RFA-AI-00-003: ORTHOPOXVIRUS GENOMICS AND BIOINFORMATICS RESOURCE CENTER

Department of Health
and Human Services (HHS)

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ORTHOPOXVIRUS GENOMICS AND BIOINFORMATICS RESOURCE CENTER Release Date: October 20, 1999 RFA: AI-00-003 National Institute of Allergy and Infectious Diseases Letter of Intent Receipt Date: December 15, 1999 Application Receipt Date: January 19, 2000 PURPOSE As part of DHHS-wide efforts directed towards improving the defense of civilians from the threat of possible bioterrorism, the Division of Microbiology and Infectious Diseases (DMID), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), invites research proposals directed toward the design and implementation of an ORTHOPOXVIRUS GENOMICS AND BIOINFORMATICS RESOURCE CENTER. Genomic analyses will include sequence and functional comparisons of conserved and variable genes to provide insights for the selection of targets for the design of antiviral and vaccine strategies. Areas of research which should be addressed by applicants include (but are not limited to): 1) The collection and/or determination of orthopoxvirus genomic sequences including variola and human and vertebrate (including human) poxviruses that might serve as surrogates for variola; 2) The design and maintenance of relational databases to store, display, annotate and query genome sequence, structural information, phenotypic data (e.g. drug susceptibility, virulence, host specificity) and bibliographic information; 3) The application of innovative methods for global functional analysis of the viral genomes; and 4)Service as a repository of well-documented viral strains (including clinical isolates and mutants, if relevant) and genomic clones that are used in the genomic sequence analysis; and 5) Develop and maintain a website. NIAID will establish an external steering committee to provide advice to the Principal Investigator and the NIAID Scientific Coordinator on research directions. Of the areas described above, items 1 and 2 are the main priorities for NIAID. However, applications which propose only to sequence orthopoxviruses are NOT responsive to this RFA. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), ORTHOPOXVIRUS GENOMICS AND BIOINFORMATICS, is related to the priority area(s) of immunization and infectious diseases. Potential applicants may obtain a copy of "Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit organizations; public and private institutions, such as universities, colleges, hospitals, laboratories, units of State and local governments; and eligible agencies of the Federal government. Foreign institutions are not eligible to apply. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT The administrative and funding mechanism to be used to undertake this program will be the Cooperative Agreement (U01), 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 partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Details of the responsibilities, relationships, and governance of a study funded under cooperative agreement(s) are discussed later in this document under the section Terms and Conditions of Award. The total project period for applications submitted in response to this RFA may not exceed five years. At present, the NIAID is administratively limiting the duration of U01 cooperative agreements to four years; this administrative limitation may change in the future. At this time, the NIAID has not determined whether and how this solicitation will be continued beyond the present RFA. FUNDS AVAILABLE The estimated total funds (direct and facilities and administrative(F&A)costs) available for the first year of support for all awards made under this RFA will be $500,000. Depending on Fiscal Year 2000 budget appropriations, this amount may increase. In Fiscal Year 2000 the NIAID plans to fund approximately one award. The usual NIH policies governing grants administration and management will apply. Although this program is provided for in the financial plans of the NIAID, awards pursuant to this RFA are contingent upon the availability of funds for this purpose and the receipt of a sufficient number of applications of high scientific merit. Funding beyond the first and subsequent years of the grant will be contingent upon satisfactory progress during the preceding years and availability of funds. RESEARCH OBJECTIVES Background In recent years, there has been a significant change in both the nature and degree of the threat posed by the use of weapons of biological warfare. The risk of using such weapons once appeared to be restricted to international conflicts involving small numbers of industrialized nations. However, an increasing number of developing countries, as well as terrorist groups, and rogue individuals now view the use of biological weapons as agents of terror, rather than as instruments of warfare. Recent events, such as disclosures of international biological weapons programs, the bacterial contamination of restaurant food by cultists, and the delivery of a putative anthrax bacterial culture to a DC office, have dramatized both the possibility of bioterrorist attack and the vulnerability of the U.S. population to such an event. Although the DOD has developed defenses for biological warfare, there are additional concerns that need to be addressed to provide an adequate civilian defense from this threat. One is that the populations to be protected are different as civilians include people of all ages and physical conditions. Thus, the important research goals for defense against biological agents delivered by a potential terrorist include: 