Armed Forces Epidemiological Board

1. 1 Armed Forces Epidemiological Board

2. 2

3. 3 Protecting Warfighters Through Integration and Teamwork

4. 4 Medical Chemical and Biological Defense Research Program Mission & Vision Provide medical solutions for military requirements to protect and sustain the force in a Chemical and/or Biological Warfare environment To Preserve Total Warfighter Effectiveness on a CW/BW Battlefield Prevent casualties Provide effective treatment of casualties for rapid return to duty Provide rapid, far-forward diagnosis of CW/BW disease Identify audience - military and civilian Mission of Medical CountermeasuresBDRP Provide MEDICAL countermeasures to Warfighters Effort is to Protect and Sustain the warfighter in the Biological Warfare Environment. Two words are even a part of our motto� Integrate medical chemical/biological defense into national/public health programsIdentify audience - military and civilian Mission of Medical CountermeasuresBDRP Provide MEDICAL countermeasures to Warfighters Effort is to Protect and Sustain the warfighter in the Biological Warfare Environment. Two words are even a part of our motto� Integrate medical chemical/biological defense into national/public health programs

5. 5 Intelligence Requirements Process THREAT ASSESSMENTS Prepared in discrete, tailored packages Evaluate impact on users Define mission needs REQUIREMENTS Joint Requirements Office for Chemical, Biological, Radiological and Nuclear Defense (JRO-CBRN) Joint Requirements Oversight Council (JROC) PROGRAMS Joint Service Materiel Group (JSMG) Defense Threat Reduction Agency (DTRA)/Joint Program Executive Office (JPEO) OSD coordinates/integrates funding requests

6. 6

7. 7 MCBDRP Locations Fort Detrick, MD MCBDRP U.S. Army Medical Research Institute of Infectious Diseases Forest Glen Annex, MD Walter Reed Army Institute of Research Naval Medical Research Center Washington D.C. Armed Forces Institute of Pathology Aberdeen Proving Ground, MD U.S. Army Medical Research Institute of Chemical Defense Natick, MA U.S. Army Medical Research Institute of Environmental Medicine Rearranged and added bullets for new WRAIR Need to add a location flag for Forest Glen, MD? Rearranged and added bullets for new WRAIR Need to add a location flag for Forest Glen, MD?

8. 8 Integration of DoD Acquisition and FDA Licensure

9. 9 Medical Biological Defense Research Program

10. 10 Medical Biological Defense Potential Threats Bacteria: Bacillus anthracis (Anthrax) Yersinia pestis (Plague) Francisella Tularensis (Tularemia) Brucella sp. (Brucellosis) Burkholderia maellei (Glanders) Coxiella burnetii (Q Fever) Viruses: Smallpox Encephalomyelitis viruses Ebola Marburg Toxins: Botulinum Toxins (Types A � G) Staphylococcal Enterotoxins (SEA/B) Ricin Toxin Marine Neurotoxins Mycotoxins Clostridium perfringens

11. 11

12. 12 CB.33 Recombinant Protective Antigen (rPA) Anthrax Vaccine Candidate(DTO completed in FY02)

13. 13 CB.31 Medical Countermeasures for Brucella(Continuing DTO) Brucellosis Nonspecific febrile illness Low infectious dose, highly infectious by aerosol Antibiotic resistance may limit treatment options Vaccine Candidate MNPH1 � live attenuated deletion mutant Orally administered Demonstrated proof of concept for protective efficacy in NHPs

14. 14 CB.34 Recombinant Plague Vaccine(Continuing DTO)

15. 15 Non-DTO Supporting Efforts(Bacterial Vaccines) Anthrax Further define pathogenesis of anthrax infection Evaluate other known antigens, new adjuvants, and delivery systems Employ functional genomics effort to identify new virulence determinants Plague Characterize the host immune response Plan and develop the next-generation plague vaccine through identification of new protective immunogens Define the genetic diversity and pathogenesis of natural plague isolates

16. 16 Non-DTO Supporting Efforts(Bacterial Vaccines) Glanders and Melioidosis Develop an animal model of aerosolized glanders infection Determine the mechanisms of immunity and establish correlates of immunity Identify new virulence determinants Potential vaccine candidates for protection against glanders Evaluate the basis for virulence of Burkholderia mallei and B.pseudomallei by genetic and molecular methods

