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APPENDIX A Background: The Current DoD Medical Biowarfare Countermeasures Program T his appendix provides background information on medical biodefense activities in the Department of Defense (DoD). The DoD components involved in planning, managing, and executing these activities are identified first, followed by a summary of the legislative mandates and DoD policies that guide work on medical countermeasures. The identification of biological agents considered to pose a threat is briefly described. The appendix concludes with information on medical biodefense countermeasures that are currently available and under devel- opment. ORGANIZATION OF DOD MEDICAL BIOLOGICAL DEFENSE ACTIVITIES As described in part in Chapters 1 and 2, the organization of DoD's program for developing medical countermeasures against biological war- fare agents reflects a 1993 congressional mandate (P.L. 103-160; 50 U.S.C. 1522) that all of DoD's chemical and biological defense activities, both medical and nonmedical, be coordinated by a single office within the Of- fice of the Secretary of Defense and managed through the DoD Acquisi- tion Board process. The current configuration of responsibilities for the DoD Chemical and Biological Defense Program is described in an implementation plan issued in April 2003 (Aldridge, 2003) (see Figure 2-1). Responsibility for chemical and biological defense activities falls under the purview of the Under Secretary of Defense for Acquisition, Technology, and Logistics 103

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104 GIVING FULL MEASURE TO COUNTERMEASURES (USD(AT&L)), who also serves as the senior acquisition official. The re- sponsibility for coordination and integration of the Chemical and Biologi- cal Defense Program is assigned to the Assistant to the Secretary of De- fense for Nuclear and Chemical and Biological Defense Programs (ATSD(NCB)) and exercised by the Deputy ATSD for Chemical and Bio- logical Defense (DATSD(CBD)). The chemical and biological defense requirements and priorities of the combatant forces from all of the military services guide program plan- ning and budgeting for the Chemical and Biological Defense Program. Those requirements and priorities are developed and managed by the Joint Requirements Office for Chemical, Biological, Radiological, and Nuclear Defense (JRO-CBRN), which was chartered in February 2003 (Pace, 2003). The responsibilities of the JRO-CBRN include coordination with the intelligence community in the development of threat assess- ments. The JRO-CBRN reports to the Chairman of the Joint Chiefs of Staff. The Army is designated as the executive agent for the Chemical and Biological Defense Program, with responsibility for coordinating and in- tegrating research, development, test and evaluation, and acquisition re- quirements for the military services. Management and execution of these activities are carried out by other organizations. Responsibility for man- aging the intramural and extramural research activities (the science and technology base) of the Chemical and Biological Defense Program is as- signed to the Defense Threat Reduction Agency (DTRA), which reports to the USD(AT&L). For medical biodefense countermeasures, intramural sci- ence and technology activities are carried out primarily through the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), which is part of the U.S. Army Medical Research and Materiel Command. Some intramural medical biodefense work is carried out at other military laboratories as well. Responsibility for advanced development and acquisition of chemi- cal and biological countermeasures is assigned to the Joint Program Ex- ecutive Office for Chemical and Biological Defense Programs (JPEO-CBD). Within the JPEO-CBD, medical biodefense countermeasures are the re- sponsibility of the Chemical Biological Medical Systems (CBMS) office, which includes the Joint Vaccine Acquisition Program (JVAP) and Medi- cal Identification and Treatment Systems (covering therapeutic drugs and diagnostics). All vaccine development is being handled through a prime systems contract, awarded in 1997 to DynPort Vaccine Company LLC (DVC). As a prime systems contractor, DVC manages the advanced de- velopment of vaccine candidates through contracts with various compa- nies to perform tasks involved in developing, testing, and delivering the vaccines. DVC does not have laboratory or vaccine production facilities of its own.

