Full Text AI-94-022 BASIC RESEARCH IN HUMAN TUBERCULOSIS NIH GUIDE, Volume 23, Number 15, April 15, 1994 RFA: AI-94-022 P.T. 34 Keywords: Pulmonary Diseases Infectious Diseases/Agents Pathogenesis Immunology Epidemiology National Institute of Allergy and Infectious Diseases Letter of Intent Receipt Date: May 20, 1994 Application Receipt Date: July 14, 1994 APPLICATIONS IN RESPONSE TO THIS RFA MUST BE PREPARED USING A MODIFIED (ABBREVIATED) GRANT APPLICATION FORMAT; SPECIFIC INSTRUCTIONS FOR COMPLETING THE APPLICATION ARE IN THE APPLICATION PROCEDURES BELOW. PURPOSE The Respiratory Diseases Branch of the Division of Microbiology and Infectious Diseases of the National Institute of Allergy and Infectious Diseases (NIAID) invites applications to conduct innovative basic research to elucidate the basic biology, immunology, epidemiology, and pathogenic mechanisms of infection with Mycobacterium tuberculosis. To better understand tuberculosis epidemiology, progression, treatment, and control, the NIAID wishes to expand research in these areas with the goals of developing rational strategies for vaccine and drug development and improving the diagnosis, treatment, and prevention of this disease. 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), Basic Research in Human Tuberculosis, is related to the priority areas of immunity, infectious diseases, and HIV infection. 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 202-782-3238). ELIGIBILITY REQUIREMENTS Research grant applications may be submitted by domestic and foreign, for-profit and non-profit organizations, public and private institutions, such as universities, colleges, hospitals, laboratories, units of State or local governments, and eligible agencies of the Federal government. Foreign institutions are not eligible to apply for First Independent Research Support and Transition (FIRST) (R29) Awards. Applications from minority individuals and women are encouraged. MECHANISM OF SUPPORT The mechanisms of support will be the NIH individual research project grant (R01) and the FIRST (R29) award. The total project period for applications submitted in response to this RFA may not exceed five years. The earliest anticipated award date is April 1995. This RFA is a one-time solicitation. Future unsolicited competing renewal applications will compete with investigator-initiated applications and be reviewed according to customary review procedures. FUNDS AVAILABLE The estimated total funds (direct and indirect costs) available for the first year of support for all awards made under this RFA will be $3,500,000. In Fiscal Year 1995, the NIAID plans to fund approximately 15 awards. Applications may not request more than four percent annual inflationary increases for future years. The usual PHS policies governing grants administration and management will apply. This level of support is dependent on the receipt of a sufficient number of applications of high scientific merit. 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. 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 On April 23, 1993, the World Health Organization declared tuberculosis a global public health emergency, an opprobrium never accorded another disease. Once believed by health officials to be contained, tuberculosis is now recognized as out of control in many parts of the world. The linkage of the tuberculosis epidemic with the AIDS epidemic and the emergence of multidrug-resistant strains of M. tuberculosis intensify the problem and present additional challenges to health officials. Without substantial measures to combat the epidemic, experts foresee a significant tragedy in both human and economic terms. More than 30 million lives will be lost to tuberculosis during the coming decade unless efforts to control its transmission and deliver effective treatment in a timely fashion are improved. Tuberculosis is responsible for an estimated 26 percent of all avoidable deaths in the 5 to 59 years age group. Most of these deaths will occur in persons aged 20 to 30 upon whom both younger and older persons rely for their support. This amplifies the economic burden of the disease. Many people in developed countries think of tuberculosis as disease that was essentially wiped out in the 1950's. Yet today, tuberculosis is a worldwide problem, not limited to developing countries nor confined by national boundaries. Most tuberculosis cases occur in developing countries where poor, crowded living conditions and inadequate nutrition contribute to the spread and susceptibility to the disease. The disease also affects developed countries. The World Health Organization has identified at least 10 industrialized countries where the number of cases of tuberculosis has increased by 5 percent to 33 percent during recent years. In the United States, an estimated 15 million people are currently infected with tuberculosis. Cases increased 20 percent during the period 1985 to 1992, and in 1992, 26,678 cases of active tuberculosis were reported to the CDC. This trend continues. Persons most likely to suffer the disease include HIV-infected persons, the homeless, chronic alcohol or drug-abusers, and those living in long-term care facilities such as nursing homes and jails. In developed countries, tuberculosis is chiefly an urban disease. Tuberculosis remains a particular burden for the Hispanic and African-American communities located in these areas. The increase of tuberculosis cases in developed countries is attributed to several causes. The most important of these include the link between tuberculosis and HIV infection and the emergence of drug-resistant strains of Mycobacterium