MULTICENTER AIDS COHORT STUDY PATHOGENESIS RESEARCH LABORATORIES Release Date: January 8, 1999 RFA: AI-99-002 P.T. National Institute of Allergy and Infectious Diseases Letter of Intent Receipt Date: May 3, 1999 Application Receipt Date: July 13, 1999 PURPOSE The Epidemiology Branch (EB) of the Division of AIDS (DAIDS), NIAID administers a major, prospective study of HIV infection and disease. The Multicenter AIDS Cohort Study (MACS) is a study of HIV infection in homosexual and bisexual men; over 5,500 men have participated in the MACS since the initial 1984 enrollment. The purpose of this Request for Applications (RFA) is to fund separate laboratories or consortia of laboratories to study the immunologic, virologic, and other biologic determinants of disease progression; factors which mitigate HIV-mediated immune system destruction; and factors which might protect individuals from acquiring HIV infection among participants in the Multicenter AIDS Cohort Study (MACS). The work to be accomplished requires collaborative, multidisciplinary expertise in HIV virology, immunology, and immunopathogenesis which must be applied in a highly coordinated manner to adequately address the issues of interest. Therefore, proposed studies should utilize a multidisciplinary approach in which the research plans are well integrated, composed of two or more laboratories, at the same or different institutions specializing in different scientific disciplines. 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 RFA, Multicenter AIDS Cohort Study Pathogenesis Research Laboratories, is related to the priority areas of HIV infection immunization and infectious diseases, and sexually transmitted diseases. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). 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 four 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 Approximately $1,750,000 will be available for funding the total costs, both direct and indirect, for the initial year of awards made pursuant to this RFA. NIAID anticipates making 3 awards (maximum $500,000 to $600,000 total costs each) as a result of this RFA. The issuance of the final awards will be dependent upon receipt of applications of high scientific merit that cover the range of scientific objectives and upon the availability of funds. The usual PHS 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 The MACS is supported by the EB, DAIDS, NIAID. Studies of HIV-related malignancy in the MACS are co-funded by the NCI. The MACS was created in 1983 as a study of HIV infection in homosexual and bisexual men; over 5,500 men have been enrolled in the MACS since 1984. The remarkable dedication of MACS participants and MACS site study staff has resulted in a high retention rate with a loss to follow-up of less than 20% among HIV-infected men after ten years. MACS study sites are located at Johns Hopkins University, Baltimore, MD; The University of Pittsburgh, Pittsburgh, PA; The Howard Brown Memorial Clinic/Northwestern University, Chicago, IL; and the University of California at Los Angeles in Los Angeles, CA. The Center for the Analysis of MACS Data (CAMACS) is located at Johns Hopkins University in Baltimore, MD. In 1995, two MACS Pathogenesis research laboratories were funded to investigate HIV pathogenesis using MACS specimens and data. These laboratories are located at Johns Hopkins University, Baltimore, MD and the University of California at Los Angeles in Los Angeles, CA. Because of the continuing unique scientific contributions of this large prospective, multi-site cohort study, the NIAID, through a separate funding mechanism, intends to renew support for the MACS to follow selected study participants for clinical and laboratory outcomes and to collect specimens for pathogenesis research. The selected participants to be followed will include: 1) all HIV- seropositive men who were enrolled in the study as seroprevalent cases or who have seroconverted while in the study, 2) HIV- seronegative men at high risk of HIV acquisition based on behavioral assessments, and 3) a matched subset of seronegative men who are at lower risk of HIV infection. The NIAID currently plans to follow these MACS participants from the present time through at least 2005. Since 1984, MACS investigations have covered a broad spectrum of research relating to HIV infection and disease. These studies have included: 1) Clinical effects of therapy, trends in survival, and trends in HIV-related clinical events, including opportunistic infections and HIV-related malignancies; 2) Correlation of host immune responses to the development of HIV disease; 3) Use of plasma HIV-1 RNA (viral load) as a CD4+ T cell-independent predictor of outcome following HIV-1 seroconversion; 4) Use of intrinsic viral factors, including HIV phenotype and sequence variation, in determining disease outcome; 5) Identification of polymorphisms in chemokine receptors that correlate with susceptibility to HIV infection and progression to AIDS; 6) Epidemiologic and laboratory correlates of HIV-related malignancy (funded through an Interagency Agreement with the National Cancer Institute); 7) HIV-related neuropsychological outcomes and neuro-pathological events; 8) Trends in the patterns of health service utilization