Download - Infectious Disease Board Review
Research and Development Priorities for Emerging Infections and Biodefense
Influenza pandemic 1918-1919 20 million deaths
worldwide 549,000 deaths in
US Greatest pandemic
in world history?
HIV/ AIDS, 1981 to date
World Health Organization. 40 million persons living with HIV in 2006.
Marburg Hemorrhagic Fever
Outbreak in Northern Angola
Onset October 2004 Recognition March 2005 275 cases 255 deaths
SARS, 2003
Avian influenza, 2003 to 2007
World Health Organization. Confirmed human cases since 2003.
Anthrax attack, 2001
Anthrax spores delivered in US mail. 22 cases, 5 deaths.
Economic impact
European shares have extended sharp opening losses, after fears over the impact of the anthrax bacterium on consumer confidence sent US and Asian stock markets tumbling. . . . Observers blamed the drops on the growing unease surrounding the anthrax scares, which have raised fears of a "further chill" in US consumption.
BBC News, October 18, 2001
Economic impact WASHINGTON, March 15 - Health officials
believe that a mix-up of samples in a Defense Department contractor's laboratory was behind an anthrax scare Monday and Tuesday that rattled the stock market, set the White House on alert, shut three post offices in the Washington area and led to more than 800 people being offered antibiotics.
Scott Shane, New York Times, March 16, 2005
December, 2001: “Prices for gas masks and antibiotics grew by as much as 1000% in some areas, including New York and Washington.”
Biodefense.com?
Research priorities
NIAID Category A, B, and C Priority Pathogens
List found on NIAID web site
CDC bioterror list
CDC/ USDA Select Agent
List
NIAID priority pathogens
Category A Diseases/Agents High-priority agents include organisms that pose a risk to
national security because they:– can be easily disseminated or transmitted from person to person; – result in high mortality rates and have the potential for major public
health impact; – might cause public panic and social disruption; and
– require special action for public health preparedness. •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 Diseases/Agents Second highest priority agents include those that
– are moderately easy to disseminate; – result in moderate morbidity rates and low mortality rates; and – require specific enhancements of CDC's diagnostic capacity and enhanced
disease surveillance. 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 Ricinus communis (castor beans) 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 Diseases/Agents Third highest priority agents include emerging pathogens that could be
engineered for mass dissemination in the future because of– availability;
– ease of production and dissemination; and
– potential for high morbidity and mortality rates and major health impact.
•Emerging infectious diseases such as Nipah virus and hantavirus
HSPD-18; Medical Countermeasures against Weapons of Mass Destruction, January, 2007
Biological Threats– Traditional agents—Natural (e.g., anthrax)– Enhanced agents—Traditional plus modification
or selection (e.g., XDR-TB, MDR-plague)– Emerging agents (e.g. SARS, avian influenza)– Advanced agents—Novel pathogen artificially
engineered in the laboratory (No example here)
Evolution in the NIAID biodefense program
Original Current
Drugs, diagnostics, and vaccines for Category A bioterror pathogens
Goals refined based on pathogenAlso high quality basic researchCategories A, B, and C
Biodefense and emerging infections
Emerging infections and biodefense
Pathogen-driven Addition: Antimicrobial researchAddition: Innate immunity
NIAID Strategic Plan for Biodefense Research
Broad spectrum activity Broad spectrum
technology Broad spectrum
platforms
Unique scientific paradigms
Potent toxins (botulinum toxin, anthrax) Low infectious doses (tularemia, TB, Q fever) High mortality rates (avian influenza, Ebola) Type three secretion system (plague) Persistence in host (TB) Persistence in environment (anthrax)
Mandate for RBLs Provide BSL3 containment to support work
with NIH priority pathogens, support RCE research programs, and support NIAID biodefense program
Be available and prepared to assist national, state, and local public health efforts in the event of a bioterrorism emergency
Existing 4-story Building
Entry/ Admin
BSL 2
BSL 3
Animal Housing/ Aerobiology
Loading Dock
GHRB timeline February 2003: Grant submission September 2003: Grant award May 2005: Groundbreaking November 17, 2006: Certificate of occupancy December 1, 2006: BSL2 labs open February 16, 2007: Ribbon-cutting
GHRB Ribbon Cutting Ceremony including Michael Kurilla, Brian Letourneau, Buck Lewis, Nancy Boyd, Bill Angus, Bill Bell, Bart Haynes, Mary Ann Black,
Victor Dzau, Rich Frothingham, Richard Broadhead, and Sandy Williams.