1) rapid, accurate diagnosis; 2) effective therapy for those infected; 3) protective vaccination for those at risk of exposure; and 4) basic research, which provides the essential underpinning of the other areas. Of the potential organisms that might be used in bioterrorism, smallpox would likely have the most horrific impact on the health of the U.S. Smallpox is highly contagious and mortality is in the range of 30%. There is no available antiviral therapy. Furthermore, the U.S. population is essentially entirely susceptible because routine immunization was terminated in the early 1960 s. Even older vaccinees are vulnerable as vaccine protection wanes significantly after ten years. As a result of the eradication of the disease, and with the exception of the development of fowlpox vaccine vectors, the amount of research on smallpox and related poxviruses has decreased significantly. This Request for Applications (RFA) will support the acquisition and analysis of orthopoxvirus genomic information to facilitate its application to the development of therapies and improved vaccines for smallpox and related viruses. Research Objectives and Scope Relevant research includes, but is not limited to, the following: 1) The collection and/or determination of orthopoxvirus genomic sequences including variola and human and vertebrate (including human) poxviruses that might serve as surrogates for variola; 2) The design and maintenance of relational databases to store, display, annotate and query genome sequence, structural information, phenotypic data (e.g. drug susceptibility, virulence, host specificity) and bibliographic information; 3) The application of innovative methods for global functional analysis of the viral genomes; and 4) Service as a repository of well-documented viral strains (including clinical isolates and mutants, if relevant)and genomic clones that are used in the genomic sequence analysis; and 5) Develop and maintain a website. NIAID will establish an external advisory committee to provide advice to the Principal Investigator and the NIAID Scientific Coordinator on research directions. Of the areas described above, items 1 and 2 are the main programmatic priorities for NIAID. However, applications that propose only to sequence orthopoxviruses, are NOT responsive to this RFA. SPECIAL REQUIREMENTS NIAID will establish an external steering committee to provide advice to the Principal Investigator and the NIAID Scientific Coordinator on research directions. Funds to support the travel of five committee members, as well as the Principal Investigator, to attend an annual one day meeting in Bethesda should be included in the budget. Other meetings will be scheduled as conference calls. TERMS AND CONDITIONS OF AWARD The administrative and funding instrument used for this program is the cooperative agreement (U01), 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 partner 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. Cooperative agreements are subject to the administrative requirements outlined in OMB circulars A-102 and A-110. All pertinent HHS, PHS, and NIH grant regulations, policies and procedures, with particular emphasis on PHS regulations at 42 CFR part 52 and HHS regulations at CFR 45 Part74, are applicable. These special terms and conditions pertaining to the scope and nature of the interaction between the NIAID and the investigators will be incorporated in the Notice of Grant Award. However, these terms will be in addition to, not in lieu of, the customary programmatic and financial negotiations that occur in the administration of cooperative agreements. 1. 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. a. The Principal Investigator defines the details of the project within the guidelines of the RFA, retains primary responsibility for the performance of the scientific activity, and agrees to accept close assistance of NIAID staff in aspects of scientific and technical management of the project in accordance with the terms mutually agreed upon prior to the award. b. The awardee is to plan and conduct the research stipulated in the application and to ensure that the results obtained are analyzed and published in a timely manner. The awardee should adhere to NIAID policy on release of genome sequence data (March 19, 1999 issue of the NIH Guide). Awardees will retain custody of and have primary rights to the data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. c. The awardee is to participate in an annual meeting of investigators funded under this and related RFAs to discuss progress and strategies for future research. d. The awardee, as described above, is to participate in meetings of the steering committee. 2. NIAID STAFF RESPONSIBILITIES Assistance via Cooperative Agreement differs from the traditional research grant in that, in addition to the normal programmatic and administrative stewardship responsibilities, the component awarding the Cooperative Agreement anticipates substantial programmatic involvement during performance of the project. NIAID staff will participate in, but not direct, the research to ensure that important disease targets are addressed. The Chief, Virology Branch, DMID will serve as Scientific Coordinator and will participate as a member of the research team. The Scientific Coordinator will interact with the Principal Investigators and Co-investigators in the overall research planning and in data analysis. During performance of the award, the NIAID Scientific Coordinator may provide appropriate assistance by participating in the design of research group activities; advising in the selection of sources or resources; coordinating