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Overview of CDC Biodefense Research Priorities, Programs, and Funding

Fifth Annual Joint Vector-Borne/Zoonotic Diseases and Bioterrorism and Public Health Threats Conference, Arizona Department of Health Services April 13, 2005

Charles A. Schable, M.S. Director Coordinating Office of Terrorism Preparedness & Emergency Response Centers for Disease Control and Prevention

Infectious Diseases

New Public Health Perspective

· Emerging infectious diseases are spreading faster and further, requiring rapid collaborative response · Local problems now viewed as having much wider implications · Naturally occurring infectious disease outbreaks can also impact national security and global economy

Factors Contributing to the Emergence of Infectious Diseases

· Human demographics and behavior · Technology and industry · Economic development and land use · International travel and commerce · Microbial adaptation and change · Breakdown of public health measures

Factors Contributing to the Emergence of Infectious Diseases

· Human susceptibility to infection · Climate and weather · Changing ecosystems · Poverty and social inequality · War and famine · Lack of political will · Intent to harm

Addressing the Threats

· Enhancing global response capacity · Improving global infectious disease surveillance · Rebuilding domestic public health capacity · Improving domestic surveillance through better disease reporting · Exploring innovative systems of surveillance · Developing and using diagnostics · Educating and training the workforce

Addressing the Threats

· Vaccine development and production · Need for new antimicrobial drugs · Inappropriate use of antimicrobials · Vectorborne and zoonotic disease control · Comprehensive infectious disease research agenda · Interdisciplinary infectious disease centers

Addressing Emerging Infectious Disease Threats

· Improve surveillance for reportable infectious diseases · Support local, regional, national, and international surveillance and research efforts · Expand the use of sentinel surveillance networks to complement other surveillance methods

Emerging Infections Programs (EIP) Epidemiology and Laboratory Capacity (ELC) Program Sentinel Networks

Emerging Infections Sentinel Networks

· EMERGEncy ID NET · IDSA Emerging Infections Network · U.S. Influenza Sentinel Physicians Surveillance Network · Global Emerging Infections Sentinel Network (Geosentinel) · Border Infectious Diseases Surveillance (BIDS) Project

Future Challenges

· Pandemic Influenza · Antimicrobial Resistance · International Foodborne Disease Outbreaks · Urban Yellow Fever in Latin America and Asia · Microbial Etiologies of Chronic Diseases · The Unexpected

CDC's Bioterrorism Program

· Begun in 1999 · Encompasses multiple centers and programs · Concept of "full use" · Focus Areas

· Preparedness planning · Epidemiology and surveillance · Biological laboratory · Chemical laboratory · Communications (Health Alert Network) · Education and Training

http://www.bt.cdc.gov

All Hazards Public Health Preparedness

Biological Terrorism Chemical Terrorism

­ ­ ­ ­ Choking agents (phosgene / chlorine) Blood agents (cyanides) Blister agents (mustard gas) Nerve agents (sarin, soman, tabun, etc.)

Radiation Terrorism

­ Dirty bombs ­ Food / water supply contamination ­ Power plants

Critical Elements in Terrorism Preparedness

· · · ·

Planning Products Personnel Practice

CDC Marcus Emergency Operations Center

Category A Biological Agents

Variola major (Smallpox) Bacillus anthracis (Anthrax) Yersinia pestis (Plague) Franciscella tularensis (Tularemia) Clostridium botulinum toxin (Botulism) Hemorrhagic fever viruses (Ebola, Marburg)

Current LRN Membership

National Labs

CDC and USAMRIID

(definitive characterization)

Reference Labs

(confirmatory testing)

Sentinel Labs

(recognize, rule-out, refer)

Recent LRN System Enhancements

· · · ·

DIG-EIA for Clostridium botulinum toxins Rapid TRF for Coxiella burnetii Real-time PCR for Ricinus communis DNA Added blood & stool as SARS PCR sample types · Expanded use of non-variola Orthopoxvirus real-time PCR for monkeypox detection

http://www.bt.cdc.gov/lrn

The Strategic National Stockpile Program

The Strategic National Stockpile

· 12 push packages ready to arrive anywhere in the

U.S. within 12 hours of deployment · Vendor Managed Inventory (VMI) ­ follow-on stores of medical supplies to augment push packages that arrive within 24-36 hours of activation

