Full Text HL-97-002 HUMAN ANTI-HIV MONOCLONAL ANTIBODIES IN IMMUNOTHERAPY OF HIV NIH GUIDE, Volume 25, Number 43, December 13, 1996 RFA: HL-97-002 National Heart, Lung, and Blood Institute P.T. 34 Keywords: Monoclonal Antibodies Immunotherapy AIDS Letter of Intent Receipt Date: March 17, 1997 Application Receipt Date: April 18, 1997 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. THIS RFA INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING AN APPLICATION IN RESPONSE TO THIS RFA. PURPOSE The Transfusion Medicine Scientific Research Group, Division of Blood Diseases and Resources, National Heart, Lung, and Blood Institute (NHLBI), announces the availability of a Request for Applications (RFA) on the above subject. The purpose of this initiative is to encourage the conduct of basic and applied research on the development of human anti-HIV monoclonal antibodies (mAb), the establishment of effective in vitro neutralization test systems or other assay systems for the evaluation of candidate mAb preparations prior to their use in in vivo studies, and the creation of animal model systems to evaluate their effectiveness as passive immunotherapy for prevention and treatment of HIV infection. The goal of this program is to produce sufficient quantities of mAb preparations, perhaps formulated as mixtures of mAbs or in combination with other products, for evaluation of their safety and efficacy in clinical trials. 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, Human anti-HIV Monoclonal Antibodies in Immunotherapy of HIV, is related to the priority areas of HIV infection, and immunization and infectious 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 and foreign for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of state or local governments, and eligible agencies of the Federal government. Awards in response to this RFA will be made to foreign institutions only for research of very unusual merit, need, and promise, and in accordance with PHS policy governing such awards. Minority individuals, women, and persons with disabiities are encouraged to apply. Newly independent investigators, who may wish to consult with a program representative, (see "INQUIRIES" section) are encouraged to apply. MECHANISM OF SUPPORT This RFA will use the NIH individual research project grant (R01) mechanism of support. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. The MODULAR GRANT concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The JUST-IN-TIME concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers, and Institute staff. For this RFA, funds must be requested in $25,000 direct cost modules. A maximum of eight modules ($200,000 direct costs) per year may be requested. Any necessary escalation must be included within the number of modules being requested. Only limited budget information will be required and any budget adjustments made by the Initial Review Group will be in modules of $25,000. Instructions for completing the Biographical Sketch have also been modified. In addition, Other Support information and the application Checklist page are not required as part of the initial application. If there is a possibility for an award, necessary budget, Other Support and Checklist information will be requested by NHLBI staff following the initial review. The APPLICATION PROCEDURES section of this RFA provides specific details of modifications to standard PHS 398 application kit instructions. Applicants, who will plan and execute their own research programs, are requested to furnish their own estimates of the time required to achieve the objectives of the proposed research project. Up to 5 years of support may be requested. At the end of the official award period, renewal applications may be submitted for peer review and competition for support through the regular grant program of the NHLBI. It is anticipated that support for this program will begin in September 1997. Administrative adjustments in project period or amount of support may be required at the time of the award. Since a variety of approaches would represent valid responses to this RFA, it is anticipated that there will be a range of costs among individual grants awarded. All current policies and requirements that govern the research grant programs of the NIH will apply to grants awarded in connection with this RFA. FUNDS AVAILABLE It is anticipated that for fiscal year 1997, the first year of support for this initiative, $3,000,000 total costs will be available. The award of grants pursuant to this RFA is contingent upon receipt of such funds for this purpose. It is anticipated that approximately ten to twelve new grants will be awarded under this program. Applicants may request up to five years of support. The specific number to be funded will, however, depend on the merit and scope of the applications received and on the availability of funds. Direct costs will be awarded in modules of $25,000, less any overlap or other necessary administrative adjustments. Facilities and Administrative costs (indirect costs) will be awarded based on the negotiated rates. If collaborative arrangements involve subcontracts with other institutions, Ms. Jane R. Davis of the NHLBI Grants Operations Branch (telephone: (301) 435-0166), should be consulted regarding procedures to be followed. RESEARCH OBJECTIVES Background Passive immunotherapy in the prevention of viral diseases prior to or shortly after exposure is a