Full Text AI-94-029 PEDIATRIC AIDS: FACTORS IN TRANSMISSION AND PATHOGENESIS NIH GUIDE, Volume 23, Number 32, August 26, 1994 RFA: AI-94-029 P.T. 34, AA Keywords: AIDS Pathogenesis National Institute of Allergy and Infectious Diseases Letter of Intent Receipt Date: November 15, 1994 Application Receipt Date: February 16, 1995 PURPOSE The Division of AIDS (DAIDS) of the National Institute of Allergy and Infectious Diseases (NIAID) invites applications for research designed to study transmission and pathogenesis of HIV-1 in infants and children. Applications are sought for laboratory studies that elucidate: (1) the timing and mechanism of transmission of HIV from mother to infant or (2) factors that determine whether infected children become long-term asymptomatic survivors or suffer from rapidly progressive disease. The NIAID seeks applications for research studies that utilize advances in virology, immunology, and genetics to address these questions. Of special interest are those basic research studies that hold promise for development of clinical strategies to prevent mother-to-infant transmission of HIV-1 or to treat perinatally infected children to prolong and improve the quality of their lives. For applications proposing use of clinical specimens, documented access to an adequate number of samples to address the study hypotheses will be required. 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), Pediatric AIDS: Factors in Transmission and Pathogenesis is related to the priority areas of: HIV infection, immunization and infectious diseases, and maternal and infant health. 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 and 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 individual research project grant (R01) and the FIRST (R29) award. Multidisciplinary approaches that involve collaborative efforts among investigators in the fields of basic immunology, molecular biology, genetics, virology, and infectious disease are strongly encouraged. The total project period for an application submitted in response to this RFA may not exceed five years. This RFA is a one-time solicitation for applications for new and competing renewal awards. Future competing renewal applications will compete with all investigator-initiated applications and will be reviewed according to customary referral and 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 $2,000,000. In Fiscal Year 1995, the NIAID plans to fund approximately 12 R01s/R29s. This level of support is dependent on the receipt of a sufficient number of applications of high scientific merit. 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. 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 Mother to infant transmission of HIV continues to be one of the fastest growing aspects in the worldwide pandemic of AIDS. The World Health Organization has estimated that over 10 million children worldwide will be infected by the year 2000. In the United States, the Centers for Disease Control and Prevention estimate that 10,000 children are currently infected with HIV, and approximately 6000 infants are born annually to HIV-infected women in the U.S. The recent success in the AIDS Clinical Trials Group (ACTG) protocol 076 suggests that prevention strategies in the perinatal period may be highly efficient at decreasing mother to infant HIV-1 transmission. The ACTG 076 study indicated that women with greater than 200 CD4 cells x 106 /cc3 who initiate treatment with zidovudine (ZDV) during pregnancy can prevent transmission of HIV to their infants in about two-thirds of the cases. However, this study did not address the effectiveness of ZDV in women with less than 200 CD4 counts or who may be infected with ZDV-resistant variants. Unfortunately, other studies have indicated that women with lower CD4 counts may have an even higher likelihood of transmitting HIV to their infants. The recently initiated trial (ACTG 185) comparing HIV Immune Globulin (HIVIG) with IVIG placebo, both combined with ZDV, will include women with a wider range of CD4 counts and prior anti-retroviral therapy, but results of that trial will not be available for four to five years. In 1991, the NIAID funded a series of grants focused on two areas of basic research in Pediatric AIDS -- early diagnosis of HIV infection and studies to investigate factors involved in mother to infant transmission of HIV. These grants focused primarily on immunological and virological factors influencing mother to infant transmission and have led to many of the concepts about the mode and timing of perinatal HIV transmission. The objectives of this RFA are: to encourage coordinated basic research on the immunology, host genetics, and virology associated with perinatal HIV-1 transmission, its timing and mode, and to identify factors that appear to delay progressive manifestations of pediatric HIV-1 infection. Scope of Research Sought in this RFA The NIAID wishes to support continued research in Pediatric AIDS in the following targeted areas. o Studies attempting to define the timing of perinatal transmission relative to HIV-1 viral load and disease progression. o Coordinated studies of immunological, virological and host genetic factors that might influence perinatal HIV-1 transmission. o Studies that evaluate viral pathogenesis with a specific focus on infection