RCE Section ReviewMarch 7, 2008

RCE Team

•Rona Hirschberg

•Susan Garges

•Bill Angus

•Michael Schaefer

•JoJo Stemple

RCE Program Goals

•Basic research to understand category A-C and EID agents

•Translational capacity leading to drugs, vaccines, and diagnostics

•Expand the pool of researchers and technical personnel for biodefense and EID research

•Regional facilities for research

•Assist emergency responses

Topics for Today

•RCE Program Evaluation – Rona

•RCE Recompetition – Mike

•Product Development and Emergency Response Activities – Bill

•RCE Database – JoJo

•RCE Highlights -- Sue

RCE Interim Program Evaluation

•Provide evidence to assess program success

•Inform development of RFA

•Enhance the effectiveness of the program as a whole

•Pilot test measures, data collection and analysis protocols to inform future, definitive evaluations of the RCE

•Plan for future, definitive evaluations

•Enhance evaluation capacity

Evaluation Goals

Overall Process•Obtain stakeholder input regarding program

success factors

•Define a representation of what the program should do (logic model)

•Determine critical areas of the program to evaluate

•Develop specific measures relating to the evaluation areas

•Gather and analyze data, prepare report

•Implement findings for improvement

Logic Model with 8 Focal Areas

RCE Program Funding

Manage Fundsflexibly and efficiently

Establish Management structures & processes

Innovative & Flexible response to changing

needs and opportunities

Synergy between Centers

(Integration & Synergy)

Capacity to serve as a regional resource

Expanded cadre of investigators

(Recruit and Train staff)

Leveraged funds from elsewhere

(Integration & Synergy)

Readiness to Respond in an Emergency

Better responseto infectious

diseasesthat threaten

humans

Translate and Apply Science

to Practice

Scientific Knowledgeon Category

A,B,C organisms (Research )

Leadership with expertise (Integration & Synergy)

Biodefense Priorities

Build Infrastructure

Recruit & Train staff

Inputs Outputs OutcomesActivities Impact

Collaboration & Communication

Conduct Research on Category A,B,C organisms

Research results on Category

A,B,C organisms

ProductDevelopment (Translational

Activities)

Areas for Evaluation

• Conduct research

• Research knowledge

• Communication/collaboration/synergy

• Support emergency response

• Translational activities

• Innovation/flexibility

• Bringing people to the field

• Leveraging funds

Collaboration and Communication

•Over 290 institutions involved in 48 states and Puerto Rico, 488 PIs and 563 projects

•41% of project teams are cross institutional

•44% of follow-on (non RCE) projects involve cross institutional teams

•51% of publications have cross institutional co-authorship

•Only 4 of 477 papers had cross-RCE authorship

Summary of Participation and Collaboration

Research Conducted on Category A, B

and C Agents

* (partial year)

* (partial year)

Scientific Knowledge on Category A, B and C Agents

Total Publications

050

100150200250300350400450500

Citations

2004 2005 2006 2007partial yr

Year

Total Number of RCE and NIAID Publications on Category A Agents,

2004-2007

Category A AgentRCE

PublicationsNIAID

Publications

Percentage of NIAID Publications by RCE

Program

Bacillus anthracis 54 474 11%

Botulinum toxin 28 151 19%

Yersinia pestis 32 200 16%

Variola major 61 2,951 2%

Francisella tularensis

40 112 36%

Ebola 15  49 31%

Totals 215 3,937 5%

Observed and Expected Citations for All RCE Program

Publications by Year, 2004-2007

Publication Year

All Publication

s

Observed Citations Expected Citations

Mean sd Mean sd

2004 50 15.2 12.84 10.05 7.95

2005 102 10.34 13.71 5.21 4.3

2006 193 3.38 4.42 0.75 0.65

2007* (partial year)

132 0.43 1.05 0 0

Total 477 5.29 9.43 2.47 4.6

Selected Journals, their Journal Impact Factor and

Number of RCE Publications in those Journals.

Journal NameJournal Impact Factor

Number of RCE

Publications

Proceedings of the National Academy of Sciences of the United States of America 9.64 28Journal of Immunology 6.29 13Journal of Biological Chemistry 5.81 12Journal of Infectious Diseases 5.36 10Journal of Virology 5.34 64Infection and Immunity 4.00 48Journal of Bacteriology 3.99 13Applied and Environmental Microbiology 3.53 10Virology 3.53 26

•RCE publication productivity is increasing over time.

•RCE publications are well regarded, as indicated by citations from other publications.