CDC's Changing Research Program Enhancing and expanding investigator-initiated, peer-reviewed extramural research to meet our nation's bioterrorism preparedness and emerging infections challenges

CDC Components Involved in Terrorism Preparedness

· National Center for Infectious Diseases (NCID)

­ Infectious agents

· National Center for Environmental Health (NCEH)

­ Chemical and radiologic agents and hazards

· National Institute for Occupational Safety and Health (NIOSH)

­ Worker protection

· National Immunization Program (NIP)

­ Immunization programs

· Agency for Toxic Substances and Diseases Registry (ATSDR)

­ Risk assessment and mitigation

· Research on any occupational safety and health concern, including biodefense in the workplace · Proposals evaluated on scientific merit and programmatic significance (e.g., estimated number of workers affected, severity of effects)

http://www.cdc.gov/niosh/extramur.html

Examples of Future Research Needs in Worker Safety

· CBRN standards for additional classes of respirators · Improved sensors and detectors

­ protective equipment (service-life indicators) ­ field sampling instruments

· Improved worker screening and health tracking tools · Working with employers, workers, and responders to address other needs

CDC's Biodefense and Emerging Infectious Diseases (EID) Extramural Research Program

· Established in 2002 to support research to develop countermeasures for bioterrrorism and EIDs · CDC priority areas: surveillance, agent detection, interruption of transmission, environmental microbiology · Initial funding and research priorities for FY 03 announced in collaboration with NIAID

http://www.cdc.gov/ncidod/oer/ March 2003

CDC's Biodefense and EID Extramural Research Program

· $9 M awarded to 9 grantees in FY 03 · Animal and human syndromic surveillance · Detection of bioterrorism agents · Understanding immune response · Testing drug candidates and developing viral vaccines · Five global infectious disease research training grants co-funded with the NIH Fogarty International Center

CDC's Biodefense and EID Extramural Research Program

· FY 04 applications under review · FY 05 announcement to be published in NIH Guide for Grants and CDC website during February 2004 · Approximately $9 M in new awards each year

http://www.cdc.gov/ncidod/oer/

Addressing Emerging Global Microbial Threats

· Importance of strong national and international partnerships · Need for strengthened collaborations among the clinical, laboratory, veterinary, and public health communities · Importance of preparedness planning · Proactive communications, training, and education · Expect the unexpected

CDC FY2005 ANNUAL APPROPRIATION ­ TERRORISM & EMERGENCY RESPONSE · Total Appropriation - $1.539 Billion · State & Local Readiness - $857.3 Million · For CDC extramural and intramural use $141.9 Million

BT Environmental Microbiology:

What we Know

What We Know Today

· Detecting and Quantitating BT Agents on Surfaces, in Water Systems, and in Other Environments · Determining Survival Times, Recovery, and Pathogenicity of BT Agents in the Environment · Determining the Efficiency of Disinfectants in Various Environments

Detection of Potential Agents of Bioterrorism in Drinking Water

· Project Goals

­ Develop field-deployable method for rapidly concentrating viruses, bacteria and parasites in large-volume drinking water samples (10-100 L) ­ Concentrates from sample processing method should be compatible with culture, molecular and immunodiagnostic assays ­ < 3 hrs for sample processing and < 2 hrs for rapid molecular analysis ­ Experiment criteria: Recovery efficiency, method sensitivity (by culture, microscopy and PCR)

Summary of Water Analysis Project Results To Date

· Ultrafilter method generally achieving > 50% recovery, including secondary concentration (Exception: B. subtilis spores) · Sensitivity as low as 1 microbe/L (100 microbes per 100 L), depending on microbe, assay design and amount of sample analyzed · Method compatible with agar culture, tissue culture, PCR, RT-PCR and immunodiagnostic assays (SMART Tickets for Salmonella) · Analytical times: Ultrafiltration (2-2.5 hrs), secondary concentration (1-3 hrs), real-time PCR (1.5-2 hrs) · Concentration method supplies cost = $75

