Full Text AI-92-08 PAPILLOMAVIRUS IN VITRO CELL CULTURE SYSTEMS NIH GUIDE, Volume 21, Number 36, October 9, 1992 RFA: AI-92-08 P.T. 34 Keywords: Viral Studies (Virology) Cell Lines Chemotherapeutic Agents National Institute of Allergy and Infectious Diseases Letter of Intent Receipt Date: November 6, 1992 Application Receipt Date: December 10, 1992 PURPOSE The Antiviral Research Branch of the Division of Microbiology and Infectious Diseases (DMID), National Institute of Allergy and Infectious Diseases (NIAID), invites Cooperative Agreement applications from organizational entities willing to participate, with the assistance of the NIAID, in furthering innovative in vitro approaches to the study of papillomavirus infections and their therapeutic control. The goals of this solicitation are to stimulate the use of in vitro papillomavirus replication systems for research on (1) the events of papillomavirus replication and pathogenesis and (2) the antiviral potential of experimental therapeutic agents. 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), Papillomavirus In Vitro Cell Culture Systems, is related to the priority area of sexually transmitted diseases. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or 'Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign for-profit or nonprofit organizations, public and private, such as universities, medical colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government having adequate resources or access to resources to support papillomavirus in vitro cell culture research. Applications from minority individuals and women are encouraged. MECHANISM OF SUPPORT Support for this program will be through the cooperative agreement (U01) funding instrument. The U01 is an assistance mechanism in which NIAID programmatic involvement with the recipient during the performance of the planned activity is anticipated. The nature of NIAID program involvement is described under SPECIAL REQUIREMENTS. The awardee will be responsible for the planning, direction, and execution of the proposed project and interrelated activities. Except as otherwise stated in this RFA, the award will be administered under PHS grants policy as stated in the Public Health Service Grants Policy Statement, DHHS Publication No. (OASH) 90-50,000, revised October 1, 1991. The total project period for applications submitted in response to the present RFA may not exceed four years. This RFA is a one-time solicitation. NIAID has no plans to reissue this announcement at any future date. Future competing continuation applications will compete under the R01 mechanism with all investigator-initiated applications and will be reviewed by an appropriate DRG study section according to the customary peer review procedures for unsolicited applications. FUNDS AVAILABLE The NIAID anticipates making at least one award as a result of this request. However, the number of awards to be made is dependent upon receipt of a sufficient number of applications of high scientific merit and upon availability of funds. Although this program is provided for in the financial plans of NIAID, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. If appropriate, collaboration with other investigators or institutions is permissible. It is expected that the total direct costs for the first year for successful applications will be around $175,000. However, individual awards may be higher or lower. In general, awards will be made for a project period of up to four years. The earliest possible award date is July 1, 1993. Specific selections for awards will be made by a NIAID/DMID senior staff committee. Criteria will be scientific excellence, expertise, program balance, and cost. RESEARCH OBJECTIVES Background Papillomavirus infections are the most rapidly spreading viral sexually transmitted disease today. It is estimated that as many as 24 million people in the United States are infected with HPV. This infection not only has a serious detrimental impact on the infected individual's quality of life, but several types of the etiologic agent are almost certainly a cofactor in the development of cervical carcinoma which kills 7000 American women annually. In immunocompromised patients, warts may grow exuberantly and cause serious morbidity. In addition, recurrent respiratory papillomatosis (RRP), a fortunately rare disease believed to be acquired during passage through the birth canal of an infected mother, can be life-threatening. None of the currently available therapies, including interferon, 5-fluorouracil, cryotherapy, laser surgery and podophyllotoxin are adequate. Therefore, the NIAID made two awards in 1988 to investigators to utilize rabbit, nude mouse, and primate models of papillomavirus infections for the evaluation of experimental therapies. As a result of these studies, several compounds have been identified which appear to warrant clinical evaluation. Phase I studies of one of these, ribavirin, as a therapy for RRP have recently begun. Further preclinical study of the others, PMEG and HPMPC, members of the phosphonate family of nucleotides, are targeted for clinical studies in the near future. Although preliminary evaluations of experimental agents are performed in vitro prior to in vivo evaluation for all other DMID-supported animal models, until recently there has not been a suitable in vitro system for evaluation of anti- HPV agents. In the past few years, several research groups have developed in vitro systems in which many of the events of papillomavirus replication have been reported to occur. The availability of these systems provides an unparalleled opportunity to investigate the mechanisms of papillomavirus replication and pathogenesis at a molecular level. This basic research may also result in the identification of viral genes which are promising targets for therapeutic intervention. In addition, these systems should provide a means to evaluate the potential anti-papillomavirus activity of experimental agents and provide a rational basis for selecting agents whose activity warrants further study in the animal models. RESEARCH OBJECTIVES The research