Full Text AI-95-004 MATERNAL ANTIBODIES FOR PASSIVE INFANT IMMUNIZATION NIH GUIDE, Volume 23, Number 40, November 18, 1994 RFA: AI-95-004 P.T. 34 Keywords: Immunology Immune System Prenatal Factors National Institute of Allergy and Infectious Diseases Letter of Intent Receipt Date: January 15, 1995 Application Receipt Date: March 15, 1995 PURPOSE The National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) invites applications for basic studies on maternal immunization that will lead to passive, protective immunization of infants against infectious pathogens. The applications should present plans for altering the structure of antibody molecules, either by methods of protein chemistry or manipulation of antibody-encoding genes, that will (a) improve the efficiency with which antibody molecules are transported into the fetus via the placenta and/or into the newborn via breast milk; (b) prolong the metabolic half-lives of antibodies, both in mother and infant; and/or (c) improve the efficacy of antibodies to protect the infant from pathogenic microorganisms. Applications that deal with antibodies against known, critical antigens (those likely to elicit protective antibodies) of infant pathogens, or propose to identify such antigens, are of particular interest. 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), Maternal Antibodies for Passive Infant Immunization, is related to the priority areas of family planning, educational and community-based programs, maternal and infant health, HIV infection, sexually transmitted diseases, immunization and infectious diseases and clinical prevention services. 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 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. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT The mechanisms of support will be the 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; foreign applications may not request more than three years of support. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. This RFA is a one-time solicitation. 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 funds available for the total (direct and indirect) first-year costs of all awards made under this RFA will be $500,000. In Fiscal Year 1995, the NIAID plans to fund approximately three R01/R29s. The NIH is currently limiting annual inflationary increases to no more than four percent for future years of awards. 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. The National Institute of Child Health and Human Development (NICHD) is also interested in research concerned with protective immunization in infants. Applications that are of mutual interest may be given secondary assignment to the NICHD in accordance with Division of Research Grants (DRG) referral guidelines. RESEARCH OBJECTIVES Background Maternal immunization to elicit antibodies that can be transported to the fetus, and/or to the newborn via colostrum and breast milk, is an approach that has been utilized for years to prevent tetanus in infants, particularly in developing nations. Research performed in the 1950s and 1960s showed that maternal-to-fetal transfer of antibodies occurs in a variety of common domestic and laboratory animals, the exact route of transport varying with the type of placenta, the nature of the embryonic membranes and other factors. It was found that transplacental transport varies with the class of immunoglobulin, molecules of class IgG being most efficiently transported. In the case of colostrum immunoglobulins of classes IgA and IgG predominate. In recent years, there has been little additional research concerned with maternal-infant transfer of immunoglobulins except for a few studies on Fc receptors on cells of the trophoblast. Fc receptors involved in transport of immunologlobulins across gut epithelium of the infant have attracted attention recently. At the present time, NIAID supports research concerned with natural transfer of antibodies from mother to fetus and newborn, in particular: (1) maternal to fetal transfer of antibodies of different isotypes that are elicited by conjugated and unconjugated vaccines of Hemophilus influenzae type b, unconjugated pneumococcal polysaccharide vaccines, and group B streptococcal vaccines; and (2) transfer of antibodies in colostrum following maternal immunization with a subunit of respiratory syncytial virus. However, more attention is needed on methods of enhancing the efficiency of maternal-fetal and maternal-neonatal transfer of antibodies, prolonging the persistence of antibody molecules in both maternal and newborn circulation, and enhancing the efficacy of antibodies that enter the infant. In short, up-to-date approaches and methods of molecular and cellular immunology, along with progress in identifying and engineering key antigenic components of organisms responsible for infections in infants, are necessary to ensure that maternal immunization will result in protection of the newborn from infections. Research Objectives and Scope The objective of this RFA is to support basic research (in animal or human subjects) that will lead to procedures for active or passive maternal immunization to endow mothers with antibodies that: (a) persist in the maternal circulation, (b) are transported efficiently to the fetus and/or infant via the placenta and breast milk, and (c) provide strong protection against infection with microorganisms that are pathogenic in infants. Support will be provided for the development and pre-clinical testing of modified antibody molecules suitable for: (a) injection into pregnant women and efficient transfer across the placenta and into the fetus, (b) injection into lactating females and efficient transport into colostrum and thus into the newborn, and (c) oral administration to newborns and infants and efficient transport across intestinal epithelium and into the circulation. NOTE: Studies focused on the Human Immunodeficiency Virus (HIV) and its sequelae are NOT within the scope of this RFA. Progress in this area will require the application of modern molecular biology. Presumably, the combining sites of the antibody or antibody-like molecules should be derived from authentic human antibodies. Alternatively, combining sites of monoclonal murine antibodies that are minimally immunogenic in humans might be satisfactory. An example of a worthwhile approach might be the construction and expression of a gene that would encode single-chain molecules having: (a) Fv segments of heavy and light Ig