throughout the course of HIV infection. MACS data have shown that the median time from infection with HIV to development of AIDS is approximately 10 years, although this time period for individuals is highly variable. A small proportion of the cohort participants who seroconverted in the study developed AIDS and died within two or three years of HIV infection, while others have maintained stable, high CD4+ cell counts for more than six years following HIV infection. To date, plasma HIV RNA levels are the single most important predictor of disease progression. Additional studies of host immunologic, virologic, genetic, and other determinants of HIV infection and disease progression are needed however, to gain a better understanding of what mediates the plasma HIV RNA levels and its contribution to the pathogenesis of HIV/AIDS. This information is crucial for the development of effective therapies for HIV/AIDS and design of vaccines against HIV infection. Accordingly, the NIAID is encouraging intensive broad-based laboratory studies including "state of the art" and innovative approaches to the study of host and viral factors that contribute to the pathogenesis of HIV infection and disease. The MACS research infrastructure offers a unique focus for study of HIV pathogenesis including: 1) A sixteen year prospective cohort study with well documented longitudinal clinical and laboratory outcomes data of HIV infection and disease; 2) A repository of clinical specimens of serum, plasma, and PBMCs that cover the natural history of HIV infection and disease; 3) Extensive clinical, epidemiologic, and statistical expertise within the MACS infrastructure that will be available to assist in the design and analysis of the laboratory studies; 4) Extensive expertise in human genetics, particularly the effect of various polymorphisms on susceptibility to infection and disease progression via a special collaboration between the MACS and the Laboratory of Genomic Diversity (LGD), NCI (Stephen O'Brien, Principal Investigator) Approximately 1,800 men were found to be HIV-seropositive upon initial enrollment in 1984-1985; an additional 350 HIV- seropositive men were enrolled from 1987- 1991. Over 450 of the seronegative men have seroconverted while being followed in the MACS. Approximately seventy men displayed no CD4+ cell loss despite at least nine years of HIV infection, and without receipt of antiretroviral therapy, although the CD4 counts of many of these men have demonstrated decline during extensive follow-up. On the other end of the spectrum, at least twenty men have rapidly developed immunodeficiency disease, developing AIDS within three years of documented seroconversion. Other potentially important variants from the classical pattern of HIV-mediated CD4+ cell decline have been documented among HIV-infected MACS participants, including persons remaining clinically stable for long periods despite very low CD4+ cell counts. Additionally, the MACS follows at least 250 men who did not become infected with HIV despite a history of high- risk sexual behavior. MACS participants are followed at the clinical centers at six month intervals, where they respond to a detailed health questionnaire, receive a physical examination, and have blood specimens taken. Blood specimens are processed and stored as frozen serum, plasma, and cells in the NIAID AIDS Specimen Repository. These stored specimens will be made available to the MACS Pathogenesis Research Laboratories. In addition, arrangements may be made with the MACS sites via the NIAID Program Officer to prospectively collect samples of blood and other body fluids and tissues, such as semen and lymph nodes, for specific MACS pathogenesis protocols. Availability of these additional specimens will be contingent on study feasibility and obtaining local institutional review board approval and necessary informed consent. To design valid tests of hypotheses on the pathogenesis of HIV, it will be crucial to select appropriate case and control groups. The continually expanding MACS database with its breadth of clinical, behavioral, and laboratory variables will enable the selection of the relevant nested case and control groups for this purpose. MACS biostatisticians and epidemiologists who have developed the comprehensive MACS database will be available to provide vital assistance in specimen selection and design of these laboratory-based studies. Moreover, the ongoing clinical and epidemiologic investigations in the MACS will likely generate new questions and opportunities for laboratory investigations of HIV pathogenesis. However, for the purposes of your response to this RFA, please submit completely designed study protocols. Further information regarding the MACS research infrastructure, cohort organization, sample sizes, MACS publications bibliography, specific characteristics of MACS participants (e.g., men who are rapid progressors, seroconverters, slow progressors, exposed to HIV but uninfected), specific features of the stored specimens (e.g., numbers, types, prior experience with quality of stored cells), and specific aspects of the collaboration between MACS and the LGD will be provided to all RFA requesters upon receipt of a letter of intent. Research Objectives and