COOPERATIVE RESEARCH FOR THE DEVELOPMENT OF VACCINES, ADJUVANTS, THERAPEUTICS, IMMUNOTHERAPEUTICS, AND DIAGNOSTICS FOR BIODEFENSE RELEASE DATE: August 2, 2002 RFA: AI-02-026 National Institute of Allergy and Infectious Diseases (NIAID) (http://www.niaid.nih.gov) Letter of Intent Receipt Date: October 25, 2002 Application Receipt Dates: November 26, 2002 MULTI-PROJECT APPLICATIONS IN RESPONSE TO THIS REQUEST FOR APPLICATIONS (RFA) MUST BE PREPARED USING A MULTI-PROJECT GRANT APPLICATION FORMAT; SPECIFIC INSTRUCTIONS FOR COMPLETING THE APPLICATION ARE IN THE NIAID BROCHURE ENTITLED "INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS" WHICH IS AVAILABLE AT THE FOLLOWING LINK: http://www.niaid.nih.gov/ncn/grants/multibron.htm THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations: PURPOSE OF THIS RFA The National Institute of Allergy and Infectious Diseases (NIAID) invites investigator-directed cooperative research grant applications that will lead to the development of new Vaccines, Adjuvants, Therapeutics, Immunotherapeutics or Diagnostics focused on NIAID category A-C pathogens. In addition, NIAID has identified specific products for biodefense that are of highest priority for rapid development. The objective of this program is to support research in the early stages of product development, however, for the area of immunotherapeutics more basic research is also appropriate. Research conducted through this program may fall anywhere along a broad spectrum of activities, from target identification, design of compounds, validation and testing, production scale-up and validation, through advanced preclinical evaluation. Applications should define the proposed project goal, interim objectives (development milestones) and potential ultimate product, and provide a schedule or timeline for milestone and goal attainment. Applications that include collaborations between researchers from different disciplines and/or with the private sector (e.g. pharmaceutical, chemical or biotechnological companies) are strongly encouraged. Clinical trials are supported by distinct programs and are not included in this initiative RESEARCH OBJECTIVES Background The National Institutes of Health and other agencies in the DHHS are currently supporting extramural and intramural projects to develop new products to protect the public from the health consequences resulting from the use of biological agents in acts of terrorism or war. "The NIAID Blue Ribbon Panel" convened on February 4-5, 2002 (the full report can be found at: http://www.niaid.nih.gov/dmid/pdf/biotresearchagenda.pdf) identified the development of new Vaccines, Adjuvants, Therapeutics, Immunotherapeutics and Diagnostics for Category A pathogens as one of the highest priority. These recommendations have now been extended to include Category B and C pathogens. A complete listing of NIAID Category A-C pathogens is available at http://www2.niaid.nih.gov/Biodefense/bandc_priority.htm. In response to this need, it is imperative that promising findings are translated rapidly into new approaches and strategies for product development. The involvement of diverse disciplines (e.g., biochemists, structural biologists, protein chemists, pharmacologists, immunologists, molecular biologists, engineers and clinicians) within academia and industry in early stage product development is needed to bring sufficient knowledge to bear on the development of well-designed candidates for Vaccines, Adjuvants, Therapeutics, Immunotherapeutics and Diagnostics. Research Goals and Objectives Applications should address research that will advance the development of a Vaccine, Adjuvant, Therapeutic, Immunotherapeutic or Diagnostic that is an NIAID priority biodefense product (http://www2.niaid.nih.gov/Biodefense/Research/high_priority.htm) or any other Vaccine, Adjuvant, Therapeutic, Immunotherapeutic or Diagnostic specific for an NIAID Category A, B or C pathogen (http://www2.niaid.nih.gov/Biodefense/bandc_priority.htm). VACCINES The objective of this RFA is to stimulate original, novel and innovative research of sound scientific rationale, requiring comprehensive team and multidisciplinary effort that is likely to result in the progression of promising vaccines through the product development pathway. Applications should define the proposed project goal, interim objectives (development milestones) and potential ultimate product, and provide a schedule or timeline for milestone and goal attainment. Research approaches may include target identification, developmental studies, scale-up and production, evaluation in laboratory animals, evaluation in the context of specific delivery platforms and/or adjuvants, protection of appropriate species from infection or disease following virulent challenge (where appropriate), and other considerations that relate to the acceptability and utility of candidate vaccines for clinical trials. Applications