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Army 14. 1 Small Business Innovation Research (sbir) Proposal Submission Instructions

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The purpose of this topic is to explore the potential of a third paradigm, phage based diagnostics, to address many if not all of the limitations of the currently fielded assays and instruments, and to leverage existing platforms. The general concept is to harness the specificity (natural or engineered) of attachment of phages or phage proteins to bioagents in addition to exploiting the sensitivity of Quantum Dots for developing a fluorescent detection technology that can be used in currently fielded detection platforms. Phages are also useful for live agent detection unlike the current approaches that can detect both live and inactive agents.

The proof of concept for phage Quantum Dot technology has been established in some phage-bacterial systems1, 2. The specificity of phages to their cognate bacterial species or strain is fairly well established. It is also conceivable to engineer specificity for any type of agent onto phages using affinity panning3. Quantum Dots are superior to many other fluorophores available today. They have a broad absorption spectrum and a narrow emission spectrum, highly tunable based on size and hence multiplex detection of agents is possible. Quantum Dots can also be synthesized to carry specific functional groups or moieties on their surface for binding specific agents.

This topic seeks technologies to demonstrate the utility of a phage-QD assay in a platform that can be readily fielded. Some of the proposed paths are: manipulate whole phage or phage structures such as tail fibers, or phage tail fiber like bacteriocins5, phage proteins such as cell wall binding domains of endolysins6, (modify to chemically link a functional group such as biotin or genetically engineer phage/protein to express a functional moiety such as biotin binding peptide on the surface) and use Quantum Dots for detection upon binding to specific bacteria. Engineering a universal phage with binding specificities in combination with QD for detection of any agent type (spore, vegetative cells or protein) is also desired.
PHASE I: This phase will demonstrate the feasibility of the phage-QD assay in a user-friendly, fieldable fluorescent detection system.
Milestones and deliverables for Phase I:

• Demonstrate a phage/phage protein-bacterium-QD assay detection in a biodefense relevant pathogen (e.g., B. anthracis vegetative cells or spore, Y. pestis etc.) in a fieldable platform

• Demonstrate multiplex capability

• Delineate assay sensitivity and LoD in buffer and a clinical matrix

• Produce a summary report of the results that demonstrates a comparative evaluation, establishes suitability of the technology, and provides research findings with supplemental documentation to justify selection by providing insights into expanding the proposed technology to other agents of interest. A clear description of a path forward for expanding the technology to other agents of interest is required
PHASE II: This phase will involve expanding the work performed in Phase I to include multiple agents and developing a 510 K package for FDA licensure of the platform technology.
Milestones and deliverables for Phase II:

• Expand the phage-QD detection concept for detection of viral agents and proteins such as toxins

• Develop inclusivity/exclusivity testing of a phage-bacterial pair

• Develop and establish LoD for the assays

• Conduct clinical trials with contrived samples or real specimens to establish sensitivity/specificity

• Prepare initial packages for submission to FDA

PHASE III: This phase will expand the work in Phase II in integrating and commercialization/fielding of the platform.
Milestones and deliverables for Phase III:

• Extend the work accomplished in Phase II. Focus will be on integrating the Phase II assays with the fieldable platform

• Demonstrate the multiplexing and high-throughput applications in a field/point of care setting

• Establish quantitative parameters of detection

• Describe a commercialization strategy of the technology to commercial healthcare settings and /or transition to military operations and acquisitions
PHASE III Dual Use Applications: Further research and development during Phase III efforts will be directed towards expanding the panel of phages for detection of all bacterial and viral pathogens of interest to the medical community beyond DoD using the plug and play format afforded by this technology. Inexpensive, portable fluorescence readers with the ability to exceed visual detection limits and to document test results would find extensive use by first responders, in civilian medical facilities, in the public health field, and for point of care diagnostics in remote regions throughout the world.

1. Edgar R, McKinstry M, Hwang J, Oppenheim AB, Fekete RA, Giulian G, Merril C, Nagashima K, Adhya S. High-sensitivity bacterial detection using biotin-tagged phage and quantum-dot nanocomplexes. Proc Natl Acad Sci U S A. 2006 Mar 28; 103(13):4841-5.