Scope Applications are invited from investigators to conduct laboratory investigations on the pathogenesis of HIV infection using clinical specimens available from the MACS. The proposed studies should emphasize close integration of the immunologic, virologic, and other biological investigations being planned. Preference will be given for studies of high scientific merit for which the cohort research approach is essential, including effective utilization of the unique MACS database and the MACS-derived specimens stored at the NIAID AIDS Specimen Repository. Examples of research areas that would be responsive to the RFA are listed below. Highly innovative and creative approaches concerning the study of HIV pathogenesis in MACS participants, are encouraged. o Humoral antibody responses (e.g., binding, neutralizing, enhancing, ADCC), cell-mediated responses (e.g., cytotoxic T cell activity, T helper responses), and nonspecific immune responses or immunoregulatory events (e.g., lymphokine secretion, natural killer cell activity, apoptosis) that may mediate or protect against immune system destruction or other HIV-related pathology, including characterization of the pattern of responses in the various stages of HIV infection and identification of the specific epitopes of HIV involved. o Viral variables associated with HIV pathogenesis (e.g., HIV phenotype, viral load, pattern of sequence variation during infection). o Viral variables associated with latent reservoirs (e.g.; tropism, chemokine receptor usage, cytopathicity, resistance to antiretroviral agents). o Definition of the size, turnover rate, and immunologic and virologic characteristics of latent cellular reservoirs for HIV-1, particularly viral reservoirs that persist in patients on HAART and development of an experimental system of identifying stimuli that could be used to mobilize latent reservoirs for elimination. o Host and viral factors that may explain long-term clinical stability sometimes noted in subjects with low CD4+ cell counts. o Immunologic and virologic factors associated with non-infection despite continual high risk sexual behavior. (Note: These experiments may be planned utilizing the approximately 250 HIV-seronegative MACS participants with a history of high risk sexual behavior and the 30 discordant couple pairs followed in the MACS). o Other host factors that enhance viral replication, HIV pathogenesis, (e.g., studies of histopathology, immune dysregulation, etc.) during the course of HIV infection from initial infection through development of disease. SPECIAL REQUIREMENTS A. Cooperation, Collaboration and Meetings The MACS Pathogenesis Research Laboratories will propose and conduct the relevant studies in collaboration with the MACS research infrastructure. As work progresses, the Principal Investigators may seek input from the MACS and the NIAID Program Officer regarding design and implementation of studies. Therefore, to be considered responsive to this RFA, an applicant must include a statement of willingness to work in close cooperation and collaboration with the MACS research infrastructure, whenever this is indicated. The Principal Investigators of the MACS Pathogenesis Research Laboratories will be responsible for the scientific conduct of these collaborative studies. The Principal Investigators of the MACS clinical sites and CAMACS will be responsible for the quality of the data and specimens obtained from cohort participants. The NIAID Program Officer will be responsible for facilitating collaborations between the MACS Pathogenesis Research Laboratories, MACS clinical sites, CAMACS and will have the final authority for release of the study specimens from the NIAID AIDS Specimen Repository. For more information, refer to "Terms and Conditions of Awards." The Principal Investigators of the MACS Pathogenesis Research Laboratories will serve as members of the Executive Advisory Committee (EAC) of the MACS. This participation will facilitate integration and coordination of the collaborative pathogenesis research within the MACS. The MACS EAC membership includes Principal Investigators of the clinical sites and CAMACS, the NIAID Program Officer, and the NCI Associate Program Officer. The EAC has monthly conference calls and meets approximately three times yearly, either in the Rockville, MD area or in conjunction with national HIV/AIDS scientific meetings. Senior investigators of the MACS Pathogenesis Research Laboratories are also expected to participate as committee members of the MACS Laboratory Research Working Group (LRWG). This group, which includes the senior investigators in the MACS clinical site laboratories, has regular conference calls and two annual meetings per year that are usually held at one of the MACS clinical sites. In addition, each senior investigator of the MACS Pathogenesis Research Laboratories will be expected to attend and present data at the Annual Research Meeting of the MACS which is held in the Rockville, MD area. Applicants should include in their application a statement of their willingness to participate in the required meetings described above and should include funds for these meetings in their budget requests. Note that one of the EAC and one of the LRWG meetings will be held in conjunction