or participating in collection and/or analysis of data; and, advising in management and technical performance. The Scientific Coordinator may assist with arrangements for the further evaluation, both in vitro and in animal models, of agents resulting from this research. However, the role of NIAID will be to facilitate and not to direct the activities. Specifically, it is presently envisioned that the NIAID will be actively engaged in the facilitation of components including assisting the awardees in: a. Collaborative participation in overall research planning and data analysis. Specifically, the NIAID Scientific Coordinator may suggest studies within the scope of the award's objectives and research activities; may present to the investigators experimental findings from published sources or from contract projects in support of these suggestions; may participate in the design of experiments; and may participate in the analysis of results. b. Provision of needed resources and information that may not be otherwise available to the investigator. This will include the facilitation of collaborations between awardee and awardees funded under other components of the Bioterrorism program to expedite application of genetic information to the development of drugs, diagnostics and vaccines. c. In the event that an awardee's research results in a procedure or a product that requires testing of a nature beyond the awardee's capabilities, the NIAID Scientific Coordinator may provide resources available to the Institute for comprehensive preclinical efficacy evaluations. d. Coordination of consultations with the Steering Committee and implementation of their recommendations which the Principal Investigator and NIAID Scientific Coordinator agree warrant action. e. Coordination of communications and collaborations, when appropriate, with other genomics and or bioterrorist research activities supported by NIAID, DoD (DARPA, USAMRIID), CDC and DoE. f. The NIAID Scientific Coordinator will organize an annual symposium in Bethesda, Maryland at which the Principal Investigators will discuss their progress. This will facilitate overall program planning and development, the evaluation of the feasibility of the attempted approaches, and will promote productive interactions among the successful applicants. The NIAID Scientific Coordinator will also ensure the participation in this symposium of investigators from other NIAID preclinical and clinical programs to provide the most relevant antiviral expertise possible to facilitate planning for future research and expedite the design and development of novel antiviral agents. 3. Collaborative Responsibilities NIAID will establish an external steering committee to provide advice to the Principal Investigator and the NIAID Scientific Coordinator on research directions. In planning research programs, the awardee will consider recommendations from the steering committee. In addition, the steering committee will make recommendations to NIAID and the awardee concerning policy for release and distribution of repository reagents. 4. 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 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. LETTER OF INTENT Prospective applicants are asked to submit, by December 15, 1999, a letter of intent that includes a descriptive title of the overall proposed research; the name, address and telephone number of the Principal Investigator; and the number and title of this RFA. In addition, the letter of intent should identify other key personnel who will be involved in the research and their institutions. Although the letter of intent is not required, is not binding, does not commit the sender to submit an application, and does not enter into the review of subsequent applications, the information that it contains allows NIAID staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to Dr. Anna Ramsey-Ewing at the address listed under INQUIRIES. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS 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 biomedical and behavioral research projects involving human subjects, unless a clear, compelling rationale, and justification are provided 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 research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research", published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994 which is available via the WWW. at: http://grants.nih.gov/grants/guide/notice-files/not94-100.html NIH POLICY AND GUIDELINES ON THE INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: It is the policy of NIH 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 was published in the NIH Guide for Grants and Contracts, March 6, 1998, and which is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html Investigators may obtain copies from these sources or from Dr. Catherine Laughlin (listed in INQUIRIES below) who may also provide additional relevant information concerning the policy. APPLICATION PROCEDURES Applicants are strongly encouraged to call NIAID program staff with any questions regarding the responsiveness of their proposed project to the goals of this RFA. Applications are to be submitted on the grant application form PHS 398 (rev. 4/98). These forms are available at most institutional offices of sponsored research; from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6700 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: grantsinfo@nih.gov and on the internet at http://grants.nih.gov/grants/funding/phs398/phs398.html For purposes of identification and processing, item 2a on the face page of the application must be marked YES and the RFA number (AI-99-015) and the words ORTHOPOXVIRUS GENOMICS AND BIOINFORMATICS must be entered on the face page. The RFA label and line 2 of the application should both indicate the RFA number. The RFA label must be affixed to the bottom of the face page. 