An integral part of HJF’s work is carrying out medical research and education projects under cooperative efforts with USU. From its inception, USU recognized the importance of working with a foundation to more readily fulfill its mission: to educate, train and prepare uniformed services health professionals, officers and leaders to directly support the Military Heath System, national security and defense strategies of the U.S., and the readiness of our armed forces.
USU is home to preeminent centers and programs that advance its research, education and public service mission. At these 16 centers, USU faculty members and students partner with leading scientific experts to expand knowledge across diverse biomedical disciplines. At their side are hundreds of HJF employees who are working as scientific directors, postdoctoral fellows, research assistants and administrators to support the pursuit of scientific endeavors on a full range of medical science issues.
In 2018, the USU centers held a first-ever forum, affording attendees the opportunity to learn what USU centers are and the advancements they have made in the fields of combat casualty care, warfighter readiness, resilience and human performance, traumatic brain injury, posttraumatic stress and suicide prevention, emerging and infectious disease, disaster medicine and global health, precision medicine, and cancer care.
The forum provided a high-level overview of each center to understand how they can and do leverage each other’s expertise and that of Walter Reed National Military Medical Center. It closed with thought-provoking discussions about the future of military medical research and efficient ways to accelerate innovation.
During the 2018 Nipah virus outbreak in India, HJF became one of five partners to collaborate on developing a human vaccine to save others from infection in the future.
HJF entered into a license agreement of the vaccine for Nipah virus and Hendra virus from the Joint Technology Transfer Office of the Uniformed Services University (USU) and HJF. The license, supported by the Coalition for Epidemic Preparedness Innovations (CEPI), was awarded to Profectus BioSciences, Inc. who is collaborating with USU and Emergent BioSolutions Inc., to develop the human vaccine for Nipah and Hendra viruses. This investment of up to $25 million represents an innovative approach to funding vaccine development, unlocking research and development potential so that vaccines are ready for efficacy studies during an outbreak. The agreement will enable funding for development efforts over a five-year period.
The vaccine is based on Nipah virus and Hendra virus technology developed more than 15 years ago by Christopher Broder, Ph.D. and Katharine Bossart, Ph.D., in the Department of Microbiology and Immunology at USU. The vaccine has already been evaluated in multiple animal models and has been demonstrated to be completely protective against not only Nipah virus infection but also Hendra virus infection, Nipah’s close relative.
Broder, now chair of the Department of Microbiology and Immunology, began a collaboration with Antony Dimitrov, Ph.D., of Profectus BioSciences to develop the human vaccine with financial support from the U.S. National Institutes of Health several years ago. “Based on the success of this vaccine technology against both Nipah virus and Nipah’s close relative, Hendra virus, it is highly likely that the Nipah vaccine to be developed here will also work against Hendra virus,” Broder said.
The vaccine component is a single protein from the virus known as the G glycoprotein that is produced in a soluble form (sG) in cell culture by genetic means and purified to exceedingly high levels. No virus or any infectious agent is involved in the production of the sG glycoprotein vaccine.
“It is extremely safe, simple and highly effective vaccine that has proven time and time again to provide complete protection against two incredibly deadly viral pathogens that are a biological threat to not only people but important livestock as well,” Broder said. The same vaccine component was licensed to Zoetis Inc., which is currently formulated as the horse vaccine, Equivac® HeV, currently marketed in Australia for the prevention of Hendra virus infection in horses.
During the India outbreak, the Indian government requested that the government of Queensland, Australia, send them a supply of the experimental m102.4 human monoclonal antibody, the only known treatment against the virus, for compassionate use. In other words, compassionate use is treating a seriously ill patient using a new, unapproved drug, when no other treatments are available.
The m102.4 human monoclonal antibody and the cell line that produces it was developed in collaboration with Broder with colleagues formerly at the National Institutes of Health, and was previously sent to Queensland after Australian residents were exposed to the Hendra virus, the sister virus to Nipah. Under additional agreements from HJF, Queensland produced the m102.4 and conducted a successful Phase 1 clinical trial showing the safety of the antibody in humans.
After receiving the request from the Indian government, HJF completed agreements with both governments authorizing the transfer.
