COOPERATIVE RESEARCH FOR THE DEVELOPMENT OF VACCINES, ADJUVANTS, THERAPEUTICS, IMMUNOTHERAPEUTICS, AND DIAGNOSTICS FOR BIODEFENSE AND SARS RELEASE DATE: June 16, 2003 RFA: AI-03-017 National Institute of Allergy and Infectious Diseases (NIAID) (http://www.niaid.nih.gov) CATALOGUE OF FEDERAL DOMESTIC ASSISTANCE NUMBERS: No. 93.855, Immunology, Allergy, and Transplantation Research No. 93.856, Microbiology and Infectious Diseases Research LETTER OF INTENT REFCEIPT DATE: September 22, 2003 APPLICATION RECEIPT DATES: October 22, 2003 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. These products should be focused on the toxins or pathogens listed in the NIAID Categories A, B and C list of priority pathogens (http://www2.niaid.nih.gov/Biodefense/bandc_priority.htm), or their arthropod vectors. Products focused on the newly recognized SARS Coronavirus are also responsive. The objective of this program is to support research in the early stages of product development (i.e., beyond basic research); however, for the area of immunotherapeutics more basic research is also appropriate. Research may include, but is not limited to, target identification, the adaptation of platform technologies or products to biodefense or SARS applications, optimization of products, process development, early validation and testing, preclinical evaluation, scale-up, and production of quantities sufficient for preclinical regulatory requirements and clinical Phase I testing or field trials. Phase I, II, and III clinical trials and field studies are not supported by this initiative. 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. The NIAID recognizes that the inherent nature and demands of the product development process may require funding large, complex grants with interdependent specific aims. Furthermore, some aspects of the product development process (e.g., production of GLP and cGMP product) are inherently not innovative. Recognizing that product development is often an iterative and sequential process, and that steps early in the process may not be successful and may need to be modified or reworked, NIAID staff, through the cooperative agreement grant mechanism, will be actively involved in evaluating the milestones of awardees and determining whether additional investment in the development is warranted. RESEARCH OBJECTIVES Background The National Institutes of Health (NIH) and other agencies in the Department of Health and Human Services (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 biological agents deemed to pose the greatest threat to civilian populations have been prioritized in the NIAID Category A, B, and C priority pathogens and toxins list, which is available at http://www2.niaid.nih.gov/Biodefense/bandc_priority.htm. NIAID convened three Blue Ribbon Panels to address the research priorities for Category A pathogens and toxins, Category B and C pathogens and toxins, and immunology research. The research agendas that resulted from these three meetings are published at: http://www.niaid.nih.gov/biodefense/research/biotresearchagenda.pdf, http://www.niaid.nih.gov/biodefense/research/categorybandc.pdf and http://www.niaid.nih.gov/publications/pdf/biodimmunpan.pdf. In addition to the NIAID research agendas, the DHHS has identified the highest priority products for bioterror preparedness (http://www2.niaid.nih.gov/Biodefense/Research/high_priority.htm). The recent emergence of SARS, its relative ease of transmission, disease severity, and potential for epidemic spread require the rapid development of interventions by the research community and the private sector. To this end, NIAID is interested in supporting the early stages of development of specific high priority products against the newly recognized SARS Coronavirus. High priority products against the SARS Coronavirus include the development of vaccines, therapeutics, and diagnostics. In response to these needs, it is imperative that promising findings are translated rapidly into new approaches and strategies for product development. The involvement of experts from 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 specific for an NIAID Category A, B or C priority toxin, pathogen, or their arthropod vector; or the SARS Coronavirus. Research is not required to result in a "final" product but must advance the development of a candidate product. One objective of this RFA is to stimulate scientifically sound, original, and innovative research requiring comprehensive team and multidisciplinary effort that is likely to advance promising candidate products or platform technologies through the product development pathway. All applications should define the proposed project goal, interim objectives (development milestones), a general description of the potential ultimate product (a specific product profile that is defined by licensing indication is not requested), and provide a schedule or timeline for milestone and goal attainment. When appropriate, research plans should include an awareness of guidelines that govern GLP (as defined by 21 CFR(58)) and GMP (as defined by 21 CFR(211)) manufacturing and/or IND enabling studies that will be performed with this award as they would be applicable to eventual product licensure in the U.S. Phase I, II, and III clinical trials and field trials are not supported by this RFA. However, the use of human tissues and samples, as well as appropriate human cell lines, is encouraged. More advanced stages of biodefense product development that include significant industry participation are supported by a parallel mechanism "Partnership Challenge Grants for Product Development: Vaccines, Adjuvants, Therapeutics, Diagnostics, and Resources". This is also a cooperative agreement mechanism and includes funding for Phase I and II clinical trials. VACCINES Applications for vaccines against any of the NIAID Category A-C pathogens or toxins, or the SARS Coronavirus, are invited. Approaches should consider the ultimate potential of candidate vaccines to quickly induce safe and protective responses in a diverse civilian population. 