chains, of the same or different epitope specificities at either end; (b) a linker segment consisting of an epitope of the key microbial antigen, or an analog of an adhesion molecule that would prevent attachment of antibody-coated microorganisms to epithelial cells. Such a molecule would require further refinement to, at least, ensure its efficiency of secretion or transplacental transfer and its non-immunogenicity. The ultimate objective of the research to be supported under this RFA is to obtain the knowledge needed to be able to prepare antibodies that are specific for key antigens of microbial pathogens and have the following properties: o are secreted into colostrum and breast milk and/or traverse the placenta with high efficiency; o possess combining sites of optimum affinity; o are microbicidal, prohibit growth of target microorganisms or interfere with their attachments (adherence) to host epithelial cells; o bear idiotopes (or introduced epitopes) that mimic one or more epitopes of the critical microbial antigen; o have prolonged metabolic half-lives both in the maternal and fetal or neonatal environment; o are, themselves, non-antigenic in humans; and o produce no harmful side-effects either in the pregnant or lactating female or in the fetus or newborn. 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 has been published in the Federal Register of March 28, 1994 (FR 59 14508-14513), 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 the program staff or contact person listed below. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by January 15, 1995, 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 NIH 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 Applications are to be submitted on the standard research grant application form PHS 398 (rev. 09/91). These application forms may be obtained from the institution's office for sponsored research or its equivalent, or from the Grants Information Office, Division of Research Grants, National Institutes of Health, 5333 Westbard Avenue, Room 449, Bethesda, Maryland 20892, telephone (301) 710-0267. 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 "MATERNAL ANTIBODIES FOR PASSIVE INFANT IMMUNIZATION" must be typed in. 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 in INQUIRIES below.) Applications that do not conform to the instructions contained in PHS 398 (rev. 09/91) application kit, will be judged nonresponsive 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) award applications must include at least three sealed letters of reference attached to the face page of the original application. FIRST applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. Applications must be received by March 15, 1994. Applications received after the receipt date will be returned without review. The Division of Research Grants (DRG) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. This does not exclude the submission of substantial revisions of an application already reviewed. These applications must, however, 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 the appendix must also 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 could be included with the application. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the NIH Division of Research Grants (DRG) and for responsiveness by NIAID staff. Incomplete and non-responsive applications will be returned to the applicant without further consideration. 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 (triage) may be used by the initial review group in which applications will be determined to be competitive or non-competitive based on their scientific merit relative to other applications received in response to the 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 and the official signing for the applicant organization will be promptly notified. The second level of review will be provided by the National Advisory Allergy and Infectious Diseases Council. Review, Council and award dates can be found in SCHEDULE, below. Review Criteria o scientific, technical, or medical significance and originality of proposed research; o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research; o qualifications and research experience of the Principal Investigator and staff, particularly, but not exclusively, in the area of the proposed research; o availability of the resources necessary to perform the research; o appropriateness of the proposed budget and duration in relation to the proposed research; o adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. The initial review group will also examine the provisions for the protection of human and animal subjects and the safety of the research environment. 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. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Joseph F. Albright, Ph.D. Division of Allergy, Immunology and Transplantation National Institute of Allergy and Infectious Diseases Solar Building, Room 4A25 6003 Executive Boulevard Bethesda, MD 20892-7640 Telephone: (301) 496-1886 FAX: (301) 402-2571 Email: JA250@NIH.GOV Carole A. Heilman, Ph.D. Division of Microbiology and Infectious Diseases National Institute of Allergy and Infectious Diseases Solar Building, Room 3B06 6003 Executive Boulevard Bethesda, MD 20892-7630 Telephone: (301) 496-5305 FAX: (301) 496-8030 Email: CH25V@NIH.GOV Direct inquiries regarding review issues, mail two copies of the application and all five sets of appendices, and mail the letter of intent to: Olivia T. Preble, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4C19 6003 Executive Boulevard Bethesda, MD 20892-7610 Telephone: (301) 496-8208 FAX: (301) 402-2638 Email: OP2T@NIH.GOV Direct inquiries regarding fiscal matters to: Mr. Carl Lucas Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4B28 6003 Executive Boulevard Bethesda, MD 20892-7610 Telephone: (301) 496-7075 Email: CL37E@NIH.GOV Schedule Letter of Intent Receipt Date: January 15, 1995 Application Receipt Date: March 15, 1995 Scientific Review Date: June 1995 Advisory Council Date: September 1995 Earliest Award Date: September 1995 AUTHORITY AND REGULATIONS The NIAID program is described in the Catalog of Federal Domestic Assistance, No. 93.855 - Immunology, Allergy and Transplantation Research. Awards for NIAID will be made under the authority 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 Public Health Service (PHS) 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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