Profectus will receive development funding from CEPI for advancing its Nipah virus vaccine and Emergent BioSolutions will provide technical and manufacturing support for the CEPI-funded program. Emergent, through a separate agreement with Profectus, has an exclusive option to license and to assume control of development activities for the Nipah virus vaccine from Profectus. The international nonprofit health organization PATH will also work with the group under a separate agreement with CEPI to conduct human clinical trials.
As a next step in the Nipah vaccine development for use in people, Thomas Geisbert, Ph.D., at the University of Texas Medical Branch at Galveston and the Galveston National Laboratory, will conduct the preclinical studies at its biosafety level 4 facility, and HJF, USU, and Profectus will collaborate on the development of a clinical assay for the evaluation of the anti-Nipah virus vaccine response.
The Collaborative Health Initiative Research Program (CHIRP) is a strategic alliance between the National Heart, Lung, and Blood Institute (NHLBI) and the Uniformed Services University (USU). The goal of this interagency endeavor is to transform patient care by harnessing genomics, high-performance computer clusters and bioinformatics to predict and preempt disease, mitigate and repair traumatic injury, optimize human performance and resilience, and generate novel personalized therapies that will benefit civilians and service members alike.
In 2018, CHIRP continued its focus on developing expertise in large-scale whole genome sequencing of patient DNA and mRNA taken from hypothesis-based cohorts with comprehensive clinical phenotyping. To date, more than 18,000 whole genomes have been sequenced.
Sequencing activities progressed in 2018. This effort, begun in 2016, included examining risk and resilience to posttraumatic stress disorder (PTSD) and coinciding conditions such as cardiovascular heart disease (CVD) or major depressive disorder (MDD) in three established cohorts. Since its establishment, CHIRP has so far sequenced 1,740 DNAs from the VA’s Vietnam-Era Twins Repository of twins who fought in Vietnam and have a unique coincidence of PTSD, MDD and CVD.
CHIRP has also sequenced the first 3,000 of the 48,000 samples in the Army STARRS cohort, which focuses on PTSD, MDD and suicidal ideation. In collaboration with Scripps Research Institute (SRI), CHIRP sequenced 1,200 DNAs from the “wellderly” (well elderly) cohort comprising subjects who are more than 80 years old and are also cognitively and cardiovascularly intact. In these and related groups, CHIRP has focused attention on variants in candidate and genomewide association studies—sourced genes that could influence susceptibility or resilience to both PTSD and CVD.
Additional ongoing efforts include studies on sleep disorders, chronic obstructive pulmonary disease, sudden cardiac arrest in the active-duty population and heart failure in large military cohorts being carried out at Walter Reed National Military Medical Center. With approval from NHLBI leadership, CHIRP is also a part of the Department of Defense/Department of Veterans Affairs/National Institutes of Health-sponsored APOLLO (Applied Porteogenomics OrganizationaL Learning and Outcomes) cancer project.
Under the APOLLO study, led by retired Army Col. (Dr.) Craig Shriver of the Murtha Cancer Center, CHIRP has screened 8,000 patients across several cancer types, including lung, breast, prostate and gynecological cancers, for Department of Defense force protection.
CHIRP is also partnering with intramural NHLBI collaborators to study rare mutation-dependent vascular defects, sickle cell disease, PD1 immune checkpoints, tuberous sclerosis and age-related mutations in non-human primates. In addition, some USU intramural projects focus on NHLBI-centric problems, all vetted by an ad hoc NIH study section and 13 members from different universities in the U.S. These represent just a few of the 72 total projects ongoing in the CHIRP/The American Genome Center portfolio that collectively resulted in 22 publications between 2015 and 2018 in high impact journals including Nature, Cell and Cancer Cell.
The Uniformed Services University’s National Center for Disaster Medicine and Public Health (NCDMPH) leads the way in the ‘Stop the Bleed’ initiative. Launched in 2015 by the White House, the ‘Stop the Bleed’ initiative educates and trains citizens to assist in the event of life-threatening bleeding.