17. 17 Non-DTO Supporting Efforts(Bacterial Therapeutics) Licensed antibiotics/novel antimicrobials Primary focus is evaluation of licensed and investigational antibiotics for efficacy against BW bacterial threats Specific effort to evaluate a series of licensed antibiotics as a post-exposure treatment for plague Demonstrated proof-of-concept for small molecule inhibitors of anthrax toxin Immunotherapy/Immunomodulators Passive prophylactic antibody treatment protects animals against aerosolized plague or anthrax Evaluating compounds capable of priming the immune response

18. 18

19. 19 CB.25 Multiagent Vaccines for Biological Threats(DTO completed in FY02) A vaccine or delivery approach that can concurrently immunize an individual against a range of biological warfare threats. Reduce vaccination schedules Decrease production costs Streamline regulatory requirements RNA Replicon and DNA Vaccine

20. 20 Live attenuated VEE vaccines derived by site-directed mutagenesis of a full length infectious cDNA clone Our approach is two-fold: First is to construct a Genetically Engineered Live Attenuated Alphavirus Vaccine We start with a full-length cDNA clone of the wild-type virus � our prototype is the IA/B subtype of VEE. From this we engineer in attenuating mutants through site-directed mutagenesis. These mutations have been identified by a variety of approaches over a period of about 12 years. From this new DNA clone, we can rescue live vaccine virus for further testing. The same approach is utilized to prepared GMP standard virus for human clinical trial, and such a preparation has been prepared, and is undergoing the necessary testing for planned Phase I trials.Our approach is two-fold: First is to construct a Genetically Engineered Live Attenuated Alphavirus Vaccine We start with a full-length cDNA clone of the wild-type virus � our prototype is the IA/B subtype of VEE. From this we engineer in attenuating mutants through site-directed mutagenesis. These mutations have been identified by a variety of approaches over a period of about 12 years. From this new DNA clone, we can rescue live vaccine virus for further testing. The same approach is utilized to prepared GMP standard virus for human clinical trial, and such a preparation has been prepared, and is undergoing the necessary testing for planned Phase I trials.

21. 21 CB.54 Therapy for Smallpox and Other Pathogenic Orthopoxviruses(New DTO in FY03) Clinical trials of cidofovir against smallpox are not possible (smallpox has been eradicated) FDA licensure is possible under the new Animal Efficacy Rule Variola and monkeypox primate models are proposed to demonstrate antiviral efficacy

22. 22 Multivalent Equine Encephalitis (VEE/EEE/WEE) Vaccine (MEEV) Use infectious cDNA clone & site-directed mutagenesis technology from DTO CB.24 to rationally derive live-attenuated eastern & western equine encephalitis (EEE & WEE) vaccine components to be combined with V3526 candidate into a MEEV Investigate and assess alternative vaccine technologies Recent Accomplishments Developed an EEE vaccine component based on the cleavage deletion mutation Successfully tested one WEE vaccine component in mouse model for: Protective response within 30 days of vaccination Duration of immunity of 1 year

23. 23 Non-DTO Supporting Efforts(Viral Vaccines) Filovirus Vaccine Develop a multiagent vaccine capable of protecting against various Ebola (EBOV) and Marburg (MARV) viruses (panfilovirus vaccine) Leverage vaccine platform technology from Multiagent Vaccine DTO (CB.25) & from outside collaboration Next Generation Smallpox Vaccine Leverage DNA vaccine approach from DTO CB.25 to identify orthopoxvirus immunogens that contribute to protective immunity Test if a gene-based vaccine technology can serve as an alternative to the live-vaccinia virus vaccine, or as a prime to a vaccinia boost

24. 24

25. 25 Antivirals for Smallpox Develop an oral therapeutic antiviral drug based on cidofovir to treat smallpox and other naturally occurring or genetically modified pathogenic orthopoxviruses Develop a second therapeutic antiviral drug based on non-DNA polymerase target (recommendation from IOM) Antivirals for Filoviruses Identified filovirus targets Develop high thorough-put screening assays Identify lead compounds for filoviruses Develop therapeutic antiviral drugs based on lead compounds

26. 26 Immunotherapies for Filoviruses Objectives Develop immunotherapies for treatment for infection with the various filoviruses Test therapeutic intervention in combination with immunotherapy Technology Murine monoclonals ? humanized antibodies ? production in plants (leverage ongoing DARPA transition effort) Combinatorial library from survivor monkey/human ? humanized antibodies anti-EBOV equine IgG Test intervention strategies to prevent and treat shock and hemorrhage