tuberculosis. The link between HIV and tuberculosis is anticipated to be a major factor in the spread of tuberculosis. It is the only AIDS-associated infection readily transmitted to non-HIV-infected persons. Tuberculosis and HIV are synergistic. HIV infection increases the chance of primary tuberculosis and of activation of latent tuberculosis infections. Recent reports show HIV-infected tuberculosis patients may become super-infected with a second, drug-resistant tuberculosis strain, reducing the potential for cure and increasing both treatment costs and the chance of further transmission. HIV infection also accelerates the progression of tuberculosis. Tuberculosis may also be difficult to diagnose in HIV- infected persons. Thus, these individuals may remain infectious due to delayed diagnosis. The tuberculosis crisis is sharpened by the emergence of disease caused by multidrug-resistant organisms (MDR-TB). These strains may result in an essentially incurable form of the disease, capable of spread by casual contact. Outbreaks of disease caused by virulent organisms resistant to two or more of the major anti-tuberculosis drugs have occurred at several sites in the United States. These outbreaks emphasize the importance of efforts to limit spread of the disease. In 1992 in New York City, more than one-third of the strains tested were resistant to one drug and nearly one-fifth were resistant to both isoniazid and rifampin. These strains are as contagious as drug-susceptible strains. Drug-resistant tuberculosis is more difficult and vastly more expensive to treat. Patients with drug-resistant tuberculosis may remain infectious longer due to inadequate treatment. Treatment of MDR-TB infections is difficult, expensive, and often unsuccessful. Successful treatment of tuberculosis, especially MDR-TB, depends upon early diagnosis. At present, it may take as long as 13 weeks to diagnose tuberculosis and determine the antibiotic susceptibility of the organism. This information is critical to development of an effective treatment plan. Treated effectively, almost all tuberculosis patients, including HIV co-infected patients, rapidly become non-infectious. MDR-TB response to appropriate treatment is markedly improved by early diagnosis. The resurgence of tuberculosis, especially MDR-TB, poses special problems for health care workers, social workers, prison personnel, and other contacts at risk. Particularly exposed are those charged with care of patients with active disease. Research Objectives and Scope The objective of this RFA is to encourage established investigators and investigators new to TB research to pursue innovative new research in the following representative, areas: o Epidemiology of tuberculosis infection, reactivation, and reinfection to improve understanding of disease transmission o Improved understanding of genetic mechanisms (recombination, repair and replication) and of the molecular basis by which Mycobacterium tuberculosis invades target cells, avoids host defense mechanisms, causes tissue damage, and ultimately kills the host o Mycobacterium tuberculosis antigens: identification of antigens expressed within infected macrophages, and their role in enhanced cell-mediated immunity and reduced delayed-type hypersensitivity o Development of a human in vitro model system that can predict, or help to identify, potentially protective Mycobacterium tuberculosis antigens o Immunologic mechanisms and other host factors that contribute to development of primary tuberculosis o Immune modulators in regulation of T-cell response in protection, granuloma formation, and macrophage Mycobacterium tuberculosis interactions o Design of drugs for latent Mycobacterium tuberculosis infections o Characterization of molecular or metabolic targets with potential for design of new treatment and/or prophylactic agents. o Preparation of attenuated strains of Mycobacterium tuberculosis as candidate vaccines The areas outlined above are not intended to be all-inclusive. All research strategies designed to markedly improve our understanding of tuberculosis infection and pathogenesis and with the potential for improving current diagnosis, treatment, and prevention modalities will be considered. STUDY POPULATIONS 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 and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations) which have been in effect since 1990. The new policy contains some new provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research", which have been published in the Federal Register of March 9, 1994 (FR 59 11146-11151), and reprinted in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11. Investigators may obtain copies from these sources or from Dr. Foulds (listed in INQUIRIES below) who may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by May 20, 1994, 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. 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. Olivia Preble at the address listed under INQUIRIES. APPLICATION PROCEDURES Note: See Special Instructions below for Completion of Grant Applications in response to this RFA. Applications are to be submitted on the standard research grant application form PHS 398 (rev. 9/91). For purposes of identification and processing, item 2a on the face page of the application must be marked "YES" and the RFA number "AI-94-022" and the words "BASIC RESEARCH IN HUMAN TUBERCULOSIS" must be typed in. Application forms may be obtained from the institution's office for sponsored research or its equivalent and from the Office of Grants Information, Division of Research Grants, National Institutes of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892, telephone (301) 710-0267. Applications must be received by July 14, 1994. Applications that are not received as a single package on the receipt date or that do not conform to the instructions contained in PHS 398 (rev. 9/91) 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. The RFA label available in the application form PHS 398 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. FIRST (R29) applications must include at least three sealed letters of reference attached to the face page of the original application. FIRST (R29) applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. 