well-accepted procedure and is utilized in preventing infection with hepatitis B, measles, and varicella-zoster, among other viruses. Passive immunity may also play an important role in the treatment or prevention of human immunodeficiency virus (HIV) infection as suggested by a number of clinical trials utilizing antibody preparations derived from HIV-infected plasma donors. The reagents thus far utilized in animal as well as in human studies fall into one of the following categories: 1. Polyclonal antibodies: These antibody products are obtained by plasmapheresing clinically healthy asymptomatic donors who have been found to have high titer anti-p24 antibody and who are p24 antigen negative. Plasma pools are inactivated by a solvent-detergent procedure before fractionation with the cold alcohol Cohn-Oncley process. The final product is a monomeric, unfragmented, and undenatured IgG. Currently, the NHLBI is supporting the preparation of an immunoglobulin with high titers of anti-HIV antibodies, which is under evaluation in Phase III clinical trials. One trial involves the use of this HIV-specific immunoglobulin (HIVIG) to prevent the vertical transmission of the virus from HIV-infected pregnant women to their offspring. In a pilot study, the clinical usefulness of HIVIG is being evaluated in children already infected with HIV. It is unknown whether or not HIVIG or other products of this type contain adequate levels of protective antibodies to be effective either prophylactically or therapeutically. One of the drawbacks in the use of HIVIG is that large quantities of the product are needed for adult patients and the supply is quite limited. 2. Monoclonal antibodies: With the development of human mAb, the potential for passive immunization has been enhanced, as antibodies with negligible antigenicity and defined specificity can be administered in relatively small amounts to individuals infected with or at high risk for a particular infectious agent. Several anti-HIV mAbs have been produced but few have been shown to neutralize primary HIV isolates. Human mAbs offer the advantages that they can be produced in large quantities without need for plasma donors and the viral inactivation procedures currently used to treat plasma obtained from such donors. A potential problem with mAb preparations is that they possess very specific neutralization properties, and may only bind to a specific epitope of the HIV surface protein failing to neutralize viral infectivity. Thus, mixtures of several mAbs may be required in order to achieve the broad neutralizing effect needed to be clinically effective. Such a cocktail would offer the advantages of a greater range of activity against variants of HIV, and the use of appropriately selected mAbs might lead to more effective neutralization due to synergistic interaction between antibodies. 3. Immunoadhesin (CD4-IgG): This is a genetically engineered molecule containing two to four CD4 moieties associated with the heavy and/or light chains of IgG replacing the immunoglobulin variable domains. One of the advantages that a preparation of this type offers is its broad neutralizing capacity for both laboratory and primary isolates of HIV. Its half-life is significantly shorter than that of IgG, but a half-life of a few days may be adequate in a prophylactic setting. Moreover, CD4-IgG can act in synergy with human anti-HIV mAbs. Ongoing studies and the availability of this product will determine the utility of this immunoadhesin. Most of the clinical studies conducted thus far involving the use of immune plasma or HIVIG, have shown that both products are well tolerated. However, the number of patients in the studies who received these products is generally small, and are primarily adult males. Furthermore, most of the studies have been open label and the definition of clinical response to therapy differed among studies. Nevertheless, most studies have suggested some clinical benefit, either in terms of time to development of opportunistic infections or a decrease in their number as well as a trend towards increased survival. A number of the studies have shown a decrease in plasma HIV; some showed a decline in p24 antigen; some demonstrated a reduction in plasma HIV RNA; and in some studies , CD4 cell count rose. A serious obstacle to the development of these reagents for passive immunization is the lack of a reliable in vitro assay to evaluate their effectiveness. Most assays depend on the infection of mitogen-stimulated peripheral blood mononuclear cells (PBMC) and the ability of mAbs, HIVIG, etc, to inhibit infection. Results, however, are difficult to interpret due to variations in both methods among laboratories and between experiments within the same laboratory. It is as yet unclear why there is so much variation in sensitivity to neutralization. These variations are at least partially due to the use of different PBMC donors, different sensitivity of primary isolates, and differences in assay conditions. Additionally, the criteria for determining an acceptable antiviral activity or antibody level are problematic because it is not currently known what level of antibody titer or neutralizing antibody activity is likely to prevent transmission of HIV. It is postulated, however, that the infusion of a candidate antibody product should result in antibody levels and neutralizing activity that are at least as high as those found in HIV-infected individuals. Ultimately, the