GHRB Timeline February to August, 2007: “Three-week”
commissioning August 19, 2007: BSL3 vivarium IACUC approval August 28 to Sept 11, 2007: 14-day countdown to
BSL3 certification visit October 14, 2007: BSL3 certification by Global
Biohazard Technologies (GBT) October 22 -26, 2007: BSL3 training by SERCEB
core from Emory (Sean Kaufman and Lee Alderman) January 28, 2008: CDC Select Agent amendment June 3-4, 2008: CDC Select Agent inspection
Take nothing for granted
– Check your ducts– Check your commissioning documents– Validate the ductwork– Validate the cage racks– Validate the filters– Confirm the sealed penetrations– Check your PPE
Note found among Tyvek suits
The thread is detached from the seam in the lower part of the trousers. If this happens again, we will return the job to you and punish you severely.
Existing cores located in GHRB SERCEB protein production core
– (Larry Liao, PI) SERCEB monoclonal antibody core
– (Larry Liao, PI) SERCEB viral vector core
– (Liz Ramsburg, PI) Duke immune reconstitution core
– (Greg Sempowski, PI) Duke BSL3 flow cytometry core
– (John Whitesides, PI) Duke Select Agent Program
– (Rich Frothingham, PI)
Cage Racks
New cores
SERCEB Aerobiology and Animal Models Core
SERCEB In vivo imaging core
Major equipment provided through SERCEB grant awards. Ongoing core support proposed in re-competition.
SERCEB Aerobiology and Animal Models Core
Madison
Shower
Class II BSC Class III BSC
Animal Holding Room
Autoclave
Animal Holding Room
Anteroom
Cage Rack
Madison chamber attached to a Class III glove box
Pass-through to a Class II BSC in an animal holding room
Two suites in the RBL vivarium.
Duke ID Aerobiology core practices
Detailed Standard Operating Procedures (SOPs) Preparation and confirmation of the inoculum Real-time recording of exposure parameters Characterization of the aerosol particle distribution Aerosol sampling to determine concentration of
viable microbes (estimate dose inhaled) Sentinel animal necropsy to define dose delivered
SERCEB BSL3 animal models core
The BSL3 Animal Models Core will provide animal challenge models using multiple pathogens, animal species, and routes of infection.
Animal challenge models will be established using GLP-like conditions to include detailed SOPs, inoculum confirmation, & sentinel animal necropsy.
Mice, rats, hamsters, gerbils, ferrets, guinea pigs, rabbits, others (up to 8 species at once)
70
75
80
85
90
95
100
105
-2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 13
Days after challenge
Avg
. % O
rigin
al W
eigh
t
Compound X
Control
Weight, last value carried forward.
Immunomodulator (compound X) protects against lethal plague infection
Survival
0
20
40
60
80
100
120
0 1 2 3 4 5 6 7 8 9 10 11 12 13
Days after infection
% S
urvi
val
Compound X
Control
Survival, dose administered two days prior to infection.
Greg Hopkins, Eva Click
Intranasal challenge with Yersinia pestis
Protection by immune serum– Survival– Weight (surv only)
ED50– Mortality 1.3 μl– Weight 2.8 μl
Use bead technology to measure 23 cytokine levels using 16 μl serum
Vaccinated mice have minimal cytokine response to infection
Serum cytokine levels after plague challenge
Eva Click, Greg Hopkins , Jeff Hale, Greg Sempowski
Activation of CD8 T cells in spleen 3 days after intranasal plague challenge.– Increased expression of CD69, but not CD25– Whitesides flow cytometry core– Responding cell functional analysis, cloning, etc.– Bacterial sorting capacity
Greg Hopkins, John Whitesides
Models for interaction with RBL
Researcher sends material to RBL for testing in an animal model– Experimental design, IACUC approval,
administration, challenge, endpoints, analysis, Researcher comes to RBL at Duke, works
collaboratively with RBL core Researcher comes to RBL at Duke and works
independently
Grants (partial list) Duke Center for Translational Research
(Frothingham, P30 AI 51445) Regional Biocontainment Laboratory Construction
Grant (Williams, UC6 AI 58607) Southeast Regional Center for Emerging Infections
and Biodefense (Sparling, U54 AI 57157) Alternative endpoints for plague challenge models
(Frothingham, R21 AI 59689)