Disease Non Battle Injuries remain a major risk to combat effectiveness, posing a significant burden to an Army Health System with limited capacity for extended time periods during Multi-Domain Operations. The Army will remain globally engaged across the competition continuum, exposing maneuver forces to endemic diseases and battlefield infections stemming from combat related injuries. FDA approved medical countermeasures to address these problems, to include infectious disease prophylactics and treatments for nonimmune adult populations as well as combat wound infections, are currently unavailable or insufficient for military use.

Diarrheal disease caused by bacteria had a significant impact on force readiness due to hospitalization and lost duty days during the Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF). Units experienced 1.1M lost duty days and 3.8M cases of diarrheal disease during operations from 2001-2007. Viral diseases such as Dengue fever have a major impact and in the absence of effective countermeasures, an Infantry Brigade Combat Team deployed to a highly endemic region for Dengue could experience a 15% reduction in combat effectiveness. Combat wound infection rates in battlefield injuries from OEF/OIF are from 10-30%, with an average evacuation time to a surgeon between 45 - 90 minutes. We see increasing complexity and rate of infection in those with higher injury severities. With the potential of delayed evacuation and time to care in multi-domain operations we expect these infection rates to increase dramatically.

Preventing disease is a force multiplier by keeping the Warfighter healthy and speeding return to competition. As such, MIDRP focuses on developing countermeasures against infectious diseases our deployed military forces will likely encounter. Most of these diseases are not of concern within the United States. While the MIDRP shares some common research goals with other research organizations, the military presents unique needs that are inadequately addressed by other federal agencies, academia, international programs and private industry. Infectious diseases continue to impact operational forces, as Warfighters are hospitalized more often for infectious diseases than those who are wounded in combat. Infectious diseases also place a significant burden on the medical logistics system for people requiring treatment, evacuation, and/or hospitalization. The loss of personnel to infectious diseases reduces operational readiness and effectiveness by requiring evacuation and replacement troops.

Medical countermeasures remain challenging to develop. There is still much to learn with respect to the basic biology of infectious diseases as well as how the body reacts to the invading pathogen. Understanding these mechanisms enables medical countermeasure development. Knowledge of how pathogens cause disease, and how the body responds to those pathogens can be used to design vaccines that mount a protective immune response. Additionally, these pathways can be used to develop new drugs to fight infection. Without this basic knowledge of these pathogens, vaccine and drug development is nearly impossible. Vaccine and drug development also is a high-risk, high-cost venture, with FDA approval as the ultimate goal. As such, there is a requirement for innovation to provide a robust pipeline of potential solutions for these infectious diseases of high operational impact.

All medical countermeasures developed for the Warfighter must achieve FDA approval. Stringent requirements to establish safety and efficacy of the candidate product can result in high costs, including the need for multiple human clinical trials. The ability to move forward in clinical testing is dependent upon demonstrating that the medical countermeasure candidate is safe and efficacious in both short- and long-term studies, which can take several years to complete in some cases. Additionally, review of the medical countermeasure for FDA approval, as well as manufacturing of the final approved product also add to the timeline for availability to the Warfighter.

Therapeutics, vaccines and diagnostic devices are, by law, regulated by the U.S. Government to ensure the products are safe and effective. Safety concerns are the primary driver for the guidelines and processes in place to ensure individuals are not harmed by the products being developed and marketed. In recent years, the level and complexity of regulatory oversight have increased significantly, resulting in longer development times.

Diarrhea continues to be a major problem for deployed personnel. It can cause serious dehydration and crippling disease, which impacts the ability to accomplish a mission. Some affected troops are placed on restricted duty or hospitalized for treatment. Historically, some diarrhea outbreaks have resulted in entire units becoming nonoperational. As an example, an Infantry Brigade Combat Team deployed to a highly endemic region without effective countermeasures could experience a 72% reduction in combat effectiveness.

Congress started the DoD HIV program in 1985. At the time, the impact of HIV on the military was unclear, and with the DoD's history as a vaccine developer, Congress hoped to provide a mechanism to test HIV vaccines within the context of the DoD laboratories. This effort is now being conducted in a partnership with the National Institute of Allergy and Infectious Diseases.