with the annual research meeting of the MACS. B. Specimens MACS specimens for the conduct of studies undertaken by the MACS Pathogenesis Research Laboratory(s) will be provided from the NIAID AIDS Specimen Repository. Fresh blood and body fluid specimens, and biopsy and necropsy tissue specimens, will be made available to the MACS Pathogenesis Research Laboratories according to the needs of specific protocols. In special cases when specimens are no longer available from the NIAID AIDS Specimen Repository, (e.g., due to their prior usage) replacement specimens may be obtained through the MACS Principal Investigators with approval of the MACS Executive Advisory Committee. Applicants to this RFA should be aware that the MACS Pathogenesis Research Laboratories will not have sole access to MACS specimens in the NIAID AIDS Specimen Repository. MACS specimens also will be made available to independent investigators upon review and approval of requests for specific research purposes. NIAID program staff will be responsible for ensuring that research conducted with these specimens complements but does not duplicate research in other NIAID sponsored laboratories. Applicants for this RFA also should note that core laboratory studies are conducted by the MACS clinical site laboratories, including quantitation of CD4+ and CD8+ T cell subsets, plasma HIV RNA levels on all MACS participants, and HIV serology on all seronegative MACS participants. These data are included in the general MACS epidemiologic and clinical laboratory database and are available for research sponsored under this proposal, in collaboration with the MACS clinical sites, CAMACS, and NIAID staff, through the MACS Executive Advisory Committee as detailed below. A list of the specific assays and studies to be performed by the MACS core laboratories is available from the Program Officer (address listed under "INQUIRIES"). C. Reporting, Access to Data, and Publication of Research Findings In addition to the reporting currently required of all awardees of traditional NIH research project grants, the following apply: 1. A summary of the progress of the research supported by this cooperative agreement shall be sent annually to the NIAID Program Officer. 2. Drafts of all manuscripts resulting from this cooperative agreement shall be sent to the Program Officer at the time of their circulation to co-authors. A copy of all published articles also shall be sent to the NIAID Program office. Program staff will have access to all study protocols and data generated under this cooperative agreement. Information obtained from the data may be used by NIAID for the preparation of internal reports on MACS activities. Awardees will retain rights to the data (see below). All MACS Pathogenesis Research Laboratory data that requires analysis with other MACS data will be submitted to CAMACS. These laboratory data will remain the intellectual property of the awardee from which they originated, even following submission to CAMACS, and will not be used without the permission of the Principal Investigator of the specific MACS Pathogenesis Research Laboratory which generated these data. Data forms and software for transferring laboratory data to CAMACS will be developed by CAMACS with the technical assistance of the grantee. Publication policies for data involving collaborative epidemiologic, clinical, genetic or statistical work will be established with the EAC to ensure fair and equitable participation of other MACS investigators in the research activities and publication of results. Applicants to this RFA should understand that the MACS epidemiologic and clinical laboratory database is a support component shared by all of the participating sites. Therefore the use and publication of material derived from the overall MACS database will be governed by policies established by the EAC, within the guidelines outlined above. When MACS Pathogenesis Research Laboratory data are derived from minimally characterized specimens (e.g., date, patient age, general clinical status) it will not be necessary to involve the EAC in the publication considerations. In any case, notification of the work in progress must be made to NIAID program officials and to the EAC to ensure that inappropriate or unintentional duplications of effort do not occur. Publication or oral presentation of work performed under this agreement must include appropriate acknowledgment of NIAID support. TERMS AND CONDITIONS OF AWARD Consistent with the concept of a cooperative agreement, the dominant role and prime responsibility for the activity resides with the awardee(s) for the project as a whole, although specific tasks and activities in carrying out the studies will require consultation with, or assistance from the NIAID Program Officer. 