Research and Development Priorities for Emerging Infections and Biodefense

1
Research and Development Priorities for Emerging
Infections and Biodefense

2
(No Transcript)
3
Influenza pandemic 1918-1919

• 20 million deaths worldwide
• 549,000 deaths in US
• Greatest pandemic in world history?

4
HIV/ AIDS, 1981 to date
World Health Organization. 40 million persons
living with HIV in 2006.
5
Marburg Hemorrhagic Fever

• Outbreak in Northern Angola
• Onset October 2004
• Recognition March 2005
• 275 cases
• 255 deaths

6
SARS, 2003
7
Avian influenza, 2003 to 2007
World Health Organization. Confirmed human cases
since 2003.
8
Anthrax attack, 2001
Anthrax spores delivered in US mail. 22 cases, 5
deaths.
9
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
10
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
11
Biodefense.com?
December, 2001 Prices for gas masks and
antibiotics grew by as much as 1000 in some
areas, including New York and Washington.
12
Research priorities
NIAID priority pathogens

• NIAID Category A, B, and C Priority Pathogens
• List found on NIAID web site

CDC bioterror list
CDC/ USDA Select Agent List
13

• 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)

14

• 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 O157H7, 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)
  

15

• 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
  

16
(No Transcript)
17
HSPD-18 Medical Countermeasures against Weapons
of Mass Destruction, January, 2007

• Biological Threats
• Traditional agentsNatural (e.g., anthrax)
• Enhanced agentsTraditional plus modification or
  selection (e.g., XDR-TB, MDR-plague)
  
• Emerging agents (e.g. SARS, avian influenza)
• Advanced agentsNovel pathogen artificially
  engineered in the laboratory (No example here)

18
Evolution in the NIAID biodefense program
19
NIAID Strategic Plan for Biodefense Research

• Broad spectrum activity
• Broad spectrum technology
• Broad spectrum platforms

20
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)

21
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

22
(No Transcript)
23
(No Transcript)
24
(No Transcript)
25
Entry/ Admin
BSL 2
BSL 3
Loading Dock
Animal Housing/ Aerobiology
Existing 4-story Building
26
(No Transcript)
27
(No Transcript)
28
(No Transcript)
29
(No Transcript)
30
(No Transcript)
31
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

32
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.
33
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

34
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

35
Note found among Tyvek suits
36

• 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.

37
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)

38
(No Transcript)
39
Cage Racks
40
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.
41
SERCEB Aerobiology and Animal Models Core
Class II BSC
Class III BSC

• 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.

Madison
Cage Rack
Animal Holding Room
Animal Holding Room
Autoclave
Anteroom
Shower
42
(No Transcript)
43
(No Transcript)
44
(No Transcript)
45
(No Transcript)
46
(No Transcript)
47
(No Transcript)
48
(No Transcript)
49
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

50
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)

51
(No Transcript)
52
(No Transcript)
53

Immunomodulator (compound X) protects against
lethal plague infection
Survival, dose administered two days prior to
infection.
Weight, last value carried forward.
Greg Hopkins, Eva Click
54

• Intranasal challenge with Yersinia pestis
• Protection by immune serum
• Survival
• Weight (surv only)
• ED50
• Mortality 1.3 µl
• Weight 2.8 µl

55
Serum cytokine levels after plague challenge

• Use bead technology to measure 23 cytokine levels
  using 16 µl serum
  
• Vaccinated mice have minimal cytokine response to
  infection

Eva Click, Greg Hopkins , Jeff Hale, Greg
Sempowski
56

• 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
57
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

58
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)

59
?
?
?
?
?
?
?
?
Email