•RCE articles have been published consistently in frequently cited journals.

•Citation of RCE publications is significantly higher than for comparable articles in the same journals and fields 

Publications

Overall Conclusions

•Program has had a wide reach

•Collaboration, communication and synergy are occurring

•Research on appropriate organisms and subjects

•Research is contributing to scientific knowledge

•Program structure allows for innovation and flexibility

Conclusions, con’t

•Expanded cadre of investigators has resulted

•Readiness to respond has been shown, but inconsistent

•Early indicators of progress toward products is evident

•Leveraging of RCE funds is occurring

RCE Recompetition

New RFARegional Centers of Excellence  for Biodefense and Emerging Infectious

Diseases Research (RCE) [U54] http://grants.nih.gov/grants/guide/rfa-files/RFA-AI-08-002.html

Released Dec. 21, 2007Applications due June 3, 2008Open to all applicants, new and continuingExpect to fund up to 10 centers about 3/09

Funds Available and Who May Apply

•$91M for up to 10 awards

•Awards expected to range from $3-10M direct costs (mistake in RFA)

•New and competing continuation applications will be accepted

Consortium

•An interactive group of investigators at more than one institution

•Mix of expertise and capabilities

•Big enough to get the job done

•Small enough to work

•One applicant organization, one PI

Required Elements of an RCE Application

•Background, Strategic plan, and Management Structure

•Research program•Scientific facilities cores •Developmental research plan •Career development and training

programs•Biocontainment needs and facilities•Emergency response plans•Evaluation plans

Regions - DHHS

-Region I: CT, ME, MA, NH, RI, VT-Region II: NJ, NY, PR, VI-Region III: DE, D.C., MD, PA, VA, WV-Region IV: KY, MS, NC, TN, AL, FL, GA, SC-Region V: IL, IN, MI, MN, OH, WI-Region VI: AR, LA, NM, OK, TX-Region VII: IA, KS, MO, NE-Region VIII: CO, MT, ND, SD, UT, WY-Region IX: AZ, CA, HI, NV -Region X: AK, ID, OR, WA

Regionality

• Regional hub of activity

• Must serve as a regional facilities resource

• Must respond at the regional level in the event of a biodefense emergency

• Foster new research projects and human resource development with a regional basis

• Linkages to regional institutions

• Does not need to include all institutions in the region

• May include institutions and investigators from other regions

• Funded Regional Centers will interact with each other

• Will be part of a national network

Research Themes

•One or a few

•Focal points for RCE activities

•Based on strengths

•Provide coherence and synergy

•Important review criterion

•Organisms, platforms, approaches, etc.

Research Program

•Integrated research program leading to practical solutions for category A-C and EID agents

•Basic > translational > early clinical

•At least five projects, a mix of types

•Project = R01-like or P01-like

•Integrated with themes

•Balance of organisms and approaches

•State-of-the-art approaches

•Projects phase in and out as the research evolves

Scope

•Category A-C and EID lists•Mostly BioD, at least 51%•Zoonotic diseases only if related to human

disease•Will not fund: surveillance, public health,

animal health, health care delivery, environmental detection, etc.

•Less emphasis on well studied issues: anthrax, smallpox, influenza

•Do not duplicate other programs: genomics, bioinformatics, FWDN, etc.

Clinical Studies and Trials

•Clinical studies. Clinical Terms of Award apply. Needs program approval.

•Clinical trials. Clinical Terms apply.•Phase 1 only•In application or later•Needs DMID input and approval•Discuss with program first•No foreign clinical trials•See RFA for what to submit•Use existing infrastructure

Product Development

•Translational activities beyond proof-of-concept level

•Ready for serious pre-clinical studies

•Requires a PD plan with milestones

•Requires involvement of appropriate consultants

•Consider forming partnerships for moving forward

Foreign Components

•Allowed as part of a domestic project

•Must integrate into a parent project

•Up to $100K direct costs per project per year

•Must offer unique opportunities

•Need a strong justification

•No foreign clinical trials

Facilities Cores

•Integral to the strategic plan and research•Number and kinds appropriate for each

RCE•Basic and translational, but not clinical•Available for a biodefense of EID

emergency•Regional resource•Management plans and key personnel•Leverage and linkages•Need strong justification