for vaccines against any NIAID Category A-C pathogen are invited. Those applications that address development of: smallpox vaccine, tularemia vaccine, plague vaccine, Rift Valley fever vaccine, pandemic flu vaccine, or Clostridium botulinum, botulinum toxin vaccine are particularly encouraged. Projects may include, but are not limited to, one or more of the following areas: o Identification and validation of protective epitopes for the development of recombinant or sub-unit vaccine candidates; o Optimization of production of vaccine components; o Optimization of delivery platforms, antigen and adjuvant combinations/formulations; o Optimization of dose and route of delivery in pre-clinical evaluation; o Evaluation of safety, toxicity and immunogenicity in animals; o Evaluation of efficacy in challenge models where appropriate animal models are available; and/or o Performance of required benchmarks for moving vaccine candidate into phase I clinical trials (http://www.fda.gov/cber/vaccine/vacappr.htm). Approaches should consider the potential feasibility of products for use in civilian populations, which may include pediatric, elderly, or immune compromised populations, as well as the vaccines potential to quickly induce safe and protective responses. ADJUVANTS Applications for development of novel adjuvants that could be used as stand alone immunostimulants or in conjunction with specific pathogen components are invited. Those applications that address development of new immunostimulatory agents or products to induce enhanced innate immune protection in the lungs, gastrointestinal tract or systemically are particularly encouraged. Applications should define the proposed project goal, interim objectives (development milestones) and potential ultimate product, and provide a schedule or timeline for milestone and goal attainment. Generation of safer vaccines, such as those composed of defined antigens or DNA, will require administration with additional substances, termed adjuvants, in order to stimulate effective immune responses. Adjuvants are broadly separated into two classes based upon their primary mechanism of action: vaccine delivery systems (e.g., emulsions, microparticles, iscoms, and liposomes) that target associated antigens to antigen presenting cells, and immunostimulatory adjuvants (e.g., LPS, MLP, or CpG DNA) that directly activate innate immune responses. Recent knowledge that receptors of the innate immune system mediate the stimulatory effects of adjuvants opens many new possibilities for the development of new, safer, and more effective adjuvants. In order to advance the development of vaccine adjuvants against NIAID category A-C agents of bioterrorism, this solicitation focuses on optimization and preclinical testing of prospective lead compounds, including particulate materials (vaccine delivery systems), cytokines, chemokines, or costimulatory molecule expression, and innate immune receptor/ligand leads (immunostimulatory adjuvants), that previously showed promise in early stages of discovery and development. It is expected that adjuvants defined in this program will be considered as candidates for future Phase I-II-III testing in clinical trial programs that may be supported by NIAID solicitations or other sources. This program will encompass: o Analysis of lead compounds with a high potential as adjuvant candidates based upon previous studies of their antigen targeting capability, receptor binding capacity, and effect on immune signaling; o Testing of previously-evaluated adjuvants for their capacity to stimulate desired immune responses toward specific NIAID category A, B or C pathogens/toxins; o Testing mixtures of adjuvants to evaluate additive or synergistic potential to stimulate desired immune responses; o Scale-up production under GMP to provide sufficient quantities for pre- clinical FDA-required animal studies; o Pre-clinical testing for safety and stimulatory capacity in animals, and/or o Performing required benchmarks for moving candidate into phase I clinical trials (http://www.fda.gov/cber/therapies.htm). THERAPEUTICS The need for safe and effective, broad-spectrum and specific, antimicrobials for biodefense against threats by highly pathogenic agents or their toxins is a key national priority. Applications for development of drugs against any NIAID Category A-C pathogen are invited; however, those applications that address development of: antivirals, especially against smallpox and viral hemorrhagic fevers; antitoxins to B. anthracis and C. botulinum; narrow-spectrum antibiotics, especially for anthrax; and broadly reactive antimicrobial drugs are particularly encouraged. Applicants should submit a research plan, including timelines and specific milestones, to identify and confirm targets, as well as to design, synthesize, and test drug candidates in model systems. These should be specified in the research plan