in vitro criteria for such products will have to be determined from the correlation between the in vitro antiviral characteristics of these preparations and their efficacy in clinical trials. Perhaps the best method for evaluating the effects of passive immunotherapy is the severe combined immune deficiency (SCID) mouse model. This model has been successfully used in the evaluation of HIVIG for pre- and post-exposure to HIV. The SCID mouse model has the potential of becoming the "gold standard" for the evaluation of candidate antibody preparations. Correlation between this in vivo system and a reliable, standardized in vitro antiviral activity would then form the basis for a product advancing to clinical trials. In summary, this initiative would support research leading to the development and evaluation of mAbs that can be used for passive immunization in the prevention and/or treatment of HIV infection in man. Research areas that are encouraged by this solicitation include assessments of in vitro assays for evaluating candidate mAbs and validating in vivo studies, characterization of the protective effect of the candidate mAbs, evaluation of the SCID mouse model, and preparation of sufficient amounts of the product to determine its safety in Phase I clinical trials. The candidate products could be mixtures of mAbs, or mixtures of mAbs with polyclonal antibodies, immunoadhesins, or other potentially effective products for passive immunotherapy. SPECIAL REQUIREMENTS Upon initiation of the program, the NHLBI will sponsor annual meetings to encourage the exchange of information among investigators who participate in this program. Travel funds for a one day meeting each year, most likely to be held in Bethesda, Maryland, should be included in the modules. Applicants should also include a statement in the applications indicating their willingness to participate in such meetings. 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 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 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 March 17, 1997, a 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, and the number and title of the RFA in response to which the application may be submitted. Such letters are requested only for the purpose of providing an indication of the number and scope of applications to be received; therefore, their receipt is usually not acknowledged. A letter of intent is not binding, and it will not enter into the review of any application subsequently submitted, nor is it a necessary requirement for the application. A faxed letter of intent may be used in place of a posted one. This letter of intent is to be mailed or FAXed to: Dr. C. James Scheirer Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, MSC 7924 Bethesda, MD 20892-7924 Telephone: (301) 435-0266 FAX: (301) 480-3541 Email: james_scheirer@nih.gov APPLICATION PROCEDURES Applications are to be submitted on the research grant application form PHS 398 (rev. 5/95). Applications kits are available at most institutional offices of sponsored research and may be obtained from the Grants Information Office, Office of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: ASKNIH@odrockm1.od.nih.gov. Use the conventional format for research grant applications and ensure that the points identified in the section on REVIEW CONSIDERATIONS are fulfilled. BUDGET INSTRUCTIONS The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD Do not complete Form Page 4 of the PHS 398 (rev 5/95). It is not required nor will it be accepted at the time of application. BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT Do not complete the categorical budget tables on Form page 5 of the PHS 398 (rev. 5/95). Only the requested total direct costs line for each year must be completed based on the number of $25,000 modules being requested. Applicants may not request a change in the amount of each module. A maximum of eight modules ($200,000) direct costs per year may be requested and each applicant may request up to five years of support for this RFA. Direct cost budgets will usually remain constant throughout the life of the project (i.e., the same number of modules requested for all budget periods). Any necessary escalation should be considered when determining the number of modules to be requested. However, in the event that the number of modules requested must change in any future year due to the nature of the research proposed, appropriate justification must be provided. Total Direct Costs for the entire Proposed Project Period should be shown in the box provided. BUDGET JUSTIFICATION - Budget justifications should be provided under "Justifications" on Form Page 5 of the PHS 398. - List the names, role on the project and proposed percent effort for all project personnel (salaried or unsalaried) and provide a narrative justification for each person based on his/her role on the project. - Identify all consultants by name and organizational affiliation and describe the services to be performed. - Provide a general narrative justification for individual categories (equipment, supplies, etc.) required to complete the work proposed. More detailed justifications should be provided for high cost items. Any large one-time purchases, such as large equipment requests, must be accommodated within these limits. CONSORTIUM/CONTRACTUAL COSTS - If collaborations or subcontracts are involved that require transfer of funds