel. The Nobel Prizes 1981, Editor Wilhelm Odelberg [Nobel Foundation], Stockholm, 1982.

1.

FROM THE BENCH TO THE BATTLEFIELD: THE RESEARCH TRANSITION OFFICE The Army-wide Battlemind concept developed by CMPN researchers and their USAMRU-E affiliates is one of the most prominent and widespread programs to have sprung from the center’s work, but it’s one of a multitude of valuable applications to arise from WRAIR’s military psychiatry and neuroscience research. When the center was reorganized in 2009, it established a distinct organization, the Research Transition Office (RTO), to translate the findings of each of its five research assets into training and information products that can be used by the Army through its training programs, including Initial Military Training (IMT), or “basic training,” and its Professional Military Education (PME), the progression of coursework that prepares officers for leadership.

The RTO connects the center’s research-based recommendations to the Army’s operational requirements. Its mission, said Bliese, is simple: “To take some of the research findings that might normally be published in a scientific journal and to translate that into material that would be fed back into the Army’s school system and into other programs, like Comprehensive Soldier Fitness, very quickly.” The RTO provides an internal fast track; rather than publishing and waiting for an idea to catch on, it pushes relevant data out into the field.

Such a proactive approach seems necessary for an organization such as the Army, which requires extreme agility – but it’s not always easily

CMPN

We join in celebrating with

The Walter Reed Army Institute of Research: 120 years of Advances for Military and Public Health Medical College of Wisconsin physicians and scientists are leaders in research of traumatic brain injuries to improve care for our military service members and veterans Medical College of Wisconsin: 120 years of Advancing Knowledge for Healthier Communities www.mcw.edu / Milwaukee, Wisconsin / 414- 955-8296

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120 years of advances for military and public health

The Makerere University Walter Reed Project (MUWRP) is a nonprofit partnership between the university and the Military HIV Research Program (MHRP). MHRP has been conducting HIV research in Uganda since 1998, and in 2005 expanded its portfolio to include prevention, care, and treatment activities. More recently, MUWRP expanded its portfolio of research into other communicable diseases of public health importance in Uganda. By building infrastructure and increasing the capacity of local public and private partners, MUWRP ensures quality services for communities participating in vaccine research and HIV cohort studies. Here, a lab technician catalogs slides. Makerere University Walter Reed Project photo

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PARTNERSHIPS & COLLABORATIONS

By J.R. Wilson

The

Walter Reed Army Institute of Research (WRAIR) has sought out and been open to partnerships with other U.S. and international medical research agencies, academia, industry, and allied governments. Today, the agreements defining these collaborations are varied and depend on the partner and have names like cooperative research and development agreements (CRADAs), interagency agreements (IAAs), memoranda of agreement (MOAs), and education partnership agreements (EPAs).

“In most of WRAIR’s work, we have partners. For example, for therapeutics after brain injury or new antimalarials, our researchers develop teams with industry and academia,” said Debra Yourick, Ph.D., director of Science Education and Strategic Communications. “So it’s really about collaboration in research and development [R&D] for a final product that then becomes available for our Service Members.”

CRADAs were created by the Federal Technology Transfer Act of 1986, making it easier for scientists in federal labs to work with private industry, universities, and state and local governments. Its goals include speeding technology commercialization, optimizing resources, and protecting the rights of both private companies and their government partners when intellectual property is created.

The federal lab may provide personnel, facilities, equipment, and other resources to support specific R&D efforts consistent with the lab’s mission. The outside partner provides an appropriate amount of the funding for conducting the research at the government laboratory. Both parties may file patents as appropriate and, when a private company has patents and retained patent rights, the government gets a license to the patents.

“Our two goals are to advance research and, second, especially OCONUS [outside the continental United States], to improve the medical capacity of the host nation,” according to Col. Steven Braverman, WRAIR’s commander.

WRAIR’s partnerships and collaborations stem from advancing military medical research to meet specific Army requirements. Those involving military labs are especially well connected.