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. The sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. Applications must be received by January 19, 2000. Applications not received as a single package on the receipt date or not conforming to the instructions contained in PHS 398 (rev. 4/98) Application Kit (as modified in, and superseded by, the special instructions below, for the purposes of this RFA), will be judged non-responsive and will be returned to the applicant. If the application submitted in response to this RFA is substantially similar to a grant application already submitted to the NIH for review, but that has not yet been reviewed, the applicant will be asked to withdraw either the pending application or the new one. Simultaneous submission of identical applications will not be allowed, nor will essentially identical applications be reviewed by different review committees. Therefore, an application that is essentially identical to one that has already been reviewed cannot be submitted in response to this RFA. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. Submit a signed, typewritten original of the application, including the checklist, and three signed, exact, single- sided 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 mail or 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 Dr. Anna Ramsey-Ewing at the address listed under INQUIRIES. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC Program Director or Principal Investigator should be included with the application. REVIEW CONSIDERATIONS Review Considerations Upon receipt, applications will be reviewed for completeness and adherence to the Special Instructions above by the NIH Center for Scientific Review and for responsiveness by NIAID staff; those judged to be incomplete will be returned to the applicant without review. Those considered to be non- responsive will be returned without review. 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. As part of the initial merit review, a process will be used by the initial review group in which all applications receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit will be discussed, assigned a priority score, and receive a second level review by the National Advisory Allergy and Infectious Diseases Advisory Council. Review Criteria 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 goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. 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 these 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 field forward. 1. Significance. Does this study address the goal of the RFA? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? 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? 3. Innovation. Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 4. Investigator. Is the investigator appropriately trained 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 scientific 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 environment or employ useful collaborative arrangements? Is there evidence of institutional support? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research o 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. AWARD CRITERIA Funding decisions will be made on the basis of scientific and technical merit as determined by peer review, program balance, and the availability of funds. The earliest anticipated date of award is September 2000. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic (research scope and eligibility) issues to: Dr. Catherine Laughlin Division of Microbiology and Infectious Diseases National Institute of Allergy and Infectious Diseases Rockledge-B Building, Room 3136 6700-B Rockledge Drive MSC 7630 Bethesda, MD 20892-7630 (zip for express mail is 20817) Telephone: (301) 496-7453 FAX: (301) 496-8030 E-mail: CL28R@NIH.GOV Direct inquiries regarding review issues; address the letter of intent to; and mail two copies of the application and all five sets of appendices to: Anna Ramsey-Ewing, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases 6700-B Rockledge Drive MSC 7616, Room 2220 Bethesda, MD 20892-7616 (zip for express mail is 20817) Telephone: (301) 435-8536 FAX: (301) 402-2638 E-mail: AR15O@NIH.GOV Direct inquiries regarding fiscal matters to: Annette Hanopole Division of Extramural Activities National Institute of Allergy and Infectious Diseases 6700-B Rockledge Drive MSC 7614, Room 2122 Bethesda, MD 20892-7614 (zip for express mail is 20817) Telephone: (301) 496-7075 Fax: (301) 480-3780 E-mail: ahanopole@niaid.nih.gov Schedule Letter of intent receipt date: December 15,1999 Application receipt date: January 19, 2000 Scientific review date: June, 2000 Advisory Council date: September, 2000 Earliest award date: September, 2000 AUTHORITY AND REGULATIONS This program is supported under authorization of the Public Health Service Act, Sec. 301 (c), Public Law 78-410, as amended. The Catalogue of Federal Domestic Assistance Citations are Sec. 93.856, Microbiology and Infectious Diseases Research, and No. 93.855 - Immunology, Allergy, and Transplantation Research. Awards will be administered under PHS grants policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems review. The Public Health Service strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-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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