and may include: o Identify new targets for drug discovery or develop previously identified targets for drugs by examining microbial gene products expressed during infection and/or host gene products expressed as a consequence of infection; o Identify initial lead compounds by molecular modeling and/or library screening and synthesize sufficient quantities for in vitro analysis and/or explore the use of active components of natural products as potential drug sources for development; o Perform reiterative design, chemical synthesis and in vitro analysis to develop a "mature" lead compound; o Perform preliminary pharmacokinetics and pharmacodynamics assessing bioavailability and mechanism of action; o Evaluate the potential for the emergence of drug resistance in model systems; o Synthesize, purify, and test drugs/inhibitors for efficacy and toxicity in model assays and preclinical in vivo systems; o Determine drug interactions in host molecular processes; and/or o Perform required benchmarks for moving drug candidate into phase I clinical trials (http://www.fda.gov/cder/regulatory/default.htm). IMMUNOTHERAPEUTICS Applications to discover and/or improve immune-based therapeutics including both broad-spectrum (innate immunity) and pathogen-specific (antibodies) approaches are invited. Major applications for products generated in the research program include prevention of infection in the face of an immediate threat, protection of immunocompromised individuals, or post-exposure treatment to suppress infection and disease. Research on compounds that directly affect pathogens as well as on approaches to stimulate non-specific immunity are encouraged. Passive treatments may be especially valuable during the acute emergence of infectious diseases and may complement the use of antimicrobial drugs or vaccination programs to optimize protection. Research may focus on fundamental mechanisms of immune protection by the therapeutic agents and need not require use of NIAID Category A-C pathogens. Applicants may submit a research plan, including timelines and specific milestones that addresses, but is not limited to, one or more of the following areas: Innate immunity: o Discovery and characterization of novel antimicrobial peptides, lectins, or immune modulators with broadly protective or pathogen-specific potential; o Development of candidate compounds to optimize in vivo activity, including improving the therapeutic index and specificity for NIAID Category A-C pathogens; o Testing and validation of efficacy; o GMP production; o Preclinical testing for safety and efficacy in animal models; and/or o Performing required benchmarks for moving product into Phase I clinical trials (http://www.fda.gov/cber/therapies.htm). Antibodies: o Discovery and characterization of novel antibodies with high specificity for pathogen antigens; o Methods to modify existing reagents to improve economy of production, half life in vivo, affinity for target antigens, neutralization potency, microbial clearance rates, or tissue accessibility; or to decrease adverse side effects of administration (e.g. production of humanized or fully human antibodies); o Testing and validation of efficacy; o GMP production; o Preclinical testing for safety and efficacy in animal models; and/or o Performing required benchmarks for moving product into Phase I clinical trials (http://www.fda.gov/cber/therapies.htm). DIAGNOSTICS There is an urgent need for rapid, sensitive, specific, and cost-effective diagnostics for public health laboratories and point-of-care use to identify or diagnose individuals exposed to agents and toxins of category A-C pathogens. This RFA includes agent detection in or on symptomatic or exposed individuals. Applications for the development of diagnostics specific for NIAID Category A-C pathogens are invited. Applications should define the proposed project goal, interim objectives (development milestones) and potential ultimate product, and provide a schedule or timeline for milestone and goal attainment. Tests for use on human samples may consider benchmarks required for approval (http://www.fda.gov/cber/devices.htm). Applications that focus on the following areas are encouraged: o Protocols for the rapid preparation of samples for testing; o Methods demonstrating the highest performance of specificity, sensitivity, rapidity and cost when applied to relevant clinical samples; o Tests capable of detecting an infectious or toxic doses of agent; o Tests capable of resolving engineered or otherwise acquired genetic traits, such as patterns of microbial resistance or enhanced virulence; o Tests capable of identifying characteristic microbial genetic signature profiles; o Tests capable of high or ultrahigh throughput, robotics, and automated data analyses; o Tests that target multiple agents simultaneously in a single sample; o Tests that distinguish viable (or active) from non-viable (or inactive) agents; o Non-destructive tests that permit subsequent confirmation and forensic characterizations; o Tests based on the minimum number of platforms for the maximum number of targets; and o Clinical diagnostic tools for human eczema are particularly encouraged. Examples include: o Microchip-based platforms exploiting functional genomic tools and the determination of multi-locus genetic signature profiles; o Novel assays based on human immune or other physiological responses, identification of novel or improved biomarkers for human immune activation, in vivo imaging methods, and the development of contrast reagents for the visualization of pathogens or host responses in vivo; and, o Development of a flexible or expandable platform possessing potential spin-off applications in the detection in remote settings of naturally-occurring and deliberately released emerging threats. Diagnostics should be easy to produce, inexpensive and translatable to field conditions, where applicable. The latter condition is likely to exclude cell- based technologies. Preliminary data should be presented to support the basis of the method. Capabilities of the diagnostics should be described. Plans for determining the sensitivity, specificity and validation of the diagnostic should be included in the application. MECHANISM OF SUPPORT This RFA will use the single project (U01) or multi-project (U19) cooperative agreement(s). The U01 and U19 are cooperative agreement award mechanisms in which the Principal Investigator retains the primary responsibility and dominant role for planning, directing and executing the proposed project, with NIH staff being substantially involved as a partner with Principal Investigator, as described under "Cooperative Agreement Terms and Conditions of Award". Essential elements of the U19 multi-project cooperative agreement mechanism include: (1) a minimum of three interrelated individual research projects organized around a central theme; (2) collaborative efforts and interaction among independent projects and their investigators to achieve a common goal; (3) a single Principal Investigator who will be scientifically and administratively responsible for the group effort; (4) a single applicant institution that will be legally and financially responsible for the use and disposition of funds awarded; and (5) support provided, as necessary, for "Core" resources or facilities, each of which is expected to be utilized by at least two research projects in order to facilitate the research effort. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The total project period for applications submitted in response to this RFA may not exceed five years. FUNDS AVAILABLE The NIAID intends to commit approximately $50M in FY 2003 to fund approximately 12 to 25 new grants in response to this RFA. An applicant may request a project period of up to 5 years. Applicants may request up to $500,000 for significant alterations and renovations and/or up to $300,000 for major equipment to ensure that research aims can be met and biohazards can be contained. Prior approval from program staff must be obtained for requests that exceed these amounts. Funds for these purposes must be included in the first year's requested budget Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NIAID provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, the NIAID has not determined whether or how this solicitation will be continued beyond the present RFA. ELIGIBILE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of U.S. State and local governments o Eligible agencies of the U.S. Federal government o Domestic or foreign Institutions must be in compliance with U.S. laws and regulations and DHHS and NIH policies in effect at the time of grant award and during the period of performance of the research. INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. SPECIAL REQUIREMENTS Each application must propose a research and development project whose goal is to advance a Vaccine, Adjuvant, Therapeutic, Immunotherapeutic or Diagnostic specific for an NIAID Category A, B or C pathogen through the product development process. Single project U01 and multi-project U19 applications must define the proposed project goal, interim objectives (development milestones) and potential ultimate product, and provide a schedule or timeline for milestone and goal attainment. Due to the possible complexity of multi-project cooperative agreements it is suggested, but not required, that the Principal Investigator and the Project Leaders contribute a minimum of 20% (time) effort to the study. Mandatory Meetings: Single project awards: The Principal Investigator, one or two key personnel designated by the Principal Investigator and NIAID Scientific Coordinator will meet once a year to review progress, aid program development, and foster collaborations among the programs. This meeting will likely