“The Army, Navy, and the Department of Defense [DoD] recognize that there are important military medical research gaps that guide the work of the medical research laboratories like WRAIR; we also work closely with the Naval Medical Research Center,” said Yourick. “Many of our programs are moving toward being neither just Army nor Navy.

Military Infectious Diseases Research Program [MIDRP] is joint, and within MIDRP we now have a joint Military Malaria Research Program [MMRP].”

“We also do military operational medicine and casualty care through other groups. We’re moving toward a joint military health care system.

It’s all evolving very rapidly,” said D. Renee Davis, the new director of WRAIR’s Business Management Office.

The collaborations negotiated by WRAIR’s Office of Research Technology Applications (ORTA) are true partnerships, with principal investigators (PIs) on both sides, government and nongovernment.

“We create agreements where each partner does its piece, as defined from the beginning. Although, because it’s research and you can have both breakthroughs and setbacks, new partners coming aboard, etc., we frequently have to renegotiate modifications. It’s always bilateral,” Davis said. “‘Whom’ is not as important as the type. We partner with other government entities, academia, nonprofit, and for-profit – anyone with a mission set that can further our core research mission. They do not have to be U.S. – we have a substantial number of international agreements.”

MALARIA AND OTHER INFECTIOUS DISEASE COLLABORATIONS The oldest and most intensive research WRAIR conducts – focused on malaria – also has the most partnerships, of all kinds and at all levels.

“The current Phase III efforts, the big efficacy study for a malaria vaccine, is being conducted largely by GSK [GlaxoSmithKline] and with the largest amount of funding, I think to the tune of about $200 million, from the [Bill & Melinda] Gates Foundation,” said Col. Robert Paris, MMRP director. “Our malaria research program here is not directly involved with that, although we are indirectly involved with doing some assays from the study.

“However, our own lab in Kenya is a participating site for testing this malaria vaccine, in and around Kisumu. Our investigators there delivered the most recent data on that study in South Africa at the MIM [Multilateral Initiative on Malaria] conference. Those studies are the culmination of 20 years or more of effort here at WRAIR.”

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120 years of advances for military and public health

left: The Walter Reed Biosystematics Unit (WRBU), WRAIR, U.S. Army Medical Research and Materiel Command, and their predecessors, and the Section of Entomology, Department of Systematic Biology, National Museum of Natural History (NMNH), Smithsonian Institution, have worked together effectively since 1961.

During that time the NMNH Mosquito Collection has developed into the largest in the world, comprising more than 1.5 million specimens. Pictured: Anopheles multicolor Cambouliu, secondary malaria vector. Judith A. Stoffer/Walter Reed Biosystematics Unit right: The U.S. Army Medical Component of the Armed Forces Research Institute of Medical Sciences helped execute the Phase III HIV vaccine trial in Thailand on behalf of the trial sponsor. This successful vaccine trial is an example of the longstanding, productive collaboration among U.S. and Thai military and civilian scientists to conduct infectious disease research.

The Military HIV Research Program is the single largest program supported by the Henry M. Jackson Foundation for the Advancement of Military Medicine. U.S. Military HIV Research Program OPPOSITE: Laboratory evaluation of the Rift Valley fever (RVF) virus assay. The validation process for VecTOR’s RVF virus assay was a joint effort among researchers from the Entomology Branch, WRAIR Virology Division, U.S. Army Medical Research Institute of Infectious Diseases, the Kenya Medical Research Institute, and the U.S. Army Medical Research Unit-Kenya. Photo courtesy of CPT Elizabeth Wanja

All programs depend on collaboration, from dengue vaccine and therapeutics research to a vaccine for diarrheal diseases. Any new therapeutic or preventive vaccine requires industry involvement before it can be marketed. WRAIR’s studies, via DoD funding and through its mission to find military relevant products, often take away early financial risk in product development by identifying promising leads that can then be collaboratively researched and finally approved for the benefit of the health of Service Members and others at risk.

MULTIDRUG RESISTANCE Another major WRAIR effort in recent years has centered on research to identify organisms that have developed a resistance to multiple drugs typically used to combat such diseases.