To train and empower the public to save lives, NCDMPH has developed, tested and released several educational tools that are designed to share how to stop life-threatening bleeding during an emergency. The ‘Stop the Bleed’ website, https://stopthebleed.usuhs.edu, which has reached over 10,500 visitors in 2018, provides information to guide readers through management of both serious and non-serious bleeding events.
In May 2018, the NCDMPH released the ‘Stop the Bleed’ app with more than 3,500 downloads on both Apple and Android devices. This free app is designed to teach users how to stop life-threatening bleeding in an emergency by applying a tourniquet. The app features a quiz, formatted as frequently asked questions that guides bystanders through the process. A step-by-step video for applying a tourniquet and other educational resources are also provided to assist in saving lives.
Additionally, the Center has expanded its public outreach by training staff at USU and HJF’s Bethesda offices on how to stop bleeding and to help equip staff with the knowledge whether they are at work or home.
The ‘Stop the Bleed’ Tourniquet Application Instructions became available in September 2018 in Spanish and Spanish closed captions on the ‘Stop the Bleed’ training video which is now available on the NCDMPH YouTube channel.
“We all have the potential to be first responders during an emergency,” said Victoria Klimczak, project coordinator at NCDMPH. “People will be able to prevent a friend, loved-one, colleague or stranger from losing their life due to life-threatening bleeding with the use of the educational tools we created. As a prior Navy Hospital Corpsman, I can’t think of a better way to continue to serve the American people other than sharing the life saving skills I learned while serving in the military.”
At its inception, the initiative was instituted to save lives. With each new educational tool, the public will be provided with the knowledge and tools to do just that.
This year was a year of transition for the U.S. Military HIV Research Program (MHRP), HJF’s single largest supported program, as the organization welcomed a new U.S. government director, refocused and expanded HIV vaccine development efforts, concluded a landmark acute HIV infection cohort study and supported a growing portfolio of emerging infectious disease research.
Centered at the Walter Reed Army Institute of Research (WRAIR), MHRP works to protect U.S. troops from HIV and reduce the global impact of the disease through a combined focus on developing an effective vaccine and finding a cure. In 2018, under the leadership of new director Dr. Robert Gramzinski, the program renewed its focus on addressing HIV sub-type B, which is the most prevalent subtype in the U.S. military, the Americas and Europe. To that end, MHRP researchers initiated site development activities in Germany specifically to build a cohort of volunteers with sub-type B infection.
MHRP and collaborators at the Institute for HIV Research, University Duisburg-Essen, launched a longitudinal cohort study at multiple clinical sites in Germany to evaluate the incidence of HIV subtype B among an at-risk subpopulation and determine the feasibility of conducting an HIV vaccine efficacy trial there in the future. The study, called BRAHMS, is the largest systematic epidemiological study for sexually transmitted diseases in Germany, and is MHRP’s first clinical study in Europe.
MHRP’s geographic reach also extended into Jordan with the establishment of the Partnership for Research in the Middle East (PRIME). PRIME is a military-to-military partnership between WRAIR and the Jordanian Royal Medical Services. MHRP has begun site development and training activities for what will be the first observational HIV study conducted in the Kingdom of Jordan.
Advances in vaccine development aren’t possible without fundamental research building foundations of knowledge, and this year MHRP’s basic scientists have uncovered new insights into immune response and host-virus interplay.
MHRP researchers used cell sorting and transcriptional profiling to identify unique RNA signatures to help unveil the potential mechanisms through which natural killer immune cells respond to HIV infection and vaccination. Findings from the study were published in Nature Communications.
In another illuminating study, MHRP scientists found that distinct biomarker signatures arising during acute HIV infection appear to be associated with the establishment and persistence of the viral reservoir. Estimating the size of the viral reservoir is critical for HIV cure strategies, so the discovery of these biomarkers may provide an additional resource for those studying reservoir eradication.
MHRP’s two acute infection cohorts provide insight into crucial stages of early HIV infection and inform long-term remission research that seeks to find treatments to suppress the virus without a need for lifelong antiretroviral therapy (ART).
This year the Early Capture HIV Cohort study (RV217) closed after nine years. This landmark acute infection study resulted in multiple high-profile publications and presentations, and uncovered unprecedented findings about the earliest days of HIV infection.