to be supported by this RFA will be focussed on the use of in vitro culture systems for studies of the multiple events of virus replication including viral DNA replication and preferably expression of late genes. The culture systems will also be used to study the effect of experimental therapeutic agents on these events. Research applications should propose an in vitro system of studying multiple replication events of papillomaviruses such as early gene expression, viral DNA replication and preferably also the expression of late genes. Applicants should also provide a description of research plans for study of compounds with therapeutic potential. SPECIAL REQUIREMENTS Terms and Conditions of Award The Cooperative Agreement mechanism involves a partnership between the recipient of the award and the NIAID. The role of the NIAID is to provide technical assistance and guidance to the Principal Investigator. The following terms and conditions pertaining to the scope and nature of the interaction will be incorporated in the Notice of Award. These agreements will be in addition to the customary programmatic and financial negotiations which occur in the administration of grants. The Terms of Award described in this section are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines; DHHS Grant Administration Regulations at 45 CFR 74; other DHHS, PHS Grant Administration Policy Statement and other NIAID administrative terms of award. Decisions regarding a change of scope of the originally funded application must be reviewed and approved by the NIAID Scientific Coordinator in accord with the PHS Grants Policy Statement. Such changes may occur due to emerging research findings of other investigators. In the event of a dispute, the decision of a three member arbitration team, described under Arbitration Procedures, will be binding. Although the NIAID Scientific Coordinator may participate in discussions on research planning and data analysis, the recipient(s) of these award(s) will be responsible entirely for the design, conduct, and analysis of their research findings. The NIAID Scientific Coordinator will not direct, nor be liable for, the awardee's research activities. The awardee will be responsible for publishing and disseminating research results. Responsibilities of the Awardee Under Cooperative Agreement assistance mechanisms, the NIH identifies general or specific program areas for support, and the performers define and implement the specific aims, objectives and approaches for their awarded project activities. The Principal Investigator defines the details for 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 the aspects of scientific and technical management of the project as specified in the Terms and Conditions of Award. The data obtained will be the property of the awardee who will retain custody of and primary rights to the data. The awardee will be responsible for: a. Project Implementation and Management The Principal Investigator is to define and implement the specific aims, objectives, and approaches for in vitro research on papillomaviruses. Specifically, the awardee will be responsible for: Defining research objectives and approaches in accord with his/her own interests and perceptions of novel and feasible approaches to conducting in vitro research on papillomavirus replication and the effects of experimental antiviral agents on the events of replication; Designing, planning, and conducting the necessary research protocols stipulated in the application; Ensuring that the results obtained are analyzed, interpreted, and published in a timely manner; Modifying research protocols as appropriate; and Providing information to the NIAID Scientific Coordinator concerning progress. b. Budget The Principal Investigator should adequately justify the requested budget for each twelve month segment. Budget planning must include such line items as personnel, major equipment, travel, etc. Trips to the NIAID must be projected once a year for the Principal Investigator and possibly one or two other key personnel, if appropriate. Meetings will be for the purpose of maintaining project cohesiveness, program and product standards, providing technical assistance and other expertise. The NIAID Scientific Coordinator will attend each meeting. Additional communications will be made by telephone or telephone conference call. c. Reporting Requirements An annual progress report is required. In addition, the awardee will keep the Scientific Coordinator apprised of experimental results on a more frequent basis when the research involves the evaluation of an experimental compound's anti-papillomavirus activity. d. Publications The Government, via the Scientific Coordinator, will have access to data generated under this cooperative agreement and may periodically review the data and progress reports. Information obtained from the data may be used by the Scientific Coordinator for the preparation of internal reports on the awardee(s)' activities. However, the awardee will retain rights to the data and timely publication is encouraged. Publication or oral presentation of work done under this agreement is the responsibility of the Principal Investigator and will require appropriate acknowledgement of NIAID support. Responsibilities of the NIAID Assistance via U01s differs from the traditional research grant. In addition to the normal programmatic and administrative stewardship responsibilities, the awarding component anticipates substantial programmatic involvement during performance of the project. Under the U01 mechanism, NIAID staff will facilitate and participate in, but not direct, the research in order to ensure that research priorities for papillomaviruses are addressed. A member of the NIAID staff will serve as Scientific Coordinator and will participate as a member of the research team. The Scientific Coordinator will be the Chief, Antiviral Research Branch, DMID. The Scientific Coordinator will interact closely with the Principal Investigator to assist with and facilitate the overall research planning and data analysis. During performance of the project the