“We work more and more on collaborations, because the problems are so complicated, one agency can’t do it all itself,” Col. Emil Lesho, director of the Multidrug-resistant Organism Repository and Surveillance Network (MRSN), explained. “Our closest relationship is with the Navy and Marine Corps; when they come across something, they give us a warning.

“We also work with the CDC [Centers for Disease Control and Prevention], Institut Pasteur, the VA [Department of Veterans Affairs]– including trying to get projects started at polytrauma centers – and the Baltimore Shock Trauma Center, which does complicated wound care. If a wounded warfighter can’t get care at Walter Reed, we send them up there.”

MILITARY HIV RESEARCH PROGRAM (MHRP) “CRADAs or other collaborations are determined based on the needs of the scientists in our program,” Col. Jerome Kim, principal deputy for MHRP, reported. “If one of our immunologists wants to collaborate with an immunologist at Harvard, they begin a discussion and, if there will be a transfer of materials or data, a material transfer agreement is signed.

“We can do agreements with more than one partner, although they’re difficult. We have clinical trial agreements with two different companies because negotiating a three-way CRADA was too difficult.”

A lot of discussion precedes a formal agreement, with preliminary discussions sometimes going on for two or three years. Additional

120 YEARS OF ADVANCES FOR MILITARY AND PUBLIC HEALTH

agreements are made once a clinical trial starts or ends, including a data transfer agreement.

“As an organization, we put money into a cooperative agreement, which is midway between a contract and a grant. So I can do a clinical trial with the [Henry M.] Jackson Foundation [for the Advancement of Military Medicine], with much more ability to interact directly with the contractor should changes need to be made,” Kim said.

“Money goes directly from the Army to the Jackson Foundation, which can do contracts, material transfer agreements, etc. The senior military member typically decides who is involved on a team.”

HIV research and CRADAs are a significant part of WRAIR’s requirement to protect the force against infectious diseases.

“With HIV, you get a regional vaccine first, then a global vaccine. The CRADA also has key requirements for the number of doses. Seventyfive percent of the $100 million Congress allocated to NIH [National Institutes of Health] for HIV research was transferred to us under an interagency agreement. In another program, NIH has taken over funding the Army had been providing. We also receive grants, which define the studies to be done, from the Gates Foundation, although we don’t have a formal agreement with Gates,” Kim said.

“So there are contracts, CRADAs, IAAs, voluntary associations. We work closely with NIH in our collaborative research – to set up committees to evaluate proposals, approve them scientifically or request further

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funding. Once those are done, we sit down with NIH and work out a way to move NIH money to fund those studies, wherever that work is to be done.”

WRAIR’s relationship with NIH on HIV research merges DoD capabilities with NIH funding, for the costly endeavor to develop the first ever HIV vaccine, for both the military and the world.

“Our partnership with NIH is the most obvious joint success in terms of agreements. It was set up at a time when DoD was going to transfer our program to NIH without transferring the personnel.

Originally, NIH did not do much overseas research and they don’t develop products,” he explained.

“We are responsible to the U.S. ambassador, and the Army knows how to work with the State Department and foreign governments, while NIH works with them through others. The NIH focus on HIV was domestic, while the Army focus is overseas. We brought those two together, doing the research that needs to be translated into products.”

NIH has agreed to fund several MHRP studies and Kim said some of that money may be coming from a $100 million research program President Barack Obama announced last year.

“Our program is funded out of the Pentagon, using one-year money.

In general, Army money pays for all personnel; Jackson Foundation money funds Jackson researchers and so on,” he said. “There also is a clear line between government and contractor money; for example,

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120 years of advances for military and public health