The MIDRP partners with academia, industry, and other government using mechanisms such as Cooperative Research and Development Agreements, the Small Business Innovation Research Program, Congressional Special Interest-appropriated funding, and Interagency Agreements. Additionally, critical to the development of any medical countermeasure is the involvement of a commercial partner that has the ability to manufacture and market medical products to those who need them. The high cost of product development usually can only be recovered, and the product sustained by, having a commercial market for the product. In addition, the basic research and concept development for new products involve both academic and governmental research organizations that are critical for intellectual input and for providing critical research capabilities not always available at military laboratories.

• Drugs: The MIDRP fostered the S&T research necessary to the development of most synthetic drugs licensed in the United States for the prevention and treatment of malaria. Next-generation antimalarial drugs include tafenoquine and an intravenous formulation of artesunate which received FDA approval in August 2018 and May 2020, respectively.
• Diagnostics: MIDRP diagnostic products include field worthy devices to diagnose human infections (e.g., malaria and cutaneous leishmaniasis) and to determine if insects are carrying infectious agents transmissible to humans (e.g., West Nile and dengue fever viruses).
• Wound Infections: Since 2010, MIDRP has managed funds and research efforts focused on the prevention and treatment of battlefield wound infections. Key accomplishments of the Wound Program have been: generation of a diverse library of bacteriophages (>2000) for development of therapeutics and a pipeline for in-house discovery of antibodies to Acinetobacter and Klebsiella. Additionally, the MIDRP-funded Trauma Infectious Diseases Outcome Study (TIDOS) described the wound microbiology of extremity wound infections, linking specific microorganisms associated to monomicrobial and polymicrobial infections in battlefield wounds (OIF and OEF). Invasive fungal infections (IFI) epidemiology from the TIDOS dataset were analyzed using the refined IFI definition and classification. As part of the program, the bacteriophage program contributed to two products transitioning to Navy Advanced Medical Development (AMD). Two first-ever clinical trials in the US for Bacteriophage Therapy are ongoing with Navy AMD's support: one for the treatment of Staphylococcus aureus bacteremia and one for bacterial infection of the urinary tract.
• Bacterial Diarrheal Disease: The bacterial diarrheal diseases program is developing strategies to mitigate or prevent enterotoxigenic Escherichia coli (ETEC) infection by the disruption of gut colonization through the development of non-vaccine countermeasures to combat travelers' diarrhea. In vitro assays for high throughput screening of lead countermeasures (e.g. antibodies and small molecule inhibitors) against travelers' diarrhea have been developed. Additionally, animal models are being refined and established for pre-clinical testing and advancement of lead countermeasures against Campylobacter jejuni, ETEC and Shigella infections.
• COVID-19: In 2020, COVID-19 was a major priority effort for MIDRP. Since early in 2020, MIDRP has managed funds and research efforts focused on the prevention, detection, and treatment of COVID-19. These efforts include development of small and large animal models recapitulating human COVID-19 disease along with accompanying immunological assays, in order to investigate the pathogenesis of the disease, and to determine the efficacy of developed vaccines and therapeutics. For prevention, researchers developed multiple vaccine candidates and down-selected to one candidate, Spike Ferritin Nanoparticle (SpFN), which has undergone small animal efficacy testing and is currently undergoing large animal efficacy testing. In addition, hundreds of monoclonal antibodies (mAbs) are currently being characterized to develop potent SARS-CoV-2-targeting mAbs for prophylactic and therapeutic use. Treatment efforts have focused on developing antiviral drug candidates, and providing telemedical care for COVID-19 patients. Detection efforts have spanned studies of transmission among Army Recruits, through the development of wearable diagnostic devices and various diagnostic assays.
• Viral Disease: Through participation in DARPA's INTERCEPT program MIDRP is supporting the development of Therapeutic Interfering Particles (TIPs) as a new form of medical countermeasure against emerging and rapidly evolving viral disease, including influenza, coronaviruses, paramyxoviruses, and others. The TIPs technology for was featured in a recent

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