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APPENDIX A 105 The Defense Advanced Research Projects Agency (DARPA) is autho- rized to conduct a separate extramural program of basic and applied re- search in chemical and biological defense and, over the past 5 years, has included work on medical biodefense countermeasures. DARPA was es- tablished in 1958 to permit more flexible approaches to long-horizon, high- risk, high-payoff research within DoD. Its research program is shaped, in part, by the expertise and interests of program managers, who are re- cruited for 4-year periods. Programs do not necessarily continue beyond the tenure of their program managers. Some of the promising DARPA- funded projects on medical countermeasures have been transferred to the science and technology base of the Chemical and Biological Defense Pro- gram for further work. DOD POLICIES RELATED TO MEDICAL DEFENSE AGAINST BIOLOGICAL WARFARE Two directives establish DoD policies and requirements related to medical aspects of biological warfare defense. Directive 6205.3, "DoD Im- munization Program for Biological Warfare Defense," specifies that per- sonnel assigned or scheduled for deployment to a high-threat area should be immunized against validated biological warfare threat agents for which suitable vaccines are available (DoD, 1993). The priorities for vac- cine research and development are identified as including the develop- ment of vaccines against threat agents for which no vaccines exist, the improvement of vaccines that are slow to produce immunity or require multiple doses, and the development of multivalent vaccines. These vac- cines are to be either licensed by the Food and Drug Administration (FDA) or designated for use as Investigational New Drugs (INDs). The directive also calls for validating and prioritizing the biological warfare threats annually. Directive 6200.2, "Use of Investigational New Drugs for Force Health Protection," establishes DoD policies and procedures for use of IND coun- termeasures when no FDA-approved product is available (DoD, 2000), as required by 10 U.S.C. 1107 and Executive Order 13139 (Clinton, 1999). Use of FDA-approved products is preferred, but when they are not avail- able, DoD components may request approval of the Secretary of Defense to use an IND product. The request must be justified on the basis of the available evidence of the safety and efficacy of the drug or vaccine and the nature and degree of the threat. DoD must then develop a protocol for use of the IND product, including providing for informed consent of service members before they receive it. Only the President may grant a waiver of informed consent, in response to a request from the Secretary of Defense. Relevant aspects of DoD policy, as summarized in a recent report (DoD, 2002), are shown in Box A-1.

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106 GIVING FULL MEASURE TO COUNTERMEASURES BOX A-1 Key Features of DoD Policy and Requirements Concerning Acquisition and Use of Medical Countermeasures to Protect the Health of Military Forces Against Biological Warfare Threat Agents I Use FDA-licensed, commercially available medical countermeasures (i.e., vaccines) to protect the health of U.S. forces from biological warfare threat agents. I Employ IND medical countermeasures only when FDA-licensed products are unavailable and o There is a confirmed high risk to force health protection that ne- cessitates consideration of IND product use; o Only after an in-depth review and approval by the Secretary of Defense of a request initiated by a Commander of a Combatant Command through the Chairman of the Joint Chiefs of Staff and in coordination with the ASD(HA) (Assistant Secretary of Defense for Health Affairs), the Under Secretary of Defense for Policy, the Secretary of the Army as the Executive Agent, and the DoD General Counsel; o In strict compliance with a specific treatment protocol developed for the required indication that has been reviewed by the FDA and com- plies with the requirements of 21 C.F.R., including the requirement for informed consent; and o Informed consent may be waived only by the President upon re- quest by the Secretary of Defense and only under specified conditions; if a presidential waiver of informed consent is approved, then DoD Components must conduct ongoing monitoring and ad- here to periodic reporting as required by the President, The Secretary of Defense shall notify Congress, and the public by Federal Register notification, as soon as practicable, The Secretary of Defense shall notify the President and the FDA Commissioner of any changed circumstances concerning the need to waive informed consent, and The waiver of informed consent terminates after 1 year or when no longer needed--whichever is earlier. I Vaccinate "at-risk" personnel against validated biological warfare threat agents in sufficient time for them to develop immunity before de- ployment to high-threat areas. I Integrate and prioritize efforts for vaccine research, development, testing, evaluation, acquisition, and stockpiling and to improve existing vaccines against validated biological warfare threat agents. I Develop a capability to acquire and stockpile adequate quantities of vaccines to protect the programmed force against all validated biological warfare threats. SOURCE: DoD, 2002, p. 7.

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APPENDIX A 107 IDENTIFICATION OF BIOLOGICAL THREAT AGENTS Each year DoD generates a list of the biological warfare agents be- lieved to pose the highest risks to military forces. The military services, through the combatant commanders, provide Joint Chiefs of Staff with their assessment of the biological warfare threats within their respective theaters. These assessments are validated in consultation with the intelli- gence community and result in a classified "threat list." The DoD Chemical and Biological Defense Program Annual Report to Congress provides an unclassified discussion of this threat (e.g., DoD, 2003). The 2003 report notes that chemical and biological weapons are generally easier to develop, hide, and deploy than nuclear weapons and could be readily available to those with the will and resources to obtain them. According to the report, a dozen countries are believed to have biowarfare programs. Terrorist groups are also reported to be interested in these weapons, and the proliferation of chemical and biological weap- ons is expected to continue. An unclassified list of potential biological warfare threats is provided in Box A-2. The Centers for Disease Control and Prevention (CDC, no date) and the National Institute of Allergy and Infectious Diseases (NIAID, no date) have published lists of bioterrorism threats (see Box A-3). These agents are classified as Category A, B, or C hazards on the basis of the readiness with which they can be disseminated, projected mortality or morbidity rates, and the need for special actions for public health preparedness. The highest priority is addressing the threats posed by Category A agents. The CDC and NIAID lists are very similar to the lists of threats of concern to DoD (Box A-2). MEDICAL BIODEFENSE COUNTERMEASURES Countermeasures Currently Available The few FDA-approved countermeasures available against potential biological threat agents identified by DoD in its unclassified lists or against CDC's Category A agents are listed in Table A-1. Licensed vaccines exist for both anthrax and smallpox, and the military has access to adequate supplies of both. However, both vaccines pose substantial challenges. As licensed by FDA, the anthrax vaccine (BioThrax) is to be administered in six doses over 18 months.1 The smallpox vaccine (Dryvax) requires only 1CDC is carrying out a clinical trial with associated animal studies to evaluate the safety and efficacy of a reduced number of doses and a different route of administration for this vaccine.