of cell subsets in fetuses, neonates and young infants. o Studies that investigate oral or mucosal surfaces either as the exposure route for infants or as a source of perinatal infection by AIDS viruses. o Studies that evaluate the immunology, physiology, genetics and virology of children with long-term survival of HIV infection. These are examples of appropriate studies; other studies addressing risk for or timing of transmission of HIV-1 from mother to infant, or disease progression in the infant may be proposed. Advances in quantitative HIV culture techniques, polymerase chain reaction (PCR) detection of HIV, detection of immune complex-dissociated HIV-1 p24 antigen, and detection of HIV- specific IgA have enabled clinical research teams to rapidly and accurately identify HIV-infected children within the first several months of life. It now appears that, in the absence of breastfeeding, about half of the infants infected with HIV at or before birth can be identified at the time of birth, whereas HIV is not detected in the remaining children until one to twelve weeks after birth. These and other findings have suggested that there may be at least two modes of perinatal HIV infection and that the timing of infection (in utero versus intrapartum) may greatly affect viral load and disease progression in the infant. Stratification of data based on the time of initial detection of HIV-1 may be useful in studies of perinatal or postnatal (breastfeeding) infection. Several other issues regarding perinatal HIV transmission and pediatric AIDS have received only limited attention. Although early detection of HIV infection is possible, information about immunological and virological factors that influence perinatal transmission is still fragmentary and studies that have coordinately evaluated both immunological factors and viral factors are limited in scope. Although it is widely believed that genetic factors may play a role in susceptibility to or severity of HIV infection, only a few studies have evaluated genetic factors related to perinatal HIV transmission along with either virological or immunological parameters. Thus, studies of the host (mother and child) genetics and immune responses coordinated with HIV virology will be considered responsive to this RFA. Fetuses, neonates, and young infants may become infected by entry of the virus into their blood (across the placenta) or by exposure of mucosal surfaces to HIV-infected blood, cervical secretions, or milk. Certain viral characteristics may facilitate infection of infants by one or both of these routes. Non-syncytium inducing (NSI) variants of HIV that can replicate well in macrophages and monocytes appear to be the predominant type of HIV that has been obtained from infants in several small studies. Macrophage-tropic and/or cytopathic HIV variants might have a selective advantage in transmission, pathogenesis or evasion of immune defenses. Studies that address these topics with respect to perinatal infection will be considered responsive to this RFA. Some recent data suggest that intrapartum transmission of HIV may occur by the oral/mucosal route. Studies that coordinate virological and immunological studies of mucosal surfaces in HIV-infected infants and/or women during different stages of pregnancy are of utmost importance to resolve issues of intrapartum transmission. Studies to evaluate the specificity, function and timing of pediatric IgA responses to HIV might shed light on the route and mode of exposure in infants that become infected with HIV. Highly focused animal studies to address oral transmission and potential intervention strategies will be considered responsive to this RFA. Finally, a number of children that have become infected with HIV have led disease-free lives for more that seven years with relatively little impact upon their CD4 cell number, immune system or health. Intensified studies on immunology, physiology, genetics and virology in these children might shed light on the factors that allow successful control of HIV infection and progression to AIDS. Clinical samples, if required, may be drawn from clinical trials or ongoing natural history studies. This solicitation is not intended for direct conduct of clinical trials, patient care, or maintenance of natural history cohorts. Availability of adequate numbers of clinical samples or animal resources to address the study hypotheses MUST BE documented in the application. 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 subpopulations 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 as a separate Part VIII in the Federal Register of March 28, 1994 (59 FR 14508-14513). This was also reprinted in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Vol. 23, No. 11. Investigators may obtain copies from these sources, from program staff or from Dr. Fast or Dr. Mathieson (listed in INQUIRIES below) who may also provide additional relevant information concerning the policy. Note: Studies of mother-to-infant transmission may, by their nature, include women but not men as study subjects. The gender of their infants will be unknown to the investigator in studies beginning during pregnancy. If the population of HIV-infected women available for study is limited to, or primarily composed of, one racial or ethnic group, investigators should