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 subunit vaccine candidates; o Process development for the production of vaccine components, including QA/QC, methods for product recovery, characterization, purification, identity, stability etc.; o Manufacturing GLP or cGMP product in quantities sufficient for pre- clinical and early clinical evaluation; 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 o Performance of required benchmarks for successful submission and review of an Investigational New Drug application by the Food and Drug Administration (FDA) (http://www.fda.gov/cber/vaccine/vacappr.htm). ADJUVANTS Applications for development of novel adjuvants that could be used in conjunction with specific pathogen components are invited. 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. In order to advance the development of vaccine adjuvants against NIAID category A-C agents of bioterrorism and the SARS Coronavirus, this solicitation focuses on optimization and preclinical testing of prospective lead compounds that previously showed promise in early stages of discovery and development. Note: Applications proposing the development of an adjuvant in conjunction with a pathogen that is not on the NIAID Category A, B, or C priority pathogen list, with the exception of the SARS Coronavirus, will be deemed unresponsive and returned without review to the applicant. Projects may include, but are not limited to, one or more of the following areas: 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 Reiterative design, synthesis, and analysis to improve adjuvant performance; o Testing of previously-evaluated adjuvants for their capacity to stimulate desired immune responses toward specific NIAID Category A, B or C pathogens or toxins; or the SARS Coronavirus; o Testing mixtures of adjuvants to evaluate additive or synergistic potential to stimulate desired immune responses; o Process development for the manufacturing of adjuvant components, including QA/QC methods for product recovery, characterization, purification, identity, stability etc.; o Scale-up production under GLP or cGMP to provide sufficient quantities for preclinical FDA-required animal studies and Phase I clinical trials; o Pre-clinical testing for safety and stimulatory capacity in animals, and o Performance of required benchmarks for successful submission and review of an Investigational New Drug application by the (FDA) (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 priority pathogens or the SARS Coronavirus are invited. Projects may include, but are not limited to, one or more of the following areas: o Perform molecular modeling, library screening, and medicinal chemistry/structural activity analysis to optimize candidate compounds for preclinical studies o Identify and validate 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 Synthesize sufficient quantities of candidate drug for in vitro analysis and/or explore the use of active components of natural products as potential drug sources for development; o Process development for the manufacturing of drugs, including QA/QC, methods for product recovery, characterization, purification, identity, stability etc.; 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 o Performance of required benchmarks for successful submission and review of an Investigational New Drug application by the FDA (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 or toxin-specific (antibodies) approaches are invited. Major objectives for products generated in this research program include prevention of infection or intoxication in the face of an immediate threat, protection of immunocompromised individuals, and 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 or the SARS Coronavirus. Projects may include, but are 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 or the SARS Coronavirus; o Testing and validation of efficacy; o Process development for the manufacturing of product, including QA/QC, methods for product recovery, characterization, purification, identity, stability etc.; o GMP production to generate sufficient product to conduct pre-clinical studies and Phase I clinical studies; o Preclinical testing for safety and efficacy in animal models; and o Performance of required benchmarks for successful submission and review of an Investigational New Drug application by the FDA (http://www.fda.gov/cber/therapies.htm). Antibodies: o Discovery and characterization of novel antibodies with high specificity for pathogen antigens or toxins; 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. improved purification methods, production of humanized or fully human antibodies); o Testing and validation of efficacy; o Process development for the manufacturing of antibody product, including QA/QC methods for product recovery, characterization, purification, identity, stability etc.; o GLP or cGMP production to generate sufficient product to conduct pre- clinical and Phase I clinical studies; o Preclinical testing for safety and efficacy in animal models; and/or o Performance of required benchmarks for successful submission and review of an Investigational New Drug application by the Food and Drug Administration (FDA) (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, hospital-based clinical laboratories and point-of-care use to identify infectious agents or toxins so that rapid diagnostics and appropriate therapeutic intervention can be executed. Simultaneous detection and identification