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108 GIVING FULL MEASURE TO COUNTERMEASURES BOX A-2 Potential Biological Threats as Presented by DoD Medical Biological Defense Research and Development Program Bacteria: Toxins: Bacillus anthracis (anthrax) Botulinum toxins (types AG) Yersinia pestis (plague) Staphylococcal enterotoxins (SEA/B) Francisella tularensis (tularemia) Ricin toxin Brucella sp. (brucellosis) Marine neurotoxins Burkholderia maellei (glanders) Mycotoxins Coxiella burnetii (Q fever) Clostridium perfringens Viruses: Smallpox Encephalomyelitis viruses Ebola Marburg SOURCE: Skvorak, 2003. one dose, but brings with it concerns resulting from historical rates of severe side effects. Recent military experience with Dryvax suggests the occurrence of moderate or serious side effects in 0.1 percent of recipients (Grabenstein and Winkenwerder, 2003). Recent experience in the civilian community indicates that serious adverse events have been reported in 0.3 percent of recipients (CDC, 2003). The military as well as the public health community seek improved vaccines against both of these biowarfare agents. No licensed vaccines are available against botulism, plague, tularemia, or the viral hemorrhagic fevers, although vaccines against all of these diseases are under development. Table A-1 also notes the availability of drugs with approved indica- tions for the treatment of disease resulting from several of the threat agents of concern to DoD and the nation. Three antibiotics each have been ap- proved for use in treating anthrax, plague, and tularemia. No therapeu- tics have been approved for use against botulism or the viruses of greatest concern. Table A-1 also notes the availability of medical countermeasures that have reached IND status and thus might be available for contingency use.

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APPENDIX A 109 BOX A-3 Diseases and Biological Agents Identified by CDC as Posing a Threat to National Security Category A Anthrax (Bacillus anthracis) Botulism (Clostridium botulinum toxin) Plague (Yersinia pestis) Smallpox (variola major) Tularemia (Francisella tularensis) Viral hemorrhagic fevers (filoviruses [e.g., Ebola, Marburg] and arenaviruses [e.g., Lassa, Machupo]) Category B Brucellosis (Brucella species) Epsilon toxin of Clostridium perfringens Food safety threats (e.g., Salmonella species, Escherichia coli O157:H7, Shigella) Glanders (Burkholderia mallei) Melioidosis (Burkholderia pseudomallei) Psittacosis (Chlamydia psittaci) Q fever (Coxiella burnetii) Ricin toxin from castor beans (Ricinus communis) Staphylococcal enterotoxin B Typhus fever (Rickettsia prowazekii) Viral encephalitis (alphaviruses [e.g., Venezuelan equine encephalitis, eastern equine encephalitis,western equine encephalitis]) Water safety threats (e.g., Vibrio cholerae, Cryptosporidium parvum) Category C Emerging infectious diseases such as Nipah virus and hantavirus SOURCE: CDC, no date. Countermeasures Under Development With so few FDA-approved countermeasures available against the highest-priority biological threats, the list of countermeasures that are needed is long. Table A-2 identifies the medical countermeasures that are in various stages of research and development, including six vaccines and

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110 to of for for route way use months, labeling 18 for licensed difficult under different is over use for study doses support doses administration, Additional Information Vaccine 6 logistically military CDC seek change of fewer equine) vaccine and Agents Use use toxoid immune for (human for Threat INDs Contingency BioThrax postexposure Botulinum Botulinum globulins None Biological Against Approved Therapeutics Doxycycline Ciprofloxacin Penicillin No Gentamicin Doxycycline Ciprofloxacin Available Vaccine [BioThrax]) Licensed Vaccines Yes (Anthrax Adsorbed No No Countermeasures Medical ) ) botulinum A-1 anthracis pestis TABLE Disease (Agent) Anthrax (Bacillus Botulism (Clostridium toxin) Plague (Yersinia