Left: Leishmaniasis as seen under a microscope at Walter Reed Army Institute of Research in Silver Spring, Md. The U.S. Army Medical Research and Materiel Command (USMRMC) marked a major advance against the disease cutaneous leishmaniasis when the U.S. Food and Drug Administration approved the marketing of a new diagnostic test developed by a partnership of WRAIR, the U.S. Army Medical Materiel Development Activity (USAMMDA), and the molecular diagnostics company Cepheid USA Inc. U.S. Army photo by Sgt. 1st Class Roddy Rieger Right: As it continues to develop and test improvements to the RTS,S malaria vaccine, WRAIR is joining with public-private partners such as GlaxoSmithKline, Crucell NV, and the nonprofit PATH Malaria Vaccine Initiative in an innovative trial to achieve greater efficacy by “boosting” the immune response to the RTS,S particle after “priming” the immune system with a combination of weakened virus and malaria parasite surface protein. Critical field-site testing for the current Phase III study is ongoing in western Kenya at the U.S. Army Medical Research UnitKenya (USAMRU-K). Here, Kenyan health care workers participate in malaria microscopy training conducted by USAMRU-K. U.S. Army photo by U.S. Army Africa

government money can be used for salaries and travel that industry money cannot. NIH money comes to us at the end of the fiscal year.

Army funds are used first, using current fiscal year funds for payroll.”

PILOT BIOPRODUCTION FACILITY (PBF) Dr. Kenneth H. Eckels, is chief of the PBF, a pilot-scale production facility for vaccines that are needed for Phase I clinical trials in humans.

The PBF follows strict FDA guidelines called Good Manufacturing Practices (GMP) that are required for this kind of production. The PBF manufactures vaccine lots for both government (Army, Navy, NIH, and USAID) as well as private companies. “Before the Technology Transfer Act of 1986, you couldn’t partner with outside entities to bring resources back to WRAIR – everything was in one direction,” he explained. “We did vaccine research and development paid for by

the Army and had some partnerships with industry, including a big one with SmithKline Beecham – now [GSK]. They tapped into the research we were doing on hepatitis A and were able to license and market the first hepatitis A vaccine. Now we have CRADAs that enable us to partner with private businesses and universities and have the partner pay for the vaccine production. We in the PBF don’t really consider ourselves R&D – we’re way at the end of ‘D.’ We exist for the mission. The Army has a list of vaccines they need and they always have first priority, with malaria right at the top, which we have been working on since the early ’90s. At that time, USAID came to us with money and resources for malaria vaccines, supplementing what the Army was putting into it.”

Nearly from its inception, the PBF has been able to bring in various products not on the list of Army requirements and threats.

“We knew we would have no core funding and would have to do everything on a fee-for-service basis, which is still how we do it.

120 YEARS OF ADVANCES FOR MILITARY AND PUBLIC HEALTH

Companies come to us with leading-edge technologies, for the most part proprietary, so we make sure what we do for them stays in a file exclusive to them that we can’t use with someone else. These partnerships broaden our knowledge base and keep us funded as an Army resource,” Eckels said.

“We knew right from the get-go that to be able to perform GMP production we would need to bring money in from outside; the Army was not going to pay for the operation totally. We have companies come to us with limited budgets that are funded by investor money and often NIH grants. Which means they may only be here for a short time, then go away to do clinical testing. If the vaccine is successful in Phase I testing they often come back to us for more production.”

Unlike most government research facilities, the majority of those working at the PBF do not have Ph.Ds. and are heavily reliant on job skills that come from on-the-job training.

“We no longer do research, only development and manufacturing. At last count, we had 31 contract personnel, with only me and my deputy chief being government employees. We also have two Soldiers in the labs who are very eager to learn new skills and eventually take what they learn elsewhere when they leave the Army,” he said.

“WRAIR has world-class vaccine research groups that are very product oriented. I sit on many of the coordinating vaccine working groups [project teams] so I often know what will be coming to the PBF. And we are heavily dependent on these groups to keep us busy and move the products to clinical testing. Clinical testing results often bring interest from private companies looking for promising vaccines that can be marketed. One of those vaccines, for prevention of Japanese encephalitis, followed that scenario and was licensed in 2011. It is now available for Soldiers and dependents being deployed to regions of the world where the disease is endemic.”

CONCLUSION Many of WRAIR CRADAs are with pharmaceutical companies, some of which are international. Davis said many partnerships derive from their own PIs, who keep up on what’s happening in cutting-edge research in their areas.