27. 27

28. 28 CB.32 Alternative Vaccine Delivery Methods(Continuing DTO) Respiratory, transdermal, oral immunization that is safe, efficacious & expedient for stimulating mucosal and systemic immunity. Simplify administration of the multiple vaccines. Evaluation of multiple novel adjuvants in combination with alternate deliveries

29. 29 CB.46 Recombinant Ricin Vaccine(New DTO in FY03)

30. 30 Toxin vaccines Recombinant candidates for BoNT serotypes A, B, C1, E, and F (previous DTO) Candidates transitioned to advanced development Effort limited to support of advanced developer Staphylococcal enterotoxin (SE) A and B vaccines (previous DTO) Candidates ready to transition Effort limited to stability analysis on pilot lots for use in future clinical studies

31. 31 Non-DTO Supporting Efforts(Toxin Therapeutics) Toxin therapeutics Therapeutics for botulinum neurotoxins Current major efforts Active site inhibitors Immunotherapy (MAbs) Expand structural biology and high performance computing capabilities and access to compound libraries

32. 32 Non-DTO Supporting Efforts(Toxin Therapeutics) Therapeutics for exposure to SEs Block T-cell activation Block SE-stimulated cytokine release Therapeutics for exposure to Ricin Basic research effort

33. 33

34. 34 Delivered by S&T Program Milestone A in FY01 Technology Data Package on evaluation of diagnostic technologies in support of JBAIDS Continuing to transition reagents and assays to the Critical Reagents Program CB.26 Common Diagnostic Systems(DTO completed in FY02)

35. 35 CB.47 Improved Immunodiagnostic Platform(New DTO in FY03) Adjunct to nucleic acid detection Primarily for the detection and identification of toxin threats Also provides confirmatory assay for other medical diagnostic tests

36. 36

37. 37

38. 38

39. 39 Roadmap(Vaccines)

40. 40 Roadmap(Diagnostics and Therapeutics)

41. 41 FY03 Congressional Interest(Medical S&T Funding Increases: +$20.4M) Engineered Pathogen Identification and Countermeasures Program (�Bug to Drug�) (Sarnoff Corporation): +$5.0M Monoclonal Antibody-based Technology �Heteropolymer� (HP) System (EluSys Therapeutics, Inc.): +$1.0M Bioadhesion Research (Ligocyte Pharmaceuticals, Inc.): +$1.8M Mustard Gas Antidote (Mustard Consortium): +$2.1M Needleless Delivery Methods for Recombinant Protein Vaccines (BD Technologies): +$1.0M Vaccine Stabilization (U of Kansas): +$1.5M Organic Vaccine Production (TBD): +$2.5M Portable Biochip Analysis System (Cleveland Clinic): +$1.8M Piezoelectric Dry Powder Inhalation Device (U. of Pitt) : +$1.7M Bioprocessing Initiative (U. of Nebraska Lincoln): +$2.0

42. 42 Cooperation with the Department of Health and Human Services (DHHS) NIAID/CDC/FDA anthrax therapeutics NIAID/USAMRIID/JVAP rPA clinical trials NIAID/USAMRMC/USAMRIID Biodefense Campus Program coordination Program management Infrastructure USAMRIID/CDC Smallpox research program Anthrax antibodies

43. 43 Medical Biological Defense Future Trends Countermeasures for Genetically Engineered Microbes Genomic sequencing of BW threat agents to identify and understand virulence factors, toxins and drug resistance genes Immunomodulators and Therapies Alternatives to agent-specific vaccines or therapies Multiagent Vaccines Alternative to one vaccine for one BW threat agent Alternative vaccine delivery strategies Immunization via mucosal and transdermal routes Early markers of infection/host response CM: Establish genomic sequence of BW threat agents in order to recognize engineered agents. Most obvious modification to any BW agent would be to make it antibiotic resistant, therefore concentrating on detection of resistance to the military drugs of choice, Ciprofloxacin and Doxycycline. Immunomodulators: Foreign DNA from bacteria, parasites, yeast or insects may induce a protective innate immune response. The innate or initial response is triggered within minutes of infection and serves to limit the pathogen�s spread in vivo. CM: Establish genomic sequence of BW threat agents in order to recognize engineered agents. Most obvious modification to any BW agent would be to make it antibiotic resistant, therefore concentrating on detection of resistance to the military drugs of choice, Ciprofloxacin and Doxycycline. Immunomodulators: Foreign DNA from bacteria, parasites, yeast or insects may induce a protective innate immune response. The innate or initial response is triggered within minutes of infection and serves to limit the pathogen�s spread in vivo.