2. Yim PB, Clarke ML, McKinstry M, De Paoli Lacerda SH, Pease LF 3rd, Dobrovolskaia MA, Kang H, Read TD, Sozhamannan S, Hwang J. Quantitative characterization of quantum dot-labeled lambda phage for Escherichia coli detection. Biotechnol Bioeng. 2009 Dec 15;104(6):1059-67.
3. Brigati J, Williams DD, Sorokulova IB, Nanduri V, Chen IH, Turnbough CL Jr, Petrenko VA. Diagnostic probes for Bacillus anthracis spores selected from a landscape phage library. Clin Chem. 2004 Oct;50(10):1899-906.
4. Scholl D, Cooley M, Williams SR, Gebhart D, Martin D, Bates A, Mandrell R. An engineered R-type pyocin is a highly specific and sensitive bactericidal agent for the food-borne pathogen Escherichia coli O157:H7. Antimicrob Agents Chemother. 2009 Jul;53(7):3074-80.
5. Schmelcher M, Shabarova T, Eugster MR, Eichenseher F, Tchang VS, Banz M, Loessner MJ. 2010. Rapid multiplex detection and differentiation of Listeria cells by use of fluorescent phage endolysin cell wall binding domains. Appl Environ Microbiol 76:5745-5756.
KEYWORDS: bioagent; detection; diagnostics; phage; Quantum Dot; fluorescence; multiplex; assay

A14-044 TITLE: Ricin Toxin Protective Monoclonal Antibodies with Improved Serum Half-Life

TECHNOLOGY AREAS: Chemical/Bio Defense
OBJECTIVE: Develop innovative approaches to substantially improved serum half-life of the protective monoclonal antibodies for prophylaxis and/or therapy against ricin intoxication.
DESCRIPTION: Ricin from the castor oil plant Ricinus communis, is a highly toxic, naturally occurring protein. A dose the size of a few grains of table salt can kill an adult human. Although estimates vary, the LD50 of ricin is approximately 25 micrograms per kilogram in humans if exposure is from injection or inhalation.
In light of the abundant availability and relatively simple methods required to obtain ricin from castor oil plants, this toxin is considered a biological warfare threat agent. Moreover, the Department of Defense identified a capability gap to protect against exposure to the ricin toxin in the Initial Capabilities Document for Joint Medical Biological Warfare Agent Prophylaxes, approved 14 September 2004. Currently, there are no licensed, specific medical prophylactic or therapeutic measures against the ricin toxin.
To that end, the goal of this SBIR topic is to solicit innovative approaches to improved serum half-life of the protective monoclonal antibodies (mAbs) for prophylaxis and/or therapy against ricin intoxication. The approaches may include but are not restricted to methods to reduce mAb degradation, use of genetically derived immunoglobulin glycoforms, methods to reduce hepatic turnover of mAbs, methods to create slow-release mAb depots and combinations thereof. The specific improvements in duration should be determined using baseline values and ideally technologies will be developed to improve mAb duration 2-fold or more.
PHASE I: Phase I studies will focus on development of proof-of-concept in vitro and in vivo models and prototyping systems to modify ricin-specific mAbs.
PHASE II: Studies in Phase II will include small scale process development, production of material for in vivo potency and pharmokinetic/pharmodynamic studies in small animals and culminate in a pharmokinetic/pharmodynamic study in a non-human primate (NHP) model.
PHASE III: Studies in this phase will focus on scale-up manufacturing, toxicity and potency assessment in appropriate animal models, followed by cGMP manufacturing, pivotal efficacy studies in NHPs and clinical trials.
PHASE III Dual Use Applications: It is anticipated that successful development of a platform strategy to improved mAb half-life will have dual use in both improved mAb countermeasures for the warfighter and improved therapeutic mAbs for use as pharmaceutics.

1. Neal LM, O'Hara J, Brey RN 3rd, Mantis NJ. A monoclonal immunoglobulin G antibody directed against an immunodominant linear epitope on the ricin A chain confers systemic and mucosal immunity to ricin. Infect Immun. 2010 Jan;78(1):552-61.