Survival, Recovery, and Pathogenicity

Two-Fold Approach to Determining Antimicrobial Resistance in BT Agents

· Develop broth microdilution reference assays, list of drugs to test, and interpretive criteria for definitive testing of pure cultures of:

­ ­ ­ ­ ­ Bacillus anthracis Yersinia pestis Burkholderia mallei and B. pseudomallei Francisella tularensis Brucella species

· Develop molecular methods for rapid prediction of antimicrobial resistance from BT agents in environmental samples

Rationale for Molecular Approach to Antimicrobial Susceptibility Testing

· Need to guide antimicrobial chemotherapy PRIOR to isolation of a BT agent in pure culture for patient care AND stockpile mobilization ­ Powders ­ Environmental surfaces · Strategy: Use PCR products from DNA extractions (RRAT Lab) and microarray assays to predict resistant to fluoroquinolones (i.e., Cipro) and other critical antimicrobial agents

Rapid Methods to Detect Resistance in BT Agents

Accomplishments:

· PCR for resistance genes (tet, others) ~3 h · DNA sequence analysis for gyrA mutations for B. anthracis ~12 h · Master mix PCR kits for B. anthracis frozen · In-house arrays made for detecting point mutations in gyrA for B. cereus; gyrA mutations in B. anthracis Sterne selected

In Development:

Microarrays to detect multiple resistance genes/ mutations, target in 6 hr 1. In-house arrays: New microarray equipment purchased; additional resistance genes selected

2. Johns Hopkins ­ APL:

collaboration in progress, awaiting reader and slides

Survival of Bacteria on Environmental Surfaces

· Persistence is dependent upon

­ Strain ­ Surface/material characteristics

­

Roughness, porosity, hydrophobicity, presence of organics

­ Temperature - time until dry ­ Relative humidity ­ Suspension media

Swab Comparisons

Bacillus anthracis spores recovered from steel surface

(Rose L, Jensen B,Peterson A, Banerjee SN, Arduino MJ. Emerging Infectious Diseases.10:1023-1029)

-Foam -Rayon -Cotton -Polyester (Dacron)

SEM of Swab Material

cotton foam

500 um 1 mm

rayon

polyester

500 um

500 um

Percent Spore Recovery of Vortexed Swabs

Foam

Moist Dry 43.6

30.4 ­ 64.0a

Cotton

41.7

23.9 ­ 62.5

Rayon

11.5

1.4 ­ 24.1

Polyester

9.9

4.8 ­ 14.4

11.9

8.6 ­ 15.4

a

8.0

5.6 ­ 9.7

4.4

2.6 ­ 5.5

2.1

1.0 ­ 3.7

range

Chemical Terrorism Research at CDC

Clinical sample method development biomarkers of exposure metabolites protein adducts Toxicokinetics of internal dose Metabolic pathways Toxins

Rapid Toxic Screen

Chemical warfare agents Nerve gases, e.g. sarin, soman, VX Sulfur mustards, e.g. HD, sesquimustards Nitrogen mustards, e.g. NH1, NH2 Cyanide Lewisite Ricinine (marker for ricin) Saxitoxin Botulinum toxin Natural toxins Drugs of abuse Others, e.g. scopolamine Volatile organic compounds, e.g. benzene, carbon tetrachloride Pesticides, e.g. malathion, parathion Heavy metals, e.g. lead, arsenic, mercury Others

Toxins

Incapacitating agents

Industrial chemicals

Ricinine Analysis

Simple method to determine ricin exposure 1. Both ricinine and ricin share a common plant source ­ beans of ricinus communis 2. Ricinine is present in crude preparations of ricin ­ confirmed in laboratory 3. Animal study showed that ricinine can be quantified in urine up to 48 hours after exposure

N CH3

Ricinine

OCH3 CN

O

Ricinine Analysis

Ricin and Ricinine are derived from ricinus communis Ricinine

OCH3 CN

Method Characterization Operating Range Criminal ricin preparation (milky solution) Levels of ricinine in rat urine (48 hrs) Forensic Analysis