be held at the NIH in Bethesda, MD and applicants should include requests for travel funds (airfare, and per diem) specifically for this meeting. Multi-project awards: The Principal Investigator, Project Leaders, NIAID Scientific Coordinator, and where applicable, Scientific Advisors will meet once per year to review progress, plan and design research activities, and establish priorities. This meeting will likely be held at the NIH. Applicants should include requests for travel funds specifically for the above meeting in their budget requests. Informal meetings. A critical determinant of success will be the degree of communication among its members. Therefore, in addition to the one meeting listed above, additional meetings, which may be necessary for coordination of activities, may be scheduled if justified and should be included in the budget. Regular telephone and written communication will be important and are encouraged. External advisors may be appointed by the Principal Investigator in consultation with the NIAID Scientific Coordinator to assist in progress review. This activity is likely to apply to large multi-project programs. Where scientifically appropriate NIAID may ask recipients to collaborate or cooperate with other NIAID funded projects and/or US government agencies, for example Centers for Disease Control, Food and Drug Administration and United States Department of Agriculture. COOPERATIVE AGREEMENT TERMS AND CONDITIONS OF AWARD The following terms and conditions will be incorporated into the award statement and provided to the Principal Investigator as well as the institutional official at the time of award. These special Terms of Award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR part 74 and 92, and other HHS, PHS, and NIH Grant Administration policy statements. The administrative and funding instrument used for this program is the single project or multiproject cooperative agreement (U01 or U19), an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during the performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partnership role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardees for the project as a whole, although specific tasks and activities in carrying out the research will be shared among the awardees and the NIAID Scientific Coordinator. The interaction of academic and non-profit research institutions with commercial organizations and the Government is strongly encouraged and is expected to favor expeditious preclinical development of Vaccines, Adjuvants, Therapeutics, Immunotherapeutics, and Diagnostics. 1. Monitoring Clinical Studies When clinical studies or trials are a component of the research proposed, NIAID policy requires that studies be monitored commensurate with the degree of potential risk to study subjects and the complexity of the study. AN UPDATED NIAID policy was published in the NIH Guide on July 8, 2002 and is available at: http://grants2.nih.gov/grants/guide/notice-files/NOT-AI-02-032.html. The full policy, including terms and conditions of award, is available at: http://www.niaid.nih.gov/ncn/pdf/clinterm.pdf. 2. Awardee Rights and Responsibilities Awardees will have primary responsibility for defining the research objectives, approaches and details of the projects within the guidelines of the RFA and for performing the scientific activity. Specifically, awardees have primary responsibility as described below. The Principal Investigator retains primary responsibility for the performance of the scientific activity, and agrees to accept close assistance in coordination, cooperation and participation of NIAID staff in scientific and technical management of the project in accordance with the terms formally and mutually agreed upon prior to the award. The responsibility for the planning, direction, and execution of the proposed project will be solely that of the Principal Investigator. o Meetings: One mandatory progress review meeting of the awardees will be held annually at the NIH or at a site designated by the NIH during which the Principal Investigator and Project Leaders will present significant findings. The NIAID Scientific Coordinator and External Advisors (when applicable) will be present. A critical determinant of success will be the degree of communication between the Principal Investigator, Project Leaders and other significantly involved parties. Therefore, in addition to the one meeting listed above, additional meetings, which may be necessary for coordination of cooperative agreement activities, may be scheduled if justified. Regular telephone and written communication will be important and are encouraged. o Publications: The Principal Investigator will be responsible for the timely submission of all abstracts, manuscripts and reviews (co)authored by members of the grant and supported in part or in total under this Agreement. The Principal Investigator and Project