2. Yermakova A, Vance DJ, Mantis NJ. Sub-domains of ricin's B subunit as targets of toxin neutralizing and non-neutralizing monoclonal antibodies. PLoS One. 2012;7(9):e44317.
3. Jefferis R. Isotype and glycoform selection for antibody therapeutics. Arch Biochem Biophys. 2012 Oct 15;526(2):159-66.
4. Suzuki T, Ishii-Watabe A, Tada M, Kobayashi T, Kanayasu-Toyoda T, Kawanishi T, Yamaguchi T. Importance of neonatal FcR in regulating the serum half-life of therapeutic proteins containing the Fc domain of human IgG1: a comparative study of the affinity of monoclonal antibodies and Fc-fusion proteins to human neonatal FcR. J Immunol. 2010 Feb 15;184(4):1968-76.
KEYWORDS: ricin; toxin; monoclonal antibody; pharmacokinetics; biological countermeasure

A14-045 TITLE: Modernized Production of Enteric Coated Live, Oral Adenovirus Vaccine

ACQUISITION PROGRAM: Office of the Principal Assistant for Acquisition
OBJECTIVE: Develop novel technological methods for oral delivery of live adenovirus compared to the current FDA-licensed product, “Adenovirus Type 4 and Type 7 Vaccine, Live, Oral” (Barr Labs, Inc.). The new methods should provide material benefits in terms of production and comparable safety and immunogenicity.
DESCRIPTION: Adenoviruses are a frequent cause of epidemic acute respiratory disease (ARD) in military basic recruits and pose a significant threat to military readiness, especially during times of large mobilization. ARD is a debilitating febrile disease that frequently results in loss of training time, hospitalization and pneumonia and, on occasion, death. There is no FDA-licensed treatment option available for adenovirus. Before vaccines were available, adenovirus was isolated in 30-70% of recruits with ARD and 90% of cases of pneumonia. The vast majority of adenovirus infections in recruits is caused by types 4 and 7, although types 14 and 21 have also caused severe outbreaks.
A live oral vaccine against adenovirus type 4 was developed in the 1960s and determined by clinical studies to be safe and effective in preventing ARD due to adenovirus type 4. Subsequently, a similar live oral adenovirus type 7 vaccine was developed. After extensive testing, these vaccines were approved by the FDA and manufactured by Wyeth Laboratories in 1980. The Wyeth adenovirus vaccines were very safe and effective in eliminating outbreaks of ARD in recruits. However, in 1995 Wyeth elected to cease production and all DoD supplies were depleted by 1999. With the loss of the vaccine, adenovirus outbreaks and deaths in basic recruits returned to pre-vaccine levels. DoD contracted with Barr Laboratories to develop replacement live oral adenovirus vaccines. The new Barr Adenovirus vaccines were demonstrated to be safe and effective and were licensed by the FDA in March 2011. The vaccines are administered to all new basic recruits in the Army, Navy, Air Force, Marines, and Coast Guard.
The Barr and Wyeth vaccines are intentionally very similar. The type 4 and 7 virus strains in both vaccines are identical and both vaccines are prepared in WI-38 cell cultures. Both vaccines are similarly formulated as enteric coated tablets containing either adenovirus type 4 or adenovirus type 7 (at least 32,000 tissue-culture infective doses per tablet). The vaccine is described as a “tablet within a tablet” with the inner core containing live virus and excipients and the outer tablet layer consisting of cellulose and other ingredients. Oral administration of vaccine results in a self-limited, asymptomatic infection in the gastrointestinal tract and produces protective neutralizing antibodies in the serum.
This topic is intended to enhance the manufacturing methods currently used in production (or “tableting”) of the licensed adenovirus vaccine. The technology used to produce the tablets originates from the 1960s and its continued long-term sustainability is of concern to DoD. The proposed solution should utilize novel technological methods and capitalize on advances in biotechnology and pharmaceutical production technologies. The proposed novel method will be suitable for production of live adenovirus vaccine for oral administration to healthy individuals at risk of acquiring adenovirus–associated acute respiratory disease. The new method will take advantage of reliable modern production methods; will be able to achieve licensure by the FDA; will provide clear benefits compared to current tableting methods, such as as facility and equipment requirements, technical complexity, robustness, etc., and; will ultimately yield vaccine that shares comparable virologic, safety, and immunologic characteristics with the licensed vaccine. Targets for improvement may include, but are not restricted to drying, stabilization, and enteric protection of live virus for oral delivery. Ideally, the new vaccine will be reviewed by the FDA as “Biosimilar” to the reference product, the Barr Adenovirus vaccine, permitting expedited clinical development.
PHASE I: Produce a conceptual design for developing, manufacturing, and testing the proposed solution. Produce a prototype vaccine of at least two Adenovirus types (e.g., types 4 and 7) for the purpose of demonstrating feasibility of the proposed solution. Production methods and vaccine ingredients are not expected to be finalized at end of this phase; GMP product is not required. Test(s) of feasibility may include modified disintegration and/or dissolution tests demonstrating the potential for pH-controlled release of adequate amounts of live adenovirus. Additional and/or alternative feasibility tests may be proposed. DoD may provide small quantities of the licensed vaccine for relevant non-human research conducted as part of this phase. Provide a comprehensive analysis of significant risks associated with the proposal, including manufacturing, technical, regulatory, cost, and performance. Provide a comprehensive report of all testing performed during this phase.
PHASE II: Produce vaccine under GMP pilot production conditions, perform required nonclinical studies (such as microbial burden), and conduct an 8-week FDA phase 1 trial in healthy adults of at least two adenovirus types (e.g., types 4 and 7). Animal efficacy and reproductive toxicity studies are not required. Animal toxicology studies may be waived by the FDA, if the product is deemed equivalent to the Barr vaccine. The results of the clinical trial will permit a clear comparison of the new and Barr vaccines in terms of fecal shedding, absence of spread beyond the gastrointestinal tract (i.e., no detectable vaccine virus in throat, blood or urine), immune response, and preliminary safety. Vaccine shelf-life assessment will also be initiated during this phase. DoD may provide limited quantities of licensed vaccine required for testing proposed during this phase, including a clinical trial. Provide a comprehensive report of all testing performed during this phase, including a complete searchable dataset of the clinical trial.
PHASE III: The overall goal of this effort is to modernize the production of vaccine tablets administered to all military basic recruits to prevent febrile respiratory illness due to adenovirus types 4 and 7. The technological innovations utilized in the modern vaccine will also permit more efficient development of new adenovirus vaccines comprised of different adenovirus types, such as types 14 or 21, should they be needed in the future by DoD. Modernization of tableting methods will also support commercialization of the product in other markets (e.g., South Korea and China have reported problems with adenovirus type 7) and derivative products. For instance, oral adenoviruses may be very useful and widely utilized for delivery of vaccine vectors for multiple other pathogens, gene therapy, and cancer therapy. The focus of this phase should be on further development and validation of the methods and product with the objective of obtaining FDA approval of the new vaccines with an indication for use in military personnel at risk of acquiring adenovirus infections.