•May not include research

Developmental Research Projects

•Small, short term start-up projects

•Funded at RCE level

•Capitalize on progress in field

•Important for flexibility

•May “graduate” into Center projects or R01s

•Need clear plans and procedures

•Key element of success

•Projects are not submitted as part of the application

Career Development and Training

•Increase human resources for biodefense and EID research

•At least two projects: one for individuals and one for groups

•Complement the research activities and themes

•Innovative approaches

•Many options

•Individual mentored research projects are not submitted as part of the application

TimetableDecember -- June Pre-application

consultation and planning

May 3, 2008 Letter of intent due

June 3, 2008 Application due

September-October 2008

Review

March 2009 Awards

How RCEs Will Be the Same

•Same overall goals

•Same general structure

•Continued emphasis on flexibility and synergy

•Emphasis on portfolio of basic to applied research

•Goal of product concepts

•Regionality

How RCEs Will Change

•Expand to include EID as well as A-C pathogens

•Allow some foreign interactions

•Focus more on A-C and EID issues that are not covered by other programs

•Required evaluation component

•Greater focus on themes to promote synergy and collaboration

•Align priorities with new strategic plan

RCE Emergency Response

Emergency Response

Activities• Compiled list of resources that can be used in an emergency

• Participation in a public health emergency

• Compiled list of experts who can help in an emergency.

• RCE membership on state/local committees tasked with emergency response.

• Identified designated RCE contact person for each locality.

• Participation in simulations (in the field) or in table top exercises

• Conducted public outreach.

Emergency Response ExamplesSpinach Related E-coli Outbreak (Multiple states, 2006)

NWRC offered rapid, in-depth whole genome sequencing of a prototypical outbreak strain. The NWRCE analysis complemented the sequence analysis performed at Michigan State University by providing greater genetic detail in areas of ambiguity

Suspected Tularemia (St. Louis, 2006) Activated the MRCE Emergency Management Group phone tree and

disseminated information to Washington University School of Medicine and our hospitals. Also assisted local health departments with the development of an appropriate case definition to enhance surveillance.

Surge CapacityNERCE-affiliated investigators have been registered with the CDC

under the Massachusetts SLI select agent registration, allowing work as back-up personnel in their laboratories in the event of an biological emergency

Trans-RCE Emergency Response

• In March 2006, GLRCE and SERCEB convened teleconference of ER personnel from all ten RCEs.

• Database of contact information for ER leadership nationwide developed

• Discussion areas for national collaboration:

• Potential for the RCEs to provide high-end surge capacity in areas such as diagnostics, care of research animals, plans for researcher displacement, augmentation of field epidemiology capabilities if requested by public health authorities

• Provision of content expertise, education on a national level

• Development of centralized media training for RCE personnel.

• Media Training for Bioscientists (MARCE)

Scenario Exercise, Case Studies, Mock News Conference

• Policy Ethics and Law Core (SERCEB)

Dual use, public health ethics in pandemics, social and legal implications of biodefense research

• Law, Policy and Ethics Core (WRCE)

Federal policy, law and regulations, human subjects testing, intellectual property

Communications

Biosafety Training• Biocontainment Laboratory Operations & Maintenance Training

Course (MARCE)

• Biosafety Education for the Research Scientist (MRCE)

• Biosafety Fellowship Program (MRCE)

• BSL-3 /Select Agent (RMRCE)

• Education and training program in BSL4, ABSL4, BSL3, and ABSL3

laboratory safety practices that is conducted in a newly

constructed mock BSL3/4 laboratory at Emory University

(SERCEB). 

Product DevelopmentA research focus on NIAID Category A-C agents including the incorporation of

a translational component with the long term goal of developing products for human use.

In order to promote discussion and early consensus among the applicants regarding intellectual property (IP) and management matters that may arise during RCE consortium projects, the applicants are required to submit a consortium plan within six (6) months of the receipt of an award, and this requirement will be a term of award. While the specific terms of such a plan are left to the parties involved, NIAID recommends that the applicants consider the following points in the plan:

Measures to ensure the rapid utilization of inventions to benefit the public health through, inter alia, diligence in seeking patent protection for and licensing of new inventions when appropriate and the timely publication of research results.

Product Development Resources

•Core Facilities‘omicsMicroarrayMass SpecAnimal Models, inc.

aeroBiomol ProductionHTS

•Dedicated Staff Assistance

•Dedicated Committees

•Training

The overall objective for the Product Development and Manufacturing (PDM) Core is to provide infrastructure and services to develop and manufacture vaccine, diagnostic and therapeutic products sufficient for preclinical and phase I/II clinical trials.

