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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
ˇ DoD Components must conduct ongoing monitoring and ad-
here to periodic reporting as required by the President,
ˇ The Secretary of Defense shall notify Congress, and the public
by Federal Register notification, as soon as practicable,
ˇ The Secretary of Defense shall notify the President and the FDA
Commissioner of any changed circumstances concerning the need to waive
informed consent, and
ˇ 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).
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Representative terms from entire chapter:
biological warfare