1. Gray, GC, Goswami PR, Malasig, MD et al. Adult adenovirus infections: loss of orphaned vaccines precipitates military respiratory disease epidemics. Clinical Infectious Diseases 2000:31:663-70.

2. Russell KL, Hawksworth AW, Ryan MA, et al. Vaccine-preventable adenoviral respiratory illness in US military recruits, 1999–2004. Vaccine 2006;24:2835–42.
3. Lyons A, Longfield J, Kuschner R, et al. A double-blind, placebo-controlled study of the safety and immunogenicity of live, oral type 4 and type 7 adenovirus vaccines in adults. Vaccine 2008:26:2890-98.
4. Hoke CH Jr, Snyder CE Jr. History of the restoration of adenovirus type 4 and type 7 vaccine, live oral (Adenovirus Vaccine) in the context of the Department of Defense acquisition system. Vaccine 2013; 31:1623-32.
5. Gray GC. Adenovirus Vaccines, in Plotkin SA, Orenstein WA, Offit PA (eds), Vaccines- 6th edition, Elsevier, Philadelphia, 2012, p. 113.
6. Food and Drug Administration (FDA), Center for Biologics Evaluation and Research (CBER), Package Insert, Adenovirus Type 4 and Type 7 Vaccine, Live, Oral. Available at:

KEYWORDS: Adenovirus Vaccine, Adenovirus Type 4, Adenovirus Type 7, Biological Products, Vaccines, Enteric Coating, Enteric Protection, manufacturing processes, manufacturing coatings

A14-046 TITLE: Antibiotic Decision Support System for Management of Combat Casualties with Severe