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“They may come to my office about partnering with some other agency. Or the personnel in my office may hear about something interesting and approach the PIs. And sometimes others contact the ORTA business office to ask about partnering with us, because of something they’re working on or something they’ve read in a WRAIRpublished paper,” she said.

“There are always new CRADAs and agreements going into place. There is no end game to research – you’ll never come up with a product that fully solves the medical problem permanently. You may make it faster, cheaper, more effective, but even if you have a vaccine that works, you are never done, always looking for something better.”

WRAIR utilizes a host of agreement types – commercial test agreements, clinical trial agreements, cooperative agreements, memoranda of agreement, and interagency agreements with other federal agencies – each appropriate to a specific relationship and with its own legal nuances.

“There is a toolbox of agreements and details and we try to ensure we are using the right tool for the job based on the unique case, which often isn’t known until you actually get into agreement discussions,” Davis said.

“I think we get better with experience and continue to develop our staff and network with other ORTAs. I don’t think our methodologies, as such, have changed and we work hard to ensure our collaborations are mission aligned. We do more CRADAs and partnerships and agreements each year, including more across the federal government.

“Missions always change, of course, and we take our direction from our higher headquarters, who take direction from their higher headquarters and DoD. We also have BR AC 2005, which segregated the missions of the various institutes within MRMC [U.S. Army Medical Research and Materiel Command] and greatly redefined the missions, but a ll our work remains centered on the advancement of missionaligned medical research. We are, for the most part, looking into methods of prevention for deployed Soldiers. Every current drug involved with treatment or prevention of malaria has had WRAIR involvement, in some way, shape or form.

And those were supported by CRADAs.”

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120 YEARS OF ADVANCES FOR MILITARY AND PUBLIC HEALTH

The U.S. Army Medical Materiel Development Activity and the Walter Reed Army Institute of Research jointly sign a Cooperative Research and Development Agreement (CRADA) to work toward a malaria cure. Walter Reed Army Institute of Research photo

MRMC already is looking at requirements related to the Pacific pivot and WRAIR already is conducting medical research in Asia.

The military medical mission, as determined by Army leadership, will determine future partnerships or change in focus on diseases specific to that region. A weak economy and shrinking DoD budgets have raised concerns and left WRAIR uncertain about the future of its research, partnerships, and collaborations.

“Looking at current trends, we’re still growing strong and signing as many CRADAs as last year, with no impact on our ability to partner. So I’m not getting pessimistic – yet. I think we will be getting busier, that our PIs will be looking for new ways to do their mission,” Davis said.

“We have, however, seen impact on our investigators, largely driven by travel limitations for DoD personnel, which have been alleviated somewhat lately.

“But our ability to communicate what we need and want to potential partners may have an impact on future agreements. If our investigators don’t have the opportunity to go out and network, it’s hard to move forward. Many of our agreements get their start at scientific meetings, after presentations that show where we have common interests – but if we aren’t there and the light bulbs don’t go off, we won’t have CRADAs resulting from those. The number of CRADAs is not going down, but that doesn’t mean we have not lost opportunities by not being out there because we don’t know what we don’t know.”

In the future as in the past, the scope of WRAIR’s efforts and partnerships is broad, depending on the disease under investigation.

“We usually work and exist within that space that is not being addressed by industry or academia. Success to date is ‘not enough’ or we wouldn’t be working on it. Expectations of continuing research depend upon the fate of research funding within DoD,” noted Col. Peter Weina, WRAIR deputy commander, adding that includes partnerships with organizations such as the CDC and WHO. “There is an ecosystem of interactions with multiple different groups. There is no real way to tease out where one starts and the other ends. It is part of a continuum, like a fragile ecosystem; affecting one part of the system has impact on all other parts.”

Braverman sums up the future as one in which collaboration and partnerships will be even more important to WRAIR’s success.

“I’ve really come to appreciate the importance of the OCONUS labs and clinical research networks we have in our partner countries, not only for DoD and Army efforts, but for international efforts to find treatments for malaria and HIV,” he concluded.

“Without those networks and the capabilities we bring to the table, it would be very difficult for the international community to replicate the clinical trials we do. So we have built a network that is truly important to global health as well as to the DoD.”