RV245, MHRP’s acute infection cohort in Thailand, continues to provide a platform to guide functional cure research. In a publication in Nature Medicine, researchers reported that HIV viral load rebounds rapidly despite suppressive ART initiated at the earliest stage of infection before seroconversion. These findings suggest that regardless of timing of ART, future treatment research strategies should aim to eliminate cells with replication competent HIV in blood and tissues by boosting immune responses.
MHRP’s deep bench of infectious disease experts and its international laboratory and clinical research network has allowed the program to pivot efforts to address military and global health threats beyond HIV. MHRP’s research successes in other infectious disease areas have led to a spinoff at WRAIR of an Emerging Infectious Disease branch, to be directed by Dr. Kayvon Modjarrad, an alumnus of MHRP. The new branch has already launched research into MERS, Marburg, Lassa fever and tick-borne encephalitis and will oversee ongoing efforts of the Joint West Africa Research Group. The Emerging Infectious Disease branch will continue to work closely with MHRP as the HIV program redoubles its efforts in vaccine development and functional cure research.
MHRP supports HIV prevention and treatment services in the Kenyan and Nigerian militaries and in communities where research is conducted. These services, funded through PEPFAR, provide an ethical, non-coercive environment to conduct clinical research. In 2018, MHRP’s PEPFAR initiatives supported nearly 300,000 people on lifesaving antiretroviral therapy in four African countries, a figure roughly equal to the population of the city of Pittsburgh.
Soldiers deployed to war zones often need to stay vigilant while deprived of sleep. In combat operations, they may face demanding schedules, ranging from a few days without sleep, to many days of less than five hours a night. On average, however, a person needs to sleep seven to eight hours to fully recover mental acuity. This means that many sleep-deprived service members (at least 40 percent) are at increased risk of accidents.
Caffeine is the most common stimulant used to counter the effects of sleep loss. In the U.S., roughly 85 percent of adults consume the amount in two cups of coffee a day. But without specific guidance on when and how much to consume, alertness cannot be restored consistently when it matters most. And despite the boom in health-monitoring devices, no evidence-based tool had yet been developed to provide such recommendations.
In an article published in the Journal of Sleep Research in May 2018, scientists at the Telemedicine and Advanced Technology Research Center’s Biotechnology High Performance Computing Software Applications Institute (BHSAI), led by its director, Jaques Reifman, Ph.D., tackled this problem with collaborators at the Walter Reed Army Institute of Research. Their goal was to develop an algorithm that could estimate when sleep-deprived individuals should consume caffeine, and how much, to safely restore alertness at the desired time for the desired duration without overdosing.
The team had a foundation on which to build: a model of sleep developed and validated over the course of a decade by study co-author Sridhar Ramakrishnan, Ph.D., a BHSAI staff scientist and nine-year HJF employee. Using this model, which predicts alertness based on a history of sleep schedules and caffeine intake events, the team derived an optimization algorithm that suggests safe caffeine schedules that restored alertness in a timely and effective manner.
There was one problem: conventional optimization algorithms were inefficient. Francisco Vital-Lopez, Ph.D., lead author of the study, recounted how he devised a way to optimize caffeine schedules efficiently. “We first tested the two most widely used algorithms, but they took too much time to be of practical use because they required a very large number of computer simulations. So, we developed an algorithm that efficiently selected simulations that were likely to improve alertness, reducing the solution time from days to just a few seconds.”
This breakthrough, along with other tools developed by BHSAI scientists to predict the effects of sleep loss and caffeine, has set the stage for finalizing a smartphone app that warfighters can use to personally manage their caffeine and sleep schedules. Such an app, when connected to a network, may also help commanders plan missions more effectively by quantitatively assessing force status in real time and providing customized alerts and recommendations.
Naval Health Research Center-Operational Infectious Disease (NHRC-OID) established the Pacific Rim Surveillance Hub (PRSH) at Naval Hospital Yokosuka in 2006 to facilitate the expansion of shipboard Febrile Respiratory Illness surveillance into the 7th Fleet and influenza surveillance in the Pacific Rim. Since then, surveillance has expanded into the beneficiary population where an on-site research assistant collects samples and tests those samples in the hospital.