Production Services

•Process optimization•Scale-up•Stabilization•Preliminary Formulation•GLP-Compliant Documentation•BSL-3 Capacity

Training

•Regulatory Documentation

•CGMP Compliance

•GLP-Compliance

•Facilities/Equipment Operations

Rocky Mountain RCE PDM Core

Product Development Working Group

• Held August 2006 and January 2007• 12 applications (7 vaccines, three diagnostics, 2

therapeutics)• Reviewers from pharma, biotech, venture capital, non-

profit R&D• Assessment of where a product fell in development

pipeline• Suggestions for next steps

GLRCE hosted a Product Development Workshop featuring representatives from the FDA, NIAID, DoD Joint Vaccine Acquisition Program, and Project BioShield and examined the commercialization market and vaccine product development pathway

Product Development Workshops

Patent Applications

N=68

Patent Applications by Type

RCE Database

DataBase

Contacts screen - with projects linked

Projects screen - with research contacts linked

Project screen - with publications

Project screen - with protocols list

Linking Capabilities

Reports - protocols to expire in 90 days

(sorted by PI name)

Publications report - with output options

Reporting Capabilities

FileMaker TrainingAttending Basic and Intermediate Level Training Courses 3/24-3/26/2008

RCE Highlightsfrom the last year

Identification of a role for CD40-CD40L interactions in promoting T-cell migration into the brain during West Nile Virus infection, opening the door to potential therapeutic intervention that could be developed to either dissuade T-cell migration into the brain during viral encephalitis. (Klein and Diamond, MRCE)

• The delivery of anthrax LF to the cytosol requires either COPI coatomer complex or a COPI subcomplex for translocation from the endosomal lumen, using a mechanism analogous to that of DT entry. (Murphy, NERCE)

• Identification of the connection between type I IFN signaling and inflammasome activation by Francisella tularensis, highlighting how multiple innate immunity pathways interact before commitment to critical host responses. (Monack, PSWRCE)

• Identification of how arenaviruses enter the cell, and the subsequent response by the cell to infection (Cannon and Kunz, PSWRCE)

• Identification of a single amino acid change in the NS3 helicase of North American West Nile virus that may be responsible for the increased virulence of the virus. (Brault, PSWRCE)

Basic Research

• Identification of common DNA variations that underlie susceptibility to fever after smallpox vaccination, suggesting that it may be possible to develop a test that predicts which patients are at risk for vaccine-related fevers. Such a test also may help doctors anticipate and prevent more serious complications linked to the vaccines. (Stanley, Belshe, and Frey, MRCE)

• Sequencing and analysis of the entire genome of F. tularensis LVS. This effort will facilitate identification of the mutated genes responsible for the loss of human pathogenicity exhibited by this variant and aid development of attenuated vaccine strains. (Brittnacher, Olson, Petrosino, and Weinstock, NWRCE and WRCE)

• Development and demonstrated efficacy of a recombinant holo-toxoid vaccine against Botulism.

• Researchers have developed a novel nanoemulsion-based rPA vaccine for mucosal immunization that protects against B. anthracis spore challenge. (Barbieri, GLRCE)

• Development of a completely attenuated purM strain of Burkholderia pseudomallei. Besides accelerating the speed of discovery by being able to widely distribute and handle this mutant strain in any BSL2 laboratory, attenuated strains may also be candidates for a whole-cell Bp vaccine. Because of the close relatedness of Bp and Burkholderia mallei, similar strategies will be applicable for construction of attenuated Bm strains. (Schweizer, RMRCE)

Vaccines

• Development of technology permitting the production of cell lines expressing high levels of one of the essential viral proteins for West Nile virus or yellow fever virus, then using viruses that lack this single protein. These viruses are only capable of completing their infection cycle in cells expressing the C protein, and make excellent vaccine candidates. These in-infectious vaccines have been named RepliVAX, and preliminary data using a mouse model showed that a West Nile RepliVAX that was safe and protected mice from a lethal infection by this virus . (Mason, WRCE)

• Development of effective vaccines against Venezuelan, eastern, and western equine encephalitis viruses, using the backbone of Sindbis virus expressing the surface protein of the encephalitis viruses. All safe and effective in mice; EEE vaccine shown to be safe and effective in horses. Beginning testing in NHPs. (Weaver, WRCE)

• Development of reverse genetics systems for working on the current MP-12 vaccine for Rift Valley fever and for refinement of it. (Makino and Peters, WRCE)