NIAID Scientific Coordinator may provide assistance by participating in the design of specific research group activities; advising in the selection of sources or resources, replacement of staff; coordinating or participating in collection and/or analysis of data; and, advising in management and technical performance. Involvement of the Scientific Coordinator comprises: a. Coordination between NIAID and Awardee. The establishment of channels of collaboration and communication is expected. Shortly after any award is made, key project personnel and NIAID staff will meet to discuss provision of NIAID technical assistance in accordance with the RFA guidelines. b. Collaborative Participation: Providing assistance in avoiding unwarranted duplication of effort; Retaining the option to suggest possible changes of direction in the research endeavors based on the acquisition, and provision to the awardee, of new information; 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; and may participate in the design of experiments, and Providing assistance, when appropriate, in designing protocols and in analysis and interpretation of research data. c. Provision of Important Information and Collaborations: Principal Investigators may not have immediate access to needed information. Therefore, NIAID will facilitate meeting these needs and ensure that the awardee(s) become active participants in the Antiviral Research Branch Preclinical Research Program. This Program consists of: (a) twelve U01 awards for research on potential molecular targets for novel antivirals and strategies for the design of new agents; (b) two N01 awards for the application of standard, well-characterized assay methodologies for the evaluation of the anti- herpesvirus and anti-respiratory virus potential of large numbers of compounds; (c) seven N01 awards for animal models of human viral infections (including papillomaviruses) that are used for evaluation of experimental therapies and research on pathogenesis; and (d) five U01 awards for studies of viral replication and pathogenesis that are targeted towards the eventual development of improved diagnostic methodologies. The interaction of the awardee(s) with other investigators in this program, as well as the consequent early receipt of data from those laboratories pursuing related research goals, will facilitate and expedite research progress. d. Provision of Needed Resources The NIAID may provide assistance by suggesting potential sources of agents for antiviral evaluation and/or facilitating the obtaining of these agents by the Principal Investigator. The specific agents to be tested will be decided upon by the Principal Investigator with assistance from the Scientific Coordinator. The application should include an estimate of how many compounds with therapeutic potential will be studied annually. e. Monitoring There shall be periodic on-site or reverse-site monitoring of the status of the Principal Investigator's research. Such visits may include discussions regarding scientific technique and methodology, review of data, review of data analysis, suggestions to improve the quality of the research, staff recruitment and training, and overall evaluation efforts. In addition, the NIAID Scientific Coordinator, as a part of the annual review process, will review the status of the research, using information obtained from site visits and the annual progress reports to justify continued funding. f. Annual Meeting The NIAID Scientific Coordinator will organize an annual symposium in Bethesda, Maryland at which the Principal Investigator(s) will discuss their progress. This symposium will include other NIAID Antiviral Research Branch-supported investigators engaged in preclinical antiviral research. This symposium will facilitate evaluation of the feasibility of the attempted antiviral approaches, and will promote productive interactions among Principal Investigators. Applicants should include funds for travel to this meeting for the Principal Investigator, and other key personnel if warranted, in their proposed budget. g. Ongoing Communication In addition to the annual symposium, the NIAID Scientific Coordinator will interact informally with each principal investigator through additional meetings, averaging once a year, at the Principal Investigator's institution or at professional scientific meetings as well as by teleconferences, regular telephone calls, and written communication. Arbitration Procedures The Terms and Conditions of Award, listed in this RFA, require that the NIAID Scientific Coordinator participate in the decision-making process concerning the continuation of an award based on successful performance of the Awardee during the planning, developmental, and implementation period of the U01. Disagreements (e.g., programmatic, technical, and evaluation) arising pursuant to these approvals will be arbitrated by an Arbitration Panel composed of one award recipient designee, one NIAID designee, and a third designee, with expertise in the relevant area, chosen by the other two. These special arbitration procedures 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 DHHS regulations at 45 CFR, Part 16. LETTER OF INTENT Prospective applicants are asked to submit, by November 6, 1992, a letter of intent that includes a descriptive title of the proposed research, and the names and affiliation(s) of proposed key investigators. The NIAID requests a letter of intent in order to provide an indication of the number and scope of applications to be received. The letter of intent does not commit the sender to submit an application, nor is it a requirement for submission of an application. The letter of intent will not enter into the review of any application subsequently submitted. It 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. Olivia Preble Chief, Microbiology and Immunology Review Section Scientific Review Branch National Institute of Allergy and Infectious Diseases Solar Building, Room 4C20 6003 Executive Boulevard Rockville, MD 20892 APPLICATION PROCEDURES Applications are to be submitted on form PHS 398 (rev. 09/91). Application kits are available at most institutional business offices, and may be obtained from: Office of Grants Inquiries, Division of Research Grants, National Institutes of Health, 5333 Westbard Avenue, Westwood Building, Room 449 Bethesda, MD 20892, telephone (301) 496-7441. The format and detail applicable to regular research grant applications must be followed. For purposes of identification and processing, mark "yes" in item 2a on the face page of the application. Also in item 2, under "number" list the RFA number, which is RFA AI-92-08, and under title type in "PAPILLOMAVIRUS IN VITRO CELL CULTURE SYSTEMS". In item 2b, "type of grant program", type in "COOPERATIVE AGREEMENT". In addition, the RFA label available in the application form PHS 398 must be affixed to the bottom of the face page and placed on top of the entire package. 