of a broad range of infectious agents in clinical samples is highly desirable. Research for the development of diagnostics that can detect, or indicate exposure to, infectious agents or toxins in individuals that are symptomatic, pre- symptomatic, or exposed with non-specific symptoms is invited. This initiative does not support environmental detection research, which is supported by other institutes and agencies such as the National Institute for Environmental Health Sciences, the Centers for Disease Control and Prevention (CDC), the Environmental Protection Agency, and the Department of Energy. All applications should include: o Description of the capabilities of the method, technology, or assay. o Plans for determining the sensitivity, specificity, and validation of the technology, assay, and diagnostic. Applications for the development of medical diagnostics specific for NIAID Category A-C pathogens and toxins or the SARS Coronavirus are invited. Applications may include, but are not limited to, one or more of the following areas: o Rapid, hospital-based tests that differentiate the common pathogens from the Category A, B, and C priority pathogens in blood; o Methods for rapid sample preparation, processing, and concentration; o Methods demonstrating the highest performance of specificity, sensitivity, rapidity, and cost when applied to relevant clinical samples to detect an infectious agent and/or toxin; o Technologies capable of resolving engineered or otherwise acquired genetic traits in microorganisms, such as patterns of microbial resistance or enhanced virulence; o Technologies capable of identifying characteristic microbial genetic signature profiles; o Methods capable of high throughput, robotics, and automated data output and analyses; o Tests that target multiple agents simultaneously in a single sample; o Technologies that are capable of simultaneously detecting two parameters in a clinical sample such as both DNA and protein. o Process development for the manufacturing of diagnostic components, including QA/QC methods for reagent recovery, characterization, purification, identity, stability etc.; Tests for use on human samples may consider benchmarks required for approval (http://www.fda.gov/cber/devices.htm). VECTOR CONTROL Many of the pathogens on NIAID's priority organism list are transmitted by arthropod vectors, including mosquitoes of the genera Culex and Aedes, ixodid ticks, and fleas. Vector control is one means to prevent disease transmission. Applications to develop novel vector control products will also be considered under this announcement. Applicants are strongly encouraged to consult NIAID staff for details. MECHANISM OF SUPPORT This RFA will use the single project (U01) or multi-project (U19) cooperative agreement(s), an "assistance" mechanism, rather than an "acquisition" mechanism. The NIH 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 the Principal Investigator, as described under the section "Cooperative Agreement Terms and Conditions of Award." Essential elements of the U01 include: (1) a single research project that may include consortium agreements, but does not include "Core" resources and facilities as defined for U19 applications; (2) a single Principal Investigator who will be scientifically and administratively responsible for research project; and (3) a single applicant institution that will be legally and financially responsible for the use and disposition of funds awarded. Essential elements of the 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 these 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. Lack of synergy and interaction among the projects and cores will adversely affect the priority score of a multi-project application, even if the merit of individual projects is high. 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 $40 million per year (total costs), beginning in FY 2004, to fund 12 to 25 new grants in response to this RFA. An applicant may request a project period of up to 5 years. The yearly direct costs that can be requested are not limited but must be justified by the proposed research and will be evaluated by the review panel and program staff. Domestic 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 for renovations and/or equipment 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. Foreign Organizations: Several special provisions apply to applications submitted by foreign organizations. o Funds for alterations or renovations cannot be requested. o Charge back of customs and import fees is not allowed. o Format: every effort should be made to comply with the format specifications, which are based upon a standard US paper size of 8.5" x 11." o Funds for up to 8% administrative costs can now be requested, (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-028.html) o Organizations must comply with federal/NIH policies on human subjects, animals, and biohazards. o Organizations must comply with federal/NIH biosafety and biosecurity regulations. o Proposed research should provide a unique research opportunity, not available in the U.S. 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 priority toxin, pathogen, or their arthropod vector; or the SARS Coronavirus, through the product development process. It is not necessary to propose to complete the product development process up to the point of readiness for clinical trials within the time frame of this project. Applications that would significantly advance a specific product toward clinical or field usefulness are responsive. Single project U01 and multi-project U19 applications must define the proposed project goal, interim objectives (development milestones) and potential ultimate product (a specific product profile that is defined by licensing indication is not requested), and provide a schedule or timeline for milestone and goal attainment. When appropriate, research plans should include an awareness of guidelines that govern GLP, as defined by 21 CFR(58), and GMP, as defined by 21 CFR(211), manufacturing and/or IND enabling studies performed with this award as they would be applicable to eventual product licensure in the U.S. 