Leaders are requested to submit manuscripts to the Scientific Coordinator within two weeks of acceptance for publication so that an up-to-date summary of program accomplishments can be maintained and joint press conferences prepared. Publications or oral presentation of work done under this Agreement is the responsibility of the Principal Investigator and appropriate Project Leaders and will require appropriate acknowledgement of NIAID support. Timely publication of major findings is encouraged. o Data: While the NIAID Scientific Coordinator has a right of access to the data (see NIAID staff responsibilities below) the applicant will retain custody of and right to the data. For more information on data sharing go to: https://grants.nih.gov/grants/policy/data_sharing/index.htm. o Intellectual Property: Because an application may include several institutions, including the private sector, complex intellectual property- related situations may arise. To avoid delays related to intellectual property issues, each multi-project application is required to provide, as part of the application, a plan detailing (1) the approach agreed to by all parties for disposition of intellectual property, including but not limited to obtaining patent coverage and licensing, where appropriate; and (2) procedures to be followed for the resolution of legal problems that potentially may develop. o Human Subjects: Although this funding will not support clinical trials, awardees that intend to use clinical samples in their studies shall be in compliance with all Federal regulations, and NIH policies applying to the conduct of research involving human subjects. These include but are not limited to: Title 21 CFR 50, 56, 312 and Title 45 CFR 46. For research conducted in foreign countries, the Awardee must assure compliance with the host country regulations for human subjects, and must assure that the internationally recognized standards for the protection of human subjects are observed. 3. NIAID Staff Responsibilities NIAID staff assistance will be provided by Katherine Taylor who will serve as NIAID's Scientific Coordinator. The NIAID Scientific Coordinator will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination above and beyond normal program stewardship for grants, as described below. During performance of the award, the NIAID Scientific Coordinator may provide appropriate assistance, advice, and guidance by: participating in the design of the activities; advising in the selection of sources or resources (e.g., determining where a particular reagent can be found); coordinating or participating in the collection and/or analysis of data; advising in management and technical performance; or participating in the preparation of publications. However, the role of NIAID will be to facilitate and not to direct the activities. It is anticipated that decisions in all activities will be reached by consensus and the NIAID staff will be given the opportunity to offer input into this process. The manner of reaching this consensus and the final decision- making authority will rest with the Principal Investigator. Based on the research topic of the applications to be funded, relevant program staff will be assigned to assist in scientific coordination of projects in the areas of research specified. An NIAID Program Official will be assigned to perform normal program stewardship responsibilities for this award. 4. Collaborative Responsibilities The specific timelines, interim objectives and funding levels agreed to by the Principal Investigator and the NIAID shall be included in the terms and conditions of award. Given the nature of product development, it is recognized that timelines and interim objectives may require revision and renegotiation during the course of the project period. The Principal Investigator and NIAID must agree to all such revisions. Release of each funding increment by NIAID will be based on a NIAID review of progress towards achieving the previously agreed upon interim objective. Where scientifically appropriate NIAID may ask recipients to collaborate or cooperate with other NIAID funded projects and/or US government agencies, for example CDC, FDA and USDA. 5. Arbitration Any disagreement that may arise on scientific or programmatic matters (within the scope of the award) between award recipients and the NIAID may be brought to arbitration. An arbitration panel will be composed of three members -- one selected by the Steering Committee or by the individual awardee in the event of an individual disagreement, a second member selected by the NIAID, and the third member with expertise in the relevant area and selected by the two prior members will be formed to review any scientific or programmatic issue that is significantly restricting progress. While the decisions of the Arbitration Panel are binding, these special arbitration procedures will in no way affect the awardee's right to appeal an adverse action in accordance with PHS regulations at 42 CFR Part 50, subpart D, and HHS regulations at 45 CFR Part 16. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues on VACCINE RESEARCH to: Dr. Katherine Taylor Division of Microbiology and Infectious Diseases National Institute of Allergy and Infectious Diseases 6610 Rockledge Drive, Room 6003 Bethesda, MD 20892-7630 Telephone: (301) 496-7051 FAX: (301) 480-1456 E-Mail: kt148o@nih.gov o Direct your questions about scientific/research issues on ADJUVANTS RESEARCH to: Dr. Charles Hackett Division of Allergy, Immunology and Transplantation National Institute of Allergy and Infectious Diseases Room 5139, MSC-7640 6700-B Rockledge Drive Bethesda, MD 20892-7640 Telephone: (301) 496-7551 FAX: (301) 402-2571E-Mail: chackett@niaid.nih.gov o Direct your questions about scientific/research issues on IMMUNOTHERAPEUTICS RESEARCH to: Dr. Alison Deckhut Division of Allergy, Immunology and Transplantation National Institute of Allergy and Infectious Diseases Room 5138, MSC-7640 6700-B Rockledge Drive Bethesda, MD 20892-7640 Telephone: (301) 496-7551 FAX: (301) 402-2571 E-Mail: ad122x@nih.gov o Direct your questions about scientific/research issues on THERAPEUTICS RESEARCH to: Dr. Catherine Laughlin Division of Microbiology and Infectious Diseases National Institute of Allergy and Infectious Diseases Room 3105, MSC-7630 6700-B Rockledge Drive Bethesda, MD 20892-7630 Telephone: (301) 496-7453 FAX: (301) 480-1594 E-Mail: cl28r@nih.gov o Direct your questions about scientific/research issues on DIAGNOSTICS RESEARCH to: Dr. Robert Hall Division of Microbiology and Infectious Diseases National Institute of Allergy and Infectious Diseases 6610 Rockledge Drive, Room 6008 Bethesda, MD 20892-7630 Telephone: (301) 496-5305 FAX: (301) 496-8030 E-Mail: rhall@niaid.nih.gov o Direct your questions about peer review issues; address the letter of intent; mail two copies of the application and all five sets of appendices to: Dr. Dianne Tingley Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 2148A, MSC-7616 6700-B Rockledge Drive Bethesda, MD 20892-7616 Telephone: (301) 496-0818 FAX: (301) 402-2638 E-Mail: dt15g@nih.gov o Direct your questions about financial or grants management matters to: Lesia A. Norwood Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 2117, MSC-7614 6700-B Rockledge Drive Bethesda, MD 20892-7614 Telephone: (301) 402-7146 Fax: (301) 480-3780 E-mail: ln5t@nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Dianne Tingley, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 2148A, MSC-7616 6700-B Rockledge Drive Bethesda, MD 20892-7616 Telephone: (301) 496-0818 FAX: (301) 402-2638 E-Mail: dt15g@nih.gov SUBMITTING AN APPLICATION Applicants for U19 grants must follow special application guidelines in the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS; this brochure is available via the Internet at: http://www.niaid.nih.gov/ncn/grants/multibron.htm Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. SUPPLEMENTAL INSTRUCTIONS: USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: https://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: Center For Scientific Review National Institutes Of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional exact copies of the grant application and all five sets of any appendix material must be sent to: Dianne Tingley, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 2148A, MSC-7616 6700-B Rockledge Drive Bethesda, MD 20892-7616 Bethesda, MD 20817 (for express mail or courier service) Applications that are not received as a single package on the receipt date or that do not conform to the instructions contained in PHS 398 (rev. 5/01) Application Kit (as modified in, and superseded by, the NIAID BROCHURE ENTITLED "INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS"), will be judged non- responsive and will be returned to the applicant. It is highly recommended that the appropriate NIAID program contact be consulted before submitting the letter of intent and during the early stages of preparation of the application. (See program contact under INQUIRIES). SPECIAL INSTRUCTIONS FOR COMPLETION OF APPLICATIONS IN RESPONSE TO THIS RFA: Applicants for U19 cooperative agreements must follow special application guidelines in the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS; this brochure is available from NIAID listed under INQUIRIES via the WWW at: http://www.niaid.nih.gov/ncn/grants/multibron.htm. This brochure presents specific instructions for sections of the PHS 398 (rev. 5/01) application form that should be completed differently than usual. For all other items in the application, follow the usual instructions in the PHS 398. APPLICATION PROCESSING: Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an Introduction addressing the previous critique. Concurrent submission of an R01 and a Component Project