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 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. Submit a signed, typewritten original of the application, including the checklist, and three signed, exact, single-sided photocopies, in one package to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** 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. Olivia Preble 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. SPECIAL INSTRUCTIONS FOR COMPLETION OF APPLICATIONS IN RESPONSE TO THIS RFA The NIH has recently been designated a "reinvention laboratory" by the Public Health Service. One NIH reinvention objective is to simplify and improve each stage in the grant process: application, review, award, and administration. An experiment is being conducted to determine how to reduce the administrative burden in applying for an NIH grant without compromising the information needed by the initial scientific peer review group to assess the scientific merit of the application and the reasonableness of the proposed budget. The following are specific instructions for sections of the PHS 398 (rev. 9/91) application form, which should be completed differently than usual. Some sections are modified and others in the application should not be completed for the submission of the application, but will be requested if the application receives a score in the fundable range. For all other items in the application, follow the usual instructions on pages 9-32 of the PHS 398 booklet. Form AA, Face Page: o Item 10. Inventions and Patents: Do not complete. Form DD, Page 4. Detailed Budget Page for Initial Budget Period: Complete only selected portions of the Personnel section; do NOT complete balance of this page (see Form EE, page 5 below). o Personnel. Enter Names; and for each named person, enter Role on Project and percent effort on project. Do NOT complete remainder of columns for personnel. Form EE, Page 5. Budget for Entire Proposed Project Period and Justification: o Budget. Complete the budget section for all requested years of support for all budget categories including total direct costs by year and for all years. o Justification. For the INITIAL BUDGET PERIOD, provide brief justifications only for budget items that exceed the following dollar amounts and/or meet the following criteria: - Consultant Costs: Exceeds $10,000 and/or consultant(s) are key personnel. - Equipment: Exceeds $15,000. - Supplies: Exceeds $15,000 independent of animal care costs. All animal unit purchase prices and animal care costs must be itemized. - Travel: Exceeds $5,000. - Patient Care: Exceeds $15,000. - Other Expenses: Exceeds $5,000. - Consortium/Contractual: Exceeds $10,000. o Justification. For ADDITIONAL YEARS OF SUPPORT REQUESTED, briefly justify annual changes that are more than or less than four percent increases from the preceding years. Form FF - Page 6 - Biographical Sketch: For each key investigator provide a biographical sketch that does not exceed TWO PAGES and includes the following information: o Name, Position Title, Education. Complete these sections as instructed in the PHS 398 booklet. o Research and Professional Experience. This section should be used to highlight the investigator's scientific background and experience relevant to the research proposed in this application. Completing this section in the following sequence will facilitate review of this application: - Previous research position(s) relevant to this application - Honors including: title and funding sources for all current and relevant completed research on which investigator was Principal Investigator, Co-Investigator, or Project Leader; and, membership on NIH review groups, councils, or program advisory committees and length of service on each. - Complete references including titles and all authors for peer reviewed publications representative of the investigator's research career or pertinent to the research proposed in this application. Form GG - Page 7 - Other Support: Do not complete. Information on specific levels of support will be requested by the NIAID only from applicants being considered for funding. Form HH - Page 8 - Resources and Environment: Complete selected item(s) only if proposed research requires specialized unique resources for which availability must be documented. Research Plan (Booklet Pages 19-24): Note: Items 1 - 4 may not exceed twenty (20) pages. o Item 1- Specific Aims (typically less than one page): List in priority order the broad, long range objectives of the proposed project and describe concisely and realistically the hypothesis to be tested and what the specific research described in this application is intended to accomplish. o Item 2- Background and Significance (typically 1 page): The background and significance has been established by the NIAID in setting aside funds for the release of this RFA. Use this section to describe how the proposed research will contribute to meeting the goals and objectives of the RFA and explain the rationale