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. Select Agents: All participating organizations whether domestic or foreign, must comply with Select Agent regulations (http://www.cdc.gov/od/sap/) and NIH Guidelines for Research Involving Recombinant DNA Molecules (http://www4.od.nih.gov/oba/rac/guidelines/guidelines.html). Applicants must document their ability and willingness to comply. Intellectual Property: Intellectual property rights are likely to play an important role in achieving the goals of this program. To this end, the NIAID requires that at the time of the application all applicants must provide a letter (Proprietary Rights Assurance Letter" containing the following assurances, which is signed by a representative who is duly authorized to provide such assurances on behalf of the applicant organization: o. Applicant is solely responsible for the timely acquisition of all proprietary rights, including intellectual property rights, and all materials needed for applicant to perform the project o. Applicant acknowledges that prior to, during, and subsequent to the award, the U.S. Government is not required to obtain for applicant any proprietary rights, including intellectual property rights, or any materials needed by applicant to perform the project. o. Applicant acknowledges the requirement to report to the U.S. Government all inventions made in the performance of the project, as specified at 35 U.S.C. Sect. 202. Apart from the Proprietary Rights Assurance Letter, applicants are expected to exercise their Bayh-Dole rights in a manner that does not conflict with the goals of this award or the intent of the Bayh-Dole Act to promote the utilization, commercialization and availability of the U.S. Government-funded inventions for public benefit. In addition, applicants are expected to make new information and materials known to the research community in a timely manner through publications, web announcements, and reports to the NIAID or other mechanisms. Mandatory Meetings: Single project awards: The Principal Investigator, one or two key personnel designated by the Principal Investigator and NIAID program staff 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, and NIAID program staff 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 (airfare, and per diem) 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. External advisors should be identified and appointed only after the funding award is made. 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 multi-project 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 or other designated NIAID scientific program staff. 1. Monitoring Clinical Studies Note that phase I, II, and III clinical trials are not supported by this initiative. However, the use of clinical samples, when appropriate, is acceptable and will be governed by NIAID policy. When clinical studies 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://grants.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 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 NIAID program staff 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 and program staff have a right of access to the data (see NIAID staff responsibilities below) the applicant will retain custody of and right to the data. In accordance with this NIH policy a data-sharing plan should be included in the application. For more information on data sharing go to: http://grants.nih.gov/grants/policy/data_sharing/index.htm. 3. NIAID Staff Responsibilities NIAID staff assistance will be provided by Clare Schmitt who will serve as NIAID's Scientific Coordinator. The NIAID Scientific Coordinator will have substantial scientific/programmatic involvement during the conduct of awarded activities 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, with assistance from other scientific program staff who are designated based on the research topic and their relevant expertise, 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. The NIAID Scientific Coordinator will serve as a liaison /facilitator between the awardee, pharmaceutical and biotech industries, and other government agencies (e.g., FDA, USDA, CDC) will serve as a resource of scientific and policy information related to the goals of the awardee's research. 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. An NIAID Program Official will be assigned to perform normal program stewardship responsibilities for this award. The Program Official may serve as the Scientific Coordinator. 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 (with the NIAID representation not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by NIAID, and the third member selected by the two prior selected members. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR Part 50, Subpart D and HHS regulation 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. Clare Schmitt Division of Microbiology and Infectious Diseases National Institute of Allergy and Infectious Diseases Room 4005, MSC-6603 6610 Rockledge Drive Bethesda, MD 20892-6603 Telephone: (301) 496-7051 FAX: (301) 402-1456 E-Mail: cs453y@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 1127, MSC-7640 6700-B Rockledge Drive Bethesda, MD 20892-7640 Telephone: (301) 496-7551 FAX: (301) 480-2381 E-Mail: ch187q@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 4099, MSC-6603 6610 Rockledge Drive Bethesda, MD 20892-6603 Telephone: (301) 496-7453 FAX: (301) 480-1594 E-Mail: cl28r@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 1126, MSC-7640 6700-B Rockledge Drive Bethesda, MD 20892-7640 Telephone: (301) 496-7551 FAX: (301) 480-2381 E-Mail: ad122x@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 Room 4013, MSC-6603 6610 Rockledge Drive Bethesda, MD 20892-6603 Telephone: (301) 496-7051 FAX: (301) 4021456 E-Mail: rh277v@nih.gov o Direct your questions about scientific/research issues on VECTOR CONTROL PRODUCTS to: Dr. Kathryn S. Aultman Division of Microbiology and Infectious Diseases National Institute of Allergy & Infectious Diseases Room 5097, MSC-6603 6610 Rockledge Blvd Bethesda, MD 20892-6603 Telephone: (301) 435 2854 FAX: (301) 402 0659 E-Mail: ka6z@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) 496-2550 FAX: (301) 402-2638 E-Mail: dt15g@nih.gov o Direct your questions about financial or grants management matters to: Ms. Sharie Bernard Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room Number 3219, MSC-7614 6700-B Rockledge Drive Bethesda, MD 20892-7614 Telephone: 301-402-5540 FAX: 301-493-0597 E-Mail: sb34k@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) 496-2550 FAX: (301) 402-2638 E-Mail: dt15g@nih.gov SUBMITTING AN APPLICATION Applicants for U01 or U19 grants must follow the forms and standard guidelines in the NIH public Health Service grant application (PHS 398, rev. 5/2001, Sections I-III) available at http://grants.nih.gov/grants/funding/phs398/phs398.html. In addition, 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. Revisions of applications previously submitted in response to RFA-AI-02-026 must contain a special introduction to the Research Plan identifying changes from the former application, in accordance with instructions for Revised Application in PHS 398, Section I.8. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. 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: http://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) The Center for Scientific Review now accepts delivery of applications only by mail or courier service. Personal deliveries of applications will not be accepted (http://grants.nih.gov/grants/funding/phs398/instructions2/ p1_mailing_address.htm). 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 or before October 22, 2003 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, Sections I-III. APPLICATION PROCESSING: Applications must be received on or before 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 (P01 or U19) to be concurrently submitted as a traditional individual research project (R01) or SBIR application. If, following review, both the multi-project application and the R01 or SBIR application are found to be in the fundable range, the investigator must relinquish the R01 or SBIR 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. Applicants to this RFA may not submit a U01 proposal containing a project identical to a project in a U19 proposal. 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 Advisory 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. 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. SIGNIFICANCE: Is this project likely to significantly advance the development of a vaccine, adjuvant, therapeutic, immunotherapeutic, or diagnostic against an NIAID Category A, B or C priority toxin, pathogen, or associated arthropod vector; or the SARS Coronavirus? 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? INNOVATION: Many aspects of vaccine, adjuvant, therapeutics, immunotherapeutics, and diagnostics product 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 or emerging technologies and appropriate collaborations to achieve the research objectives. 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)? 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, the following items will be considered in the determination of scientific merit and the priority score: PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below). INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: 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 in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL CONSIDERATIONS DATA SHARING: The adequacy of the proposed plan to share data. 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: September 22, 2003 Application Receipt Date: October 22, 2003 Scientific Peer Review Date: February, 2004 Advisory Council Review: May, 2004 Earliest Anticipated Start Date: July, 2004 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 HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm MONITORING PLAN AND DATA AND SAFETY 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: http://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 (http://grants.nih.gov/grants/guide/notice-files/ NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http://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 http://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 http://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 http://stemcells.nih.gov/index.asp and at http://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 http://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. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule," on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Those who must comply with the Privacy Rule (classified under the Rule as "covered entities") must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html. 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 at http://www.cfda.gov/ 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 http://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. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. 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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