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 research proposed should describe plans to accommodate the RFA research program requirements and NIAID staff involvement. The original and three copies are to be mailed or delivered to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** Two copies are to be mailed or delivered to: Dr. Olivia Preble Chief, Microbiology and Immunology Review Section Scientific Review Branch National Institute of Allergy and Infectious Diseases Solar Building, Room 4C20 6003 Executive Boulevard Rockville, MD 20892 Applicants using express mail or a courier service should change the zip code to 20852 for the Solar Building. Applications must be received by both DRG and Dr. Olivia Preble by December 10, 1992. Applications received after December 10, 1992 will be returned without review or will be sent to a DRG study section as an unsolicited R01 for that study section's next review cycle. If the application submitted in response to this RFA is substantially similar to a grant application already submitted to the NIH for review, but 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 cannot be submitted in response to this RFA that is essentially identical to one that has already been 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. REVIEW CONSIDERATIONS Applications will be received by the NIH Division of Research Grants (DRG) and will usually be assigned to NIAID. Should an application contain research plans that significantly overlap with programs of another institute, PHS Referral Guidelines will prevail in the assignment of that application. Review Procedures Applications will be reviewed by DRG for completeness and by NIAID staff to determine administrative and programmatic responsiveness to this RFA. Any application that is incomplete or does not meet the minimum requirements of this RFA will be returned to the applicant without scientific peer review. Applications considered complete and responsive to the RFA may be subjected to a triage review by an NIAID peer review group to determine their scientific merit relative to the other applications in response to the RFA. The NIAID will withdraw from competition those applications judged by the triage peer review group to be noncompetitive for award and will notify the applicant Principal Investigator and the institutional official. Those applications judged to be competitive for award will be reviewed by the standard NIH dual peer review system. The initial, or first level, review for scientific and technical merit will be conducted by the Scientific Review Branch of the Division of Extramural Activities, NIAID during February/March, 1993. The second level of review will be provided by the National Advisory Allergy and Infectious Diseases Council in June, 1993. REVIEW CRITERIA o Factors to be considered in scientific evaluation of the competitive applications include: o Originality and scientific merit of research approach, design, and methodology as well as the potential scientific, technical, or medical significance of the proposed research. There will be special interest in the advantages and limitations of proposed in vitro culture systems. o Research experience and competence of the Principal Investigator and staff to conduct the proposed studies. The experience of the Investigators with in vitro culture systems for papillomaviruses and expertise in papillomavirus molecular biology are important. o Adequacy of time/effort which the Principal Investigator and staff would devote to the proposed studies. o Adequacy of facilities and resources. o Reasonableness of proposed costs. AWARD CRITERIA While scientific merit is a prime consideration for selecting applications for award, programmatic relevance, reasonableness of proposed budget, and availability of funds also will be considered. INQUIRIES Direct inquiries relevant to the programmatic aspects of this RFA to: Dr. Catherine Laughlin Chief, Antiviral Research Branch Division of Microbiology and Infectious Diseases National Institute of Allergy and Infectious Diseases Solar Building, Room 3A-22 6003 Executive Boulevard Rockville, MD 20852 Telephone: (301) 496-8285 FAX: (301) 402-1456 Direct inquiries regarding review procedures and requirements to: Dr. Olivia Preble Chief, Microbiology and Immunology Review Section Scientific Review Branch National Institute of Allergy and Infectious Diseases Solar Building, Room 4C-20 6003 Executive Boulevard Rockville, MD 20852 Telephone: (301) 496-8208 FAX: (301) 402-2638 Direct inquiries regarding fiscal matters to: Mr. Todd Ball Grants Management Branch National Institute of Allergy and Infectious Diseases Solar Building, Room 4B-22 6003 Executive Boulevard Rockville, MD 20852 Telephone: (301) 496-7075 FAX: (301) 480-3780 Timetable Letter of Intent Receipt Date: November 6, 1992 Application Receipt Date: December 10, 1992 Review by Initial Review Group: February/March 1993 Review by NIAID Advisory Council: June 1993 Earliest Award Date: July 1, 1993 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.856, Microbiology and Infectious Diseases Research. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410; as amended. 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 Agency review. .
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