• Development of a live, attenuated Salmonella strain to deliver anthrax PA as a prime, followed by a boost of Biothrax or rPA vaccine. The combination elicits a robust, rapid, and long-lived response. (Levine and Galen, MARCE)

• Development of a live, attenuated Francisella tularensis vaccine based on Schu-S4. Attenuating mutations have been identified and have been tested the mutants for efficacy vs. aerosol Schu-S4 in mice. (Barry and Mann, MARCE)

Vaccines, continued

• Development of inhibitors that prevent NF-κB activation by LCMV (Finberg, NERCE)

• Development of cathepsin inhibitors for Ebola and Marburg (Cunningham, NERCE)

• Development of an oral drug for poxvirus infections: HDP cidofovir (CMX001) was entered into early clinical trials in humans. The drug was and is being developed by Chimerix, but SERCEB has helped in many aspects including small animal screens at UAB and UF. It is synergistic with ST-246 when combined in therapy of orthopoxvirus infection of cell culture or of mice. (Whitley, SERCEB)

• Identification of small molecule compounds that activate RNase L. Current work is aimed at improving the properties of the compounds in order to develop a truly broad spectrum antiviral agent that would be effective against a wide range of viral biodefense threats. (Karn and Silverman, MRCE)

• Discovery of methods to rapidly isolate and produce human MAbs, based on a proprietary electrofusion of immune B cells isolated from convalescent or vaccinated individuals with myeloma partners. (Crowe, SERCEB)

• Identification of new classes of drugs that target virulence factors common to numerous Gram-negative bacterial pathogens. (Miller, PSWRCE)

• Identification of calixarene-based therapeutic molecules that are extremely effective at low micromolar concentrations against B. anthracis and Y. pestis. In vivo studies will determine the potential of these molecules as therapeutics. (Mayo, GLRCE)

• Identification of a new class of compounds effective against both Gram-negative and Gram-positive bacteria. (Slayden, RMRCE)

Therapeutics

• Discovery of a new virus responsible for the deaths of 3 transplant recipients in Australia. The previously unknown virus is related to lymphocytic chiomeningitis virus (LCMV) and was found using a novel pathogen discovery platform based on rapid sequencing tecnologies (454) and bioinformatics. (Lipkin, NBC)

• Development of a chip-based “panmicrobial” diagnostic array capable of identifying infectious agents in clinical samples. This universal diagnostic array, which contains 29,455 probes representing all known infecious agents, is under development by a diagnostics company. (Lipkin, NBC)

• Using in-house sequencing and bioinformatics platform to rapidly sequence and analyze the genome of the spinach-related outbreak strain of E. coli 0157:H7. (Olson, PSWRCE)

Diagnostics

• Pulendran and his collaborators have shown that the use of novel hydrophobic or hydrophilic nanoparticles can dramatically enhance dendritic cell responses to model antigens and adjuvants. (Pulendran, SERCEB)

• Targeting Y. pestis antigen to dendritic cells using a hybrid protein containing an antibody to a dendritic cell receptor linked to LcrV. This novel antigen delivery approach greatly enhanced the protective immune response to LcrV. (Steinman, NBC)

• Isaacs and colleagues have found that delivering a pox subunit vaccine in combination of alum and CpG increases the immune response in a synergistic fashion. This combination would have implications for other subunit vaccines. (Isaacs, MARCE)

Adjuvants

• The National Small Molecule Screening Laboratory for the RCEs in Biodefense and Emerging Infectious Disease (NSRB) provides access to high-throughput screening capability for all US investigators conducting research on NIAID priority pathogens. (NERCE)

• The Rocky Mountain RCE has developed a BSL3-GMP core.

• Genetic manipulation of formerly intractable bacteria (Manoil, Schweizer, Stibitz, Mann, Koehler, NWRCE, RMRCE, MARCE, WRCE)

• Mutant sets (Francisella, Burkholderia) (Manoil, Schweizer, NWRCE, RCRCE)

Resources from the RCEs

• Mouse models for inhalational and intranasal anthrax, plague, tularemia, melioidosis, VEE, West Nile fever, LaCrosse virus,ectromelia

• Small animal models for Salmonella typhimurium, Ebola virus, Lassa virus, Rift Valley fever virus, cowpox, monkeypox, rabbitpox, hantavirus cardiopulmonary syndrome, and SARS.

• NHP models: plague, Lassa fever virus, West Nile virus, Marburg disease, EEE, epidemic typhus, Shigella, anthrax intoxication. In development: Burkholderia, Brucella

Animal Models in the RCEs