The Pacific Rim Surveillance Hub successfully applied for and received the College of American Pathologist accreditation in 2017. This accreditation allows for on-site testing and quick turnaround time to clinicians, often within an hour, providing real-time, actionable results for the providers and ultimately the patients while ensuring high quality lab results are being produced during all clinical testing. The lab has a small footprint consisting of two rooms with a myriad of capabilities ranging in complexities from waived tests to high complexity assays.
Pacific Rim Surveillance Hub (PRSH) at Naval Hospital Yokosuka.
On average, 240 samples are tested per year. The primary testing method is using the Biofire FilmArray, which is an automated CLIA-moderate complexity instrument that includes sample preparation, reverse transcription for RNA viruses, and a two-stage nested multiplex PCR process. The results obtained from PRSH provides a snapshot of what type of diseases the military are encountering in the Pacific, which is often very different than what is seen in the Continental United States (CONUS) sites.
Moreover, these results enable rapid detection of disease that allows for earlier initiation of antiviral therapy and infectious diseases control. Further characterization is completed for all samples such as whole genome sequencing and phenotypic antiviral drug resistance testing on a subset of samples in NHRC-OID, San Diego.
In PRSH, there are two available extraction methods: manual extraction using the Qiagen kit and automated extraction using the MagNA Pure compact. The lab is also equipped with the ABI 7500 real-time instrument allowing for the ability to test for influenza A and subtypes, influenza B and genotypes, rhinoviruses, respiratory syncytial virus A/B, Mycoplasma penumoniae, Chlamydia pneumoniae and Bordetella pertussis. The main instrument for testing is the FilmArray Respiratory Panel, a moderate complexity assay that can simultaneously test for 20 respiratory pathogens.
“In the future, we’ll be expanding collection and testing capabilities,” said Erin Hansen, HJF program manager. “Our future collection sites will extend to Okinawa and Guam, where we’ll have a research assistant collecting samples and forwarding to PRSH for testing. This will expand the surveillance well into the Pacific, further supporting FHP and military readiness.”
In response to the 2016 Presidential Cancer Moonshot Initiative to accelerate the progress of cancer research towards a cure, the Department of Veterans Affairs (VA), Department of Defense (DoD) and the National Cancer Institute (NCI) established a Memorandum of Agreement that enabled the three agencies to increase the pace of discovery in cancer and translate findings into clinical care. This Agreement formed the Applied Proteogenomics OrganizationaL Learning and Outcomes (APOLLO) network.
The goal of APOLLO is to create the nation’s first integrated proteogenomics cancer care and early discovery-to-clinical healthcare implementation system. APOLLO will leverage the VA Precision Oncology Program, VA hospital network, the DoD Murtha Cancer Center Research Program at Uniformed Services University (MCCRP), NCI Clinical Proteomics Tumor Analysis Consortium (CPTAC), NCI-sponsored clinical trials network, NCI Genomic Data Commons, a new Proteomics Data Commons, NCI SEER registry, NCI/NIH/VA/DoD training efforts and the Uniformed Services University (USU) The American Genome Center (TAGC).
The APOLLO network will drive the process of discovery as a natural outgrowth of patient care and help transform the way evidence on clinical effectiveness is generated and used to improve health and health care for active military, dependents, veterans, and civilians. The network is designed to increase access to clinical trials; optimize federal cancer resources; increase access to translational research resources; increase access to patients’ data, tissue and oncology specialists; increase education and training opportunities; and increase recruiting and retention.
This year research protocols for the APOLLO network were approved and research efforts began. Advanced proteogenomics technologies are being deployed to characterize and compare tumors, develop a deeper understanding of cancer biology, and identify potential therapeutic targets and pathways of cancer detection and intervention.
The following projects are in various stages of processing and analysis:
APOLLO 1 – Lung Cancer
APOLLO 2 – Gynecologic cancer
APOLLO 3 – Prostate cancer
APOLLO 4 – Breast cancer
APOLLO 5 – All organ sites
APOLLO 6 – Pancreatic cancer and other cancers that are relevant to the active-duty military population.