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111 is events many use, for mortality, adverse than of vaccine vaccines Risk from including higher other vaccines globulin vaccine vaccine vaccine immune (postexposure) Pasteur inactivated dilution) vaccine and Vaccinia Cidofovir Dryvax Aventis (1:5 LVS Live Inactivated Inactivated No Gentamicin Ciprofloxacin Doxycycline No Yes (Dryvax) No No strain. ) 2003 vaccine live tularensis Clayson, major) encephalitis LVS, Venezuelan Eastern Western Smallpox (variola Tularemia (Francisella Encephalitis (equine viruses) NOTE: SOURCE:

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112 GIVING FULL MEASURE TO COUNTERMEASURES TABLE A-2 DoD-Related Research and Development Activities for Medical Biological Warfare Countermeasures Disease Projected (Agent) Countermeasure Status Licensure Smallpox Cell-cultured smallpox DVC Phase 1 testing (variola major) vaccine (CCSV) completed; "down select" decision between DoD and NIH candidates expected November 2003 from Defense Science Board Vaccinia immune DVC: FY 2005 globulin (VIG) Two Phase 1 trials on liquid product completed July 2003 Pivotal clinical trial on lyophilized product completed October 2000 Fast-track approval granted by FDA, final BLA submission anticipated 2004 Intravenous cidofovir Ongoing research at USAMRIID Oral therapeutic Ongoing research at antiviral drugs based on USAMRIID cidofovir, or on non-DNA polymerase target Anthrax Recombinant anthrax DVC Phase 1 trials (Bacillus anthracis) vaccine (rPA, derived begun October 2002; from (Escherichia coli) clinical trials will be completed but future work now on hold due to lack of funding Recombinant anthrax To undergo Phase 1 vaccine (rPA, derived trials funded by NIAID from B. anthracis, developed at USAMRIID)

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APPENDIX A 113 TABLE A-2 Continued Disease Projected (Agent) Countermeasure Status Licensure Botulism Recombinant bivalent DVC submission of IND FY 2012 (Clostridium botulinum botulinum vaccine and start of Phase 1 toxin) (against neurotoxin trial anticipated in first serotypes A and B) half of 2004 Pentavalent botulinum DVC discovery and vaccine (against preclinical development, neurotoxin serotypes to be funded by NIAID A, B, C, E, and F) Heptavalent botulinum DVC discovery and vaccine (against preclinical development, neurotoxin serotypes to be funded by NIAID A, B, C, D, E, F, and G) Plague Recombinant plague DVC: FY 2014 (Yersinia pestis) vaccine (F1-V fusion Beginning of cGMP antigen) manufacturing anticipated in 2003 Phase 1 trial start anticipated for February 2005 U.K. Recombinant DVC planning Phase 1 plague vaccine trial in 2004 (F1 + V mixture) Tularemia LVS vaccine DVC funded by DoD (Francisella tularensis) through FY 2003; funded by NIAID for Phase 1 trial Venezuelan equine Vaccine DVC: encephalitis IND submission anticipated by March 2004 Phase 1 trial start anticipated June 2004 Ricin toxin Recombinant ricin Ongoing research at vaccine USAMRIID Therapeutics for Ongoing research at exposure to ricin USAMRIID Continued

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114 GIVING FULL MEASURE TO COUNTERMEASURES TABLE A-2 Continued Disease Projected (Agent) Countermeasure Status Licensure Brucellosis Vaccine candidate: Ongoing research at (Brucella sp.) orally administered WRAIR MNPH1 live attenuated deletion mutant Staphylococcal Vaccine candidates Ready for transition to enterotoxin (SE) advanced developer A and B USAMRIID scientists conducting stability analysis on pilot lots for use in future clinical studies Therapeutics for Ongoing research at exposure to SEs USAMRIID Glanders Vaccine candidates Ongoing research at (Burkholderia mallei) USAMRIID Viral hemorrhagic Multiagent vaccine Ongoing research at fevers (filoviruses, capable of protecting USAMRIID including Ebola and against various Ebola Marburg) and Marburg viruses Antivirals Ongoing research at USAMRIID Immunotherapies for Ongoing research at filoviruses USAMRIID General Alternate vaccine Ongoing research at delivery methods USAMRIID (oral, respiratory, transdermal) and adjuvants NOTE: BLA, Biologics License Application; cGMP, current Good Manufacturing Practice; LVS, live vaccine strain, U.K., United Kingdom; USAMRIID, U.S. Army Medical Research Institute of Infectious Diseases; WRAIR, Walter Reed Army Institute of Research. SOURCES: DVC, 2003a, b, c; Skvorak, 2003; Personal communication, T. Irgens, DVC, Sep- tember 16, 2003; November 12, 2003.