ACQUISITION PROGRAM: Office of the Principal Assistant for Acquisition
OBJECTIVE: Develop an antibiotic clinical decision support (CDSS) system to improve treatment for critical care patients with severe infections. The system will provide recommendations to critical care providers in the intensive care unit (ICU) on antibiotic dosing based on multiple patient factors, including weight, infection source, infectious agent, cultures, susceptibilities, and prior treatments. The final system will include the ability to be configured to the unit’s specific antibiotic regiments, characteristics, and anti-biograms and will also integrate with hospital information technology (IT) infrastructure.
DESCRIPTION: Many military casualties survive the first few days of burn and trauma resuscitation and surgeries only to fall victim to an infection and sepsis. Intensive care for these casualties is complex, requires treatment of systemic and often multiple organ systems at a time and is highly error-prone. Permanent morbidity or death results when the right care is not delivered or is delivered too late. Evidence-based best practices are published, but yet not implemented in step by step detail at the bedside due to complexity.
Severe sepsis and septic shock have a mortality rate near 30% (1). Recent data has shown that computer based clinical decision support programs can greatly increase compliance with evidence based best practices, resulting in a 50% reduction in mortality for sepsis (2) and for initial empiric antibiotic therapy (3). Targeted antibiotic therapy is important for effective treatment of the organism and for avoiding highly toxic side effects of broad spectrum antibiotics and for avoiding increased pathogen resistance. However, choice of antibiotics often requires changing after susceptibility and cultures results are received. Burn casualties are particularly susceptible to multiple incidents of sepsis over a prolonged hospital stay. An antibiotic CDSS system is needed to quickly process a myriad of factors in determining the optimal antibiotic therapy for a patient at any given time throughout the hospital stay. This system should take into account not only empiric choice decisions but individualize dosages based on minimum inhibitory concentration (MIC) calculations.
PHASE I: Develop an initial concept design and demonstrate elements of a CDSS software program providing specific antibiotic therapy guidance from initial diagnosis through discharge. Contractors should provide a basic software application that demonstrates a basic ability to process and make recommendations on potential antibiotic therapies. Contractors should explore novel approaches to implement antibiotic decision making as additional patient data is received. The clinical decision support system should include broad spectrum, narrow spectrum, and targeted antibiotic therapy. The CDSS system should provide new recommendations when susceptibility and culture results are received. The system should include MIC calculations. The contractor will conceptualize a graphical display showing the infection status and antibiotic therapy from initial infection diagnosis to discharge.
PHASE II: The contractor will further develop and demonstrate the CDSS and will optimize bedside workflow. The contractor will demonstrate input clinical data IT integration with the hospital IT system for at least one variable. The contractor will develop and demonstrate a graphical representation of infection status and antibiotic therapy from initial infection diagnosis unto discharge. The successful clinical decision support program will allow physicians to adjust antibiotic therapy and will be easily adopted by the bedside caregivers.
PHASE III: The contractor will produce a working CDSS system capable of updating antibiotic decisions by the medical director of a unit. The CDSS system should gather most of the input laboratory data through IT integration. The CDSS system should be configured so that multiple client computers, tablets, or smartphone device can access the system simultaneously.
The final CDSS system must include evidence-based antibiotic therapy recommendations and an algorithm to optimize dosage for patients based on MIC calculations. Such a system could save lives by providing evidence-based, individualized, optimized antibiotic therapy for critical care patients throughout a hospital stay. Such a system should be of great commercial interest for all branches of the U.S. armed services as well as civilian critical care professionals in multiple critical care units.

1. Dellinger P, et al. "Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2008." Crit Care Med 2008; Vol. 36, No. 1, pp 296-327.

2. McKinley B, et al. “Computer Protocol Facilitates Evidence-Based Care of Sepsis in the Surgical Intensive Care Unit." May, 2011. J Trauma, Vol. 70; No. 6, pp 1153-67.
3. Paul M, et al. “Improving Empirical Antibiotic Treatment using TREAT, a Computerized Decision Support System: Cluster Randomized Trial.” JAC 2006, Vol. 58, pp 1238-45.
KEYWORDS: decision support, antibiotics, becteremia, critical care

A14-047 TITLE: Portable Closed Loop Burn Resuscitation System to Optimize and Automate Fluid

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