explain the circumstances in the application and address potential ways to overcome this limitation. LETTER OF INTENT Prospective applicants are asked to submit, by November 15, 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. Dianne Tingley at the address listed under INQUIRIES. APPLICATION PROCEDURES 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 and the words "PEDIATRIC AIDS: FACTORS IN TRANSMISSION & PATHOGENESIS" 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. It is highly recommended that the Program Officers in the Vaccine Research and Development Branch be contacted in the early stages of preparation of the application. (See program contact in INQUIRIES below.) Applications must be received by February 16, 1995. Applications that are not received by the receipt date or that do not conform to the instructions contained in PHS 398 (rev. 09/91) application kit, 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 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, three signed, exact, single-sided photocopies, and one copy of any appendix material, 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 five sets of any appendix material must be sent to Dr. Dianne Tingley at the address listed under INQUIRIES. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or Principal Investigator should be included with the application. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by DRG and for responsiveness to the RFA by NIAID staff. Incomplete applications will be returned to the applicant without further consideration. If NIAID staff find that the application is not responsive to the RFA, it will be returned without further consideration. Applications that are complete and responsive to this RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIAID. As part of the initial merit review, a process (triage) may be used by the initial review group in which the applications will be determined to be competitive or non-competitive based on their scientific merit relative to other applications received in response to this RFA. Applications judged to be competitive will be discussed and be assigned a priority score. Applications determined to be non-competitive will be withdrawn from further consideration and the principal investigator/program director and the official signing for the applicant organization will be promptly notified. The factors to be considered in the evaluation of scientific merit of each application will be those used in the review of traditional research project grant applications, including: the novelty, originality, and feasibility of the approach; the training, experience, and research competence of the investigator(s); the adequacy of the experimental design; and the adequacy and suitability of the facilities. The initial review group will also be instructed to provide an assessment of the extent to which the proposed research that might advance the fields of research specifically targeted by this RFA. While the following review factors do not usually influence the priority score, they are nonetheless carefully considered by the initial review group: the appropriateness of the requested budget to the work proposed; the adequacy of protection of human subjects and/or animals in research; and the adherence, whenever appropriate, to NIH guidelines concerning adequate representation of women and minorities in clinical research. Any documented concerns expressed by the initial review group about any of these factors on a given application 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 priorities, and the availability of funds. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. Potential applicants are welcome to seek clarification of any issues or questions. Direct inquiries regarding programmatic issues to: Bonnie J. Mathieson, Ph.D. or Patricia E. Fast, M.D., Ph.D. Division of AIDS National Institute of Allergy and Infectious Diseases Solar Building, Room 2B06 6003 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-8200 FAX: (301) 402-1506 or (301) 480-5703 Direct inquiries regarding review issues; address the letter of intent to; and mail two copies of the application and five sets of appendices to: Dianne Tingley, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4C16 6003 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-0818 FAX: (301) 402-2638 Direct inquiries regarding fiscal matters to: Ms. Carol Alderson Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4B27 6003 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-7075 FAX: (301) 480-3780 Schedule Letter of Intent Receipt Date: November 15, 1994 Application Receipt Date: February 16, 1995 Scientific Review Date: June/July 1995 Advisory Council Date: September 1995 Earliest Award Date: September 1995 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance, No. 93.856 Microbiology and Infectious Diseases Research and 93.855 Immunology, Allergy and Transplantation Research. Awards will be made under the authority of the Public Health Service Act, Title III, Section 301 (Public Law 78-410, as amended; 42 USC 241) and administered under PHS grants policies and Federal Regulations 42 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency 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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