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APPENDIX A 115 one immune globulin product in clinical testing under the auspices of the DoD Chemical and Biological Defense Program. Until recently, basic research and early development of candidate countermeasures took place primarily through DoD. The substantial fund- ing that became available to NIAID in fiscal year 2003 for the research and development of bioterrorism countermeasures has greatly increased the number and variety of medical countermeasure candidates under investi- gation. Information on the NIAID research agenda to develop counter- measures against Category A agents is available from the NIAID website (http://www.niaid.nih.gov/biodefense/) and a recent progress report (NIAID, 2003). REFERENCES Aldridge EC. 2003. Memorandum: Implementation Plan for the Management of the Chemi- cal Biological Defense Program (CBDP). Washington, DC: Department of Defense. CDC (Centers for Disease Control and Prevention). No date. Biological Diseases/Agents List. [Online]. Available: http://www.bt.cdc.gov/Agent/agentlist-category.asp [ac- cessed November 4, 2002]. CDC. 2003. Update: adverse events following civilian smallpox vaccination--United States, 2003. MMWR 52(34):819820. Clayson JP. 2003. Joint Vaccine Acquisition Program (JVAP) Overview. Presentation to the Armed Forces Epidemiological Board, May 20. [Online]. Available: http://www.ha. osd.mil/afeb/meeting/052003meeting/default.cfm [accessed August 28, 2003]. Clinton WJ. 1999. Improving Health Protection of Military Personnel Participating in Par- ticular Military Operations. Executive order 13139 of September 30, 1999. Federal Regis- ter 64(192):5417554178. DoD (Department of Defense). 1993. Department of Defense Directive: DoD Immunization Program for Biological Warfare Defense. Number 6205.3. Washington, DC: Department of Defense. DoD. 2000. Department of Defense Directive: Use of Investigational New Drugs for Force Health Protection. Number 6200.2. Washington, DC: Department of Defense. DoD. 2002. Acceleration of Research, Development, and Production of Medical Counter- measures for Defense Against Biological Warfare Agents. Report to Congress required by P.L.107-107, Section 1044(e). Washington, DC: Department of Defense. DoD. 2003. Department of Defense Chemical and Biological Defense Program. Volume I: Annual Report to Congress. Washington, DC: Department of Defense. [Online]. Avail- able: http://www.acq.osd.mil/cp/nbc03/vol1-2003cbdpannualreport.pdf [accessed June 27, 2003]. DVC (DynPort Vaccine Company). 2003a. The pipeline: DVC products and technical sup- port. Vaccine Technology and Development News 2(6):2. [Online]. Available: http:// www.dynport.com/press.htm [accessed August 18, 2003]. DVC. 2003b. Press release: CSC Joint Venture Completes Phase I Vaccinia Immune Globulin Clinical Trial, July 31. [Online]. Available: http://www.dynport.com/press.htm [ac- cessed August 18, 2003]. DVC. 2003c. Press release: CSCPorton Joint Venture Wins $11 Million Award to Expedite Production of Botulinum Vaccine, September 4. [Online]. Available: http://www. dynport.com/press.htm [accessed September 8, 2003].

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116 GIVING FULL MEASURE TO COUNTERMEASURES Grabenstein JG, Winkenwerder W. 2003. US military smallpox vaccination program experi- ence. JAMA 289(24):32783282. NIAID (National Institute of Allergy and Infectious Diseases). No date. NIAID Category A, B, & C Priority Pathogens. [Online]. Available: http://www.niaid.nih.gov/biodefense/ bandc%5Fpriority.htm [accessed September 24, 2003]. NIAID. 2003. NIAID Biodefense Research Agenda for CDC Category A Agents: Progress Report. Bethesda, MD: National Institutes of Health. [Online]. Available: http:// www.niaid.nih.gov/biodefense/research/category_A_Progress_Report.pdf [accessed August 11, 2003]. Pace P. 2003. Charter for the Joint Requirements Office for Chemical, Biological, Radiologi- cal and Nuclear Defense [memorandum and enclosure]. Washington, DC: Department of Defense, Joint Chiefs of Staff. Skvorak JP. 2003. Medical Chemical Biological Defense Research Program. U.S. Army Medi- cal Research and Materiel Command. Presentation to the Armed Forces Epidemiologi- cal Board, May 20. [Online]. Available: http://www.ha.osd.mil/afeb/meeting/ 052003meeting/default.cfm [accessed August 28, 2003].