The program will expand to incorporate multiple cancer types and will aim to enable better testing of clinical questions on toxicity and response, sequencing and proteomics, analysis of samples and use of data science and analysis tools. The focus of APOLLO from the DoD and MCCRP perspective is on active duty service members with cancer, of whom there are over 1,000 new cases a year across the Military Health System. APOLLO will preferentially analyze and study these cancers from active duty so that we can identify the best treatments with the least side effects and have service members return to duty cancer-free at the highest possible rate, which positively benefits overall military readiness.
HJF Medical Research International (HJFMRI) supports the U.S. Army Medical Research Directorate—Africa (USAMRD—A), a U.S. Government-funded activity that collaborates with Kenya Medical Research Institute (KEMRI) and the Kenya Defense Force (KDF), to support infectious diseases surveillance and outbreak response in East Africa.
The Kenya program, implemented by KEMRI, uses an extensive multi-site surveillance network to respond to public health threats and to support research. Over 11 surveillance sites support 15 protocols and use seven laboratories where clinicians and supportive staff perform research on infectious diseases. Studies include: Antimicrobial Resistant Studies (ARS), Malaria Drug Resistant (MDR) Study, Influenza (Flu) Study, Enteric Pathogen Surveillance, Acute Febrile Illness Surveillance, Sexually Transmitted Infections (STI) Study, Rift Valley Fever (RVF) Study, and Vector Borne Illnesses Surveillance – Entomology Component.
The ARS project focuses on antimicrobial resistance in the military and civilian population in Kenya. The objective of the study is to determine the antibiotic susceptibility (AST) profiles of bacteria and isolate the clinical specimens of infected patient in- and out-patient populations. Researchers tracked the emergence of multidrug resistant organisms (MDRO) of global concern such as methicillin resistant Staphylococcus aureus (MRSA), vancomycin resistance enterococcus spp. (VRE) and extended spectrum B-lactam (ESBL). The work includes determining and comparing the prevalence of hospital and community-acquired MDR organisms in participating hospitals and identifying associated risk factors and strain type. They also characterize the virulence and antimicrobial resistance determinants of bacterial pathogens.
The secondary objectives are to test new assays and develop novel testing assays to facilitate and improve the efficiency of biosurveillance for MDRO and to provide outbreak and diagnostic support for infectious diseases at the request of the Ministry of Health, the Kenya Defence Forces and/or the World Health Organization.
The Kenya program infectious disease studies continue to evaluate and integrate emerging infectious disease surveillance and respond to promote preparedness, contribute to local, military and global health by looking at ways to improve hospital infection rates, resistance to antimalarial therapeutics, influenza surveillance, the detection of bacterial, parasitic, and enteric viruses among others. The health information provided by these programs is shared with collaborators to inform medical and public health practice.
In September, HJF began work with the Defense POW/MIA Accounting Agency (DPAA), providing expert operational support of DPAA’s efforts to locate and recover the remains of unaccounted-for Department of Defense (DoD) personnel from designated past conflicts.
HJF will support work on archeological sites across the globe where missing DoD personnel may be located, assisting archeological teams’ terrestrial and underwater activities to recover the remains of U.S. service members.
“HJF is honored to team with DPAA in this crucial capacity. The full weight of HJF’s research, administrative and program management teams are behind our partner,” said HJF President and CEO Joe Caravalho. “Being a part of bringing missing Soldiers, Sailors, Airmen, Marines and DoD civilians/contractors home to their loved ones is near and dear to my heart.”
When HJF joined the effort, more than 82,000 Americans remained missing from World War II, the Korean War, the Cold War, the Vietnam War, the Gulf Wars and other conflicts. Of those, 75 percent of the losses are in the Indo-Pacific region. More than 41,000 Americans are presumed lost at sea.
After spending almost seven years at the Armed Forces Medical Examiner System during Operations Enduring Freedom, Iraqi Freedom and New Dawn, John Getz, an HJF employee who manages the program, understands the vital mission of returning loved ones home to their grieving families.
“I can’t begin to imagine the pain and uncertainty the generations of the families of the missing must feel,” said Getz. “This drives my dedication in supporting the DPAA in the mission of providing the fullest possible accounting for our missing DoD personnel to their families and the nation.”
DPAA Activity Sites