Analytical Result 0.3 ­ 800 ng/mL 502 ng/mL

400 ng/mL 5 ng/mL

N CH3

O

Botulinum Toxins

100

Botulinum A Peptide Cleavage 2031.75

1476.1

% Intensity

80 60 40 20 0 649.0 100 960.8

Substrate

1016.84

1272.6 1584.4 1896.2 2208.0

T=0

% Intensity

80 60 40 20 0 649.0 100

C-Terminal Product

747.30 1016.86

742.02

2031.82

Substrate N-Terminal Product

1303.43

1272.6 1584.4 1896.2

2375.5

T = 30

% Intensity

80 60 40 20 0 649.0 100

C-Terminal 747.33 Product

1016.91

960.8

960.8

2208.0

2031.91

N-Terminal Product 1303.48

1272.6 1584.4

Substrate

3988.4

T = 120

1896.2 2208.0 9.1E+3

747.30

% Intensity

80 60 40 20 0 649.0

C-Terminal Product

730.86 1016.88

N-Terminal Product

1303.45

Substrate

2031.88

1896.2 2208.0

T = 240

1287.00

960.8

1272.6

1584.4

Mass (m/z)

Botulinum B Light Chain Cleavage

Substrate Peptide

100 90 80 70 60 50 40 30 20 10 0 100 90 80 70 60 50 40 30 20 10 0 1499.0 1759.83 2020.54 4040 1026.0 % Intensity

No Toxin

2082.4

2665.8

3249.2

3832.6

4416.0 4.8E+4

N-Terminal Product

% Intensity

BoNT-B Light Chain

2297.32

C-Terminal Product

2082.2

2665.4 Mass (m/z)

3248.6

3831.8

4415.0

Research Needs in Chemical Terrorism Response at CDC

Identification of metabolic pathways of additional chemical agents, e.g. mycotoxins, phosgene Development of methods for measuring metabolites and protein adducts resulting from exposure Animal studies to generate toxicokinetic and metabolic information in support of analysis methods Research studies on people exposed accidentally to chemical agents to determine metabolites and toxicokinetics in people

Radiological Terrorism Preparedness Research at CDC

Sources are from nuclear power generation, industrial, nuclear medicine, nuclear weapons, IND, RDD, etc. Some examples: 51Cr, 57Co, 60Co, 90Sr, 137Cs, 131I, 192Ir, 241Am,

242Am, 243Am, 226Ra, 233U, 234U, 235U, 236U, 238U, 237Np, 232Th, 238Pu, 239Pu, 240Pu, 242Pu

and many others

Actinide Analysis via ICP-MS

Polyatomic ions 230ThH and 231Pa 236UH and 237Np 237NpH and 236U 238UH and 239Pu 240PuH and 241Am 242PuH and 243Am Isobars 236U and 236Np 238U and 238Pu 241Pu and 241Am 242Pu and 242Am

1 5 0 0 0 0 1 0 0 0 0 0 5 0 0 0 0 0 0 1 0 0 2 0 0 3 0 0 4 0 0 5 0 0

U P u A m N p T h

Separation Of the Actinides By IC-ICP-MS

6 0 0

7 0 0

8 0 0

1 5 0 0 0 0 1 0 0 0 0 0

Counts

5 0 0 0 0 0 0 1 0 0

N

p ( V )

2 0 0

3 0 0

4 0 0

5 0 0

6 0 0

7 0 0

8 0 0

7 5 0 0 0

P u ( IV )

5 0 0 0 0

N

2 5 0 0 0 0 0 1 0 0 2 0 0 3 0 0

p ( IV )

N p ( V I) P u ( V I)

4 0 0

5 0 0

6 0 0

7 0 0

8 0 0

T im

e

( s )

Radionuclide Analysis by Gamma Spectrometry

Energy (keV)

Research Needs in Radiological Terrorism Response at CDC

Development of analytical methods with the following requirements: · · · · 1-50 mL of "spot" urine Detection of a wide variety of radionuclides Initial results available in 4-36 hours Sample throughput of 100-500+ samples/day/lab

Complacency is the enemy of preparedness

www.cdc.gov

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