1. Awardee Rights and Responsibilities The Principal Investigators of the MACS Pathogenesis Research Laboratories under this RFA will be responsible for the overall conduct of the studies performed at the Principal Investigator's institution or at the subcontracting laboratories within a proposed consortium. This responsibility includes the production of high quality data and the analysis and publication of the research results. Applicant institutions are reminded that adequate protection for human subjects in research is an essential requirement of the NIH. The investigators in the laboratories or laboratory consortia supported under this grant will be utilizing specimens obtained from human subjects in an NIAID-sponsored clinical study, making this concern applicable to the primary grant recipient as well as the subcontractees. As a condition of award, not as a condition of application, applicants are required to demonstrate approval of the research plan by an Institutional Review Board (IRB) or an equivalent oversight body. Applicants will be notified if additional information is required on this matter. 2. NIAID Rights and Responsibilities The NIAID Program Officer and NIAID staff will have substantial scientific- programmatic involvement during conduct of this activity, through technical assistance, advice, and coordination above and beyond normal program stewardship for grants, as described below: The NIAID staff will assist the Principal Investigators of the MACS Pathogenesis Research Laboratories selected under this RFA through a Program official who will be designated by the DAIDS. The NIAID Program Officer will have overall responsibility to ensure the scientific and technical integrity of the project on behalf of the Institute. The role of NIAID will be to facilitate and not to direct the activities of the laboratory investigators funded through this cooperative agreement. NIAID will support and facilitate the research efforts of the laboratory or laboratories selected under this RFA in the following ways: a) by providing assistance and coordination in overall research planning, data gathering methodologies, analysis, and reporting; b) by providing the assistance of the MACS data center (CAMACS) to support the grantee or grantees in areas including statistical and data collection, analysis, and publication; c) by ensuring that coordination of communication and facilitation of information exchange occur between the laboratory or laboratories selected under this RFA and the MACS clinical sites, the MACS EAC, CAMACS and the LGD; d) by releasing relevant MACS specimens from the NIAID AIDS Specimen Repository. 3. Arbitration Any disagreement that may arise on scientific/programmatic matters within the scope of the award, between award recipients and NIAID, may be brought to arbitration. An arbitration panel will be composed of three members -- one selected by the MACS Executive Advisory Committee (or by the individual awardee in the event of an individual disagreement), a second member selected by the NIAID, and a 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 PHS regulations at 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16. INCLUSION OF WOMEN, MINORITIES, AND CHILDREN IN CLINICAL RESEARCH STUDY POPULATIONS Ordinarily, for projects involving clinical research, NIH requires applicants to give special attention to the inclusion of women, minorities and children in study populations. However, the MACS is a study of homosexual and bisexual men, including men of minority racial and ethnic background. Hence, a specific justification for the absence of women and children in this study need not be provided. Seven hundred and fifty men of minority background were enrolled in the MACS from 1984-1985. An additional 432 minority men were enrolled in the MACS from 1987- 1991 in a targeted effort to enroll men from minority backgrounds in the study. Five hundred and seventy one men of minority background continue to be followed in the MACS; 299 of these men are HIV-seropositive. Applicants are encouraged to include proposals for research projects which best utilize the relatively limited specimens available from minority MACS participants. BIOHAZARD AND BIOSAFETY PROCEDURES Applicants should ensure and document that adequate procedures are in place for avoidance of biohazards and enhancing of biosafety. The following reference is available from the Occupational Safety and Health Branch, NIH Division of Safety, telephone 301-496-2960: Richmond JY, McKinney RW, eds. Biosafety in Microbiological and Biomedical Laboratories, 1993. Washington, DC: US Department of Health and Human Services, Public Health Service. HHS Publication no. (CDC) 93-8395. LETTER OF INTENT Prospective applicants are asked to submit, by the date listed under "SCHEDULE" below, a short letter of intent that includes a descriptive title of the proposed research; the name, address, and telephone number of the Principal Investigator; the identities of other key personnel and participating institutions (if applicable), and the number and title of the RFA in response to which the application may be sent. The letter of intent does not commit the sender to submit an application, is not a requirement for submission of an application, and will not enter into the review of subsequent applications. The information contained in the letter will be used to allow NIAID staff to estimate the number and scope of applications to be reviewed, and to help avoid conflict of interest in the review process. The letter of intent is to be sent to Dr. Dianne Tingley at the address listed under INQUIRIES. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 4/98). Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, email: GrantsInfo@nih.gov. Application kits are also available at: https://grants.nih.gov/grants/forms.htm 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. 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. Applications must be received by July 13, 1999. 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. 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. 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 contacts under INQUIRIES). SPECIAL APPLICATION INSTRUCTIONS. Because of the anticipated complexity of applications, the page limit for the Research Plan (sections a-d) is increased to 30 pages. Submit a signed, typewritten original of the application, 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/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. Dianne Tingley at the address listed under INQUIRIES. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the Center for Scientific Review and for responsiveness by NIAID staff. Incomplete and/or non- responsive applications will be returned to the applicant 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 in accordance with the review criteria stated below. As part of the initial merit review, a process will be used by the initial review group in which applications receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the National Advisory Allergy and Infectious Diseases Council. Review Criteria The goals of NIH-supported research are to advance the 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 an important problem? 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, collaborative arrangements, 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 proposed work 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? 6. Evidence of adequate quality assurance of laboratory assays. The proposal should include discussions of sensitivity, specificity, and reproducibility of proposed assays, or how these will be studied if the proposed assays are in the early developmental phases. The proposal should also describe appropriate positive and negative controls to be used in each assay. External performance evaluation procedures that will be done on panels of well characterized specimens should be described. To ensure objectivity in laboratory assays, the NIAID AIDS Specimen Repository will provide blinded specimens on instruction by NIAID staff. 7. Previous research productivity. Does the applicant have experience in design, evaluation and interpretation of data derived from cohort specimens? Have previous publications from the applicant critically impacted knowledge of HIV pathogenesis and development of treatment strategies? 8. Willingness to collaborate with MACS epidemiologic, clinical, and biostatistical investigators through the MACS EAC and LRWG. The initial review group will also examine: the appropriateness of proposed project budget and duration; the adequacy of plans to include minorities and their subgroups as appropriate for the scientific goals of the research and plans for the recruitment and retention of subjects; the provisions for the protection of human and animal subjects; and the safety of the research environment. AWARD CRITERIA It is anticipated that up to three MACS Pathogenesis Research Laboratories will be selected under a cooperative agreement through this RFA. Although not a requirement for selection, it is anticipated that awardees will develop a consortium with other laboratories to complement the research activities intended under this RFA. The number of awards and the specific amount to be awarded will depend on the merit and scope of the applications received and on the availability of funds. 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. Patricia D'Souza Division of AIDS National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 2C05 Bethesda, MD 20892 Telephone: (301) 496-8379 FAX: (301) 402-3211 Email: PD6N@ NIH.GOV Direct inquiries regarding review issues, address the letter of intent to, and mail two copies of the application and five sets of appendices to: Dr. Dianne Tingley Division of Extramural Activities National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 4C01 Bethesda, MD 20892 Telephone: (301) 496-2250 FAX: (301) 402-2638 Email: dt15g@nih.gov Questions regarding administrative policy and fiscal matters may be addressed to: Ms. Ann Devine Grants Management Branch National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 4B22 Bethesda, MD 20892 Telephone: (301) 496-5601 FAX: (301) 480-3780 Email: ad22x@nih.gov For express/courier services applicants should use: Rockville, MD 20852 Schedule Letter of Intent Receipt Date: May 1, 1999 Application Receipt Date: July 13, 1999 Anticipated Award Date: March 1, 2000 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Nos. 13.85 and 13.855. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99- 158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 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. The PHS 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.
Return to NIH Guide Main Index
Office of Extramural Research (OER) |
National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892 |
Department of Health and Human Services (HHS) |
||||||||
Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files. |