of a Multi-project Application: Current NIH policy permits a component research project of a multi-project grant application to be concurrently submitted as a traditional individual research project (R01) application. If, following review, both the multi-project application and the R01 application are found to be in the fundable range, the investigator must relinquish the R01 and will not have the option to withdraw from the multi-project grant. This is an NIH policy intended to preserve the scientific integrity of a multi-project grant, which may be seriously compromised if a strong component project(s) is removed from the program. Investigators wishing to participate in a multi-project grant must be aware of this policy before making a commitment to the Principal Investigator and awarding institution. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by NIAID. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIAID in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score o Receive a second level review by the National Institute of Allergy and Infectious Diseases Council REVIEW CRITERIA The general review criteria for U19 multi-project cooperative agreement applications are presented in the NIAID brochure entitled "INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS" at http://www.niaid.nih.gov/ncn/grants/multibron.htm. In addition, the following review criteria specific to this RFA will be used in evaluation of applications: The criteria to be used in the evaluation of grant applications are listed below. To put those criteria in context, the following information is contained in instructions to the peer reviewers. The reviewers will comment on the following aspects of the application in their written critiques in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of the RFA goals. Each of these criteria will be addressed and considered by the reviewers in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have a major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a product forward. (1) SIGNIFICANCE: Is this project likely to significantly advance the development of a Vaccine, Adjuvant, Immunotherapeutic, Drug or Diagnostic against a NIAID Category A, B or C pathogen? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? Is the likelihood of successful project completion high given the current state of research and development and the technical approach? Are the proposed timeline and interim milestones appropriate, feasible and technically sound? (3) INNOVATION: Many aspects of vaccine, adjuvant, therapeutics, immunotherapeutics and diagnostics development are not inherently innovative. However, each project will be judged on whether the proposed research leverages multi-disciplinary involvement to accelerate product development. In addition, the approach should represent the best use of current technology and appropriate collaborations to achieve the research objectives. (4) INVESTIGATOR: Is the research and development team appropriately trained and experienced and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? (5) ENVIRONMENT: Does the environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environments including partnerships with industry or employ useful collaborative arrangements? Is there adequate evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: o PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. o INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) o DATA SHARING: The adequacy of the proposed plan to share data. o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: October 25, 2002 Application Receipt Date: November 26, 2002 Scientific Peer Review Date: March, 2003 Advisory Council Review: May, 2003 Earliest Anticipated Start Date: July 1, 2003 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities. REQUIRED FEDERAL CITATIONS MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: https://grants.nih.gov/grants/guide/notice-files/not98-084.html). INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at https://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at https://grants.nih.gov/grants/stem_cells.htm and at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS This program is described in the Catalogue of Federal Domestic Assistance in the following citations: No. 93.855, Immunology, Allergy, and Transplantation Research and No. 93.856, Microbiology and Infectious Diseases Research. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The NIH Grants Policy Statement is available at https://grants.nih.gov/grants/policy/policy.htm. This document includes general information about the grant application and review process; information on the terms and conditions that apply to NIH Grants and cooperative agreements; and a listing of pertinent offices and officials at the NIH. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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