for the selection of the general methods and approaches proposed to accomplish the specific aims. o Items 3 - 4: Complete as instructed on pages 21-23 of the PHS 398 booklet, noting the reduced page limit stated above. The following is general guidance for information to be presented in this section: - preliminary studies pertinent to the application. - rationale for each particular set of experiments. - general methods that will be utilized. Provide specific details ONLY for those techniques that are unique, or where a significant departure from a generally accepted technique is important for the reviewers to know. - outcome measures that will be used to assess the success or failure of each set of experiments. - potential pitfalls in the experimental design and alternative studies that will be done if the proposed experiments fail. o Items 5 - 6: Complete as described on pages 22-23 of PHS 398 booklet. o Item 7 - Consultants/Collaborators: Biographical sketches should conform to the brief format described for Form FF, above. o Item 8 - Consortium, Contractual Arrangements (1 page only): Provide brief explanation (not to exceed one page) of the scientific, fiscal, and administrative arrangements made with collaborating organizations. Appendix (PHS 398 Booklet - Page 24) A maximum of five publications, manuscripts, submitted or accepted for publication, patents, invention reports may be included. Other than this change, complete as instructed. Forms II and JJ - Checklist: Do not complete. Information will be requested by NIAID only from applicants being considered for funding. If you or your business office has any questions regarding these special instructions, call, FAX, or write Dr. McGowan at the address listed under INQUIRIES. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness and adherence to the Special Instuctions above by the NIH DRG 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. Those applications that are complete and responsive may be subjected to a triage by an NIAID peer review group to determine their scientific merit relative to other applications received in response to this RFA. The NIAID will withdraw from competition those applications judged to be non-competitive for award and will notify the applicant and institutional business officials. For non-competitive applications, summary reports will be very brief and will generally highlight the major reason(s) for the non-competitive rating. Those applications judged by the reviewers to be competitive for award will be reviewed for scientific and technical merit by a review committee convened by the Division of Extramural Activities, NIAID. The second level of review will be provided by the National Advisory Allergy and Infectious Diseases Council. Review criteria for applications received in response to this RFA are generally the same as those for unsolicited applications: o Scientific, technical, or medical significance and originality of the proposed research. o Appropriateness and adequacy of the experimental approach and methodology proposed to accomplish the research. o Qualification and research experience of the Principal Investigator and staff, particularly, but not exclusively, in the area of the proposed research. o Availability of resources to carry out the proposed research. o Appropriateness of the proposed budget and duration of the project in relation to the proposed research. o Adherence, whenever appropriate, to NIH guidelines concerning adequate representation of women and minorities in clinical research. Although the following review factors do not influence the priority score, they are nonetheless carefully considered by the initial review group: o Adequacy of protection of human subjects and/or animals in research. o Biohazard issues relevant to handling infectious mycobacteria. Concerns expressed by the initial review group about any of these factors may influence the recommendation of the Advisory Council concerning funding of that 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 April 1, 1995. 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 issues to: Dr. John Foulds Division of Microbiology and Infectious Diseases National Institute of Allergy and Infectious Diseases Solar Building, Room 3B10 6003 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-5305 FAX: (301) 496-8030 E-Mail: [email protected] E-Mail (alternate): [email protected] Direct inquiries regarding the special instructions for preparation of the grant application to: Dr. John J. McGowan, Director Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 3C20 6003 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-7291 FAX: (301) 402-0369 E-Mail: [email protected] E-Mail (alternate): [email protected] 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: Olivia Preble, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4C19 6003 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-8208 FAX: (301) 402-2638 E-Mail: [email protected] Direct inquiries regarding fiscal matters to: Ms. Catherine Walker Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4B32 6003 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-7075 Schedule Letter of intent receipt date: May 20, 1994 Application receipt date: July 14, 1994 Scientific review date: October 1994 Advisory Council date: February 1995 Earliest award date: April 1, 1994 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 Citation is Sec. 93.856, Microbiology and Infectious Diseases 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 recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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