from the grantee to other institutions, it is necessary to establish formal subcontract agreements with each collaborating institution. A letter of intent from each collaborating institution should be submitted with the application. Only the percentage of the consortium/contractual TOTAL COSTS (direct and indirect) relative to the total DIRECT COSTS of the overall project needs to be stated at this time. The following example should be used to indicate the percentage cost of the consortium, "The consortium agreement represents 27 percent of overall $200,000 direct costs requested in the first year." A budget justification for the consortium should be provided as described in the "Budget Justification" section above (no Form Page 5 required for the consortium). Indicate whether the consortium will be in place for the entire project period and identify any future year changes in the percentage relative to the parent grant. If there is a possibility for an award, the applicant will be requested to identify actual direct and indirect costs for all years of the consortium. Total subcontract costs need not be calculated in $25,000 modules. However, when subcontract funds are added to the parent grant budget, the total direct cost amount must be included in the number of $25,000 modules requested. BIOGRAPHICAL SKETCH - A biographical sketch is required for all key personnel, following the modified instructions below. Do not exceed the two-page limit for each person. - Complete the educational block at the top of the form page; - List current position(s) and those previous positions directly relevant to the application; - List selected peer-reviewed publications directly relevant to the proposed project, with full citation; - The applicant has the option to provide information on research projects completed and/or research grants participated in during the last five years that are relevant to the proposed project. OTHER SUPPORT - Do not complete the "Other Support" pages (Form Page 7). Selected other support information relevant to the proposed research may be included in the Biographical Sketch as indicated above. Complete Other Support information will be requested by NHLBI staff if there is a possibility for an award. CHECKLIST - No "Checklist" page is required as part of the initial application. A completed Checklist will be requested by NHLBI staff if there is a possibility for an award. The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. Sample budgets and justification page will be provided upon request or following the submission of a letter of intent. Applications not conforming to these instructions will be considered unresponsive to this RFA and will be returned without further review. 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. The RFA label available in the PHS 398 application kit must be affixed to the bottom of the face page of the original copy of the application. 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 (HUMAN ANTI-HIV MONOCLONAL ANTIBODIES IN IMMUNOTHERAPY OF HIV) and number (HL-97-002) must be typed on line 2 of the face page of the application form and the YES box must be marked. Send or deliver the completed application and three signed, exact photocopies of it to the following, making sure that the original application with the RFA label attached is on top: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for courier/overnight service) Send an additional two copies of the application to the Chief, Review Branch, at the address listed under LETTER OF INTENT. It is important to send these two copies at the same time as the original and three copies are sent to the Division of Research Grants. Otherwise the NHLBI cannot guarantee that the application will be reviewed in competition for this RFA. Applications must be received by April 18, 1997. If an application is received after that date, it will be returned to the applicant 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. The DRG will not accept any application that is essentially the same as one already 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. Although this is a National Heart, Lung, and Blood Institute Request for Grant Applications, the National Institute of Allergy and Infectious Diseases (NIAID) also has an interest in the subject matter of this RFA. Therefore, the NIAID may be given a secondary institute assignment, if appropriate. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the DRG and responsiveness by the NHLBI. Incomplete and/or 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 view, a process 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/program director and the official signing for the applicant organization will be notified. The criteria used in the evaluation of scientific merit of each application will be similar to those used in the review of traditional research-project grant applications, including novelty, originality, and feasibility of the approach; the training experience and research competence of the investigator(s); the adequacy of the experimental design; the suitability of the facilities; and the appropriateness of the requested budget to the work proposed. The initial review group will also examine the provisions for the protection of human and animal subjects and the safety of the research environment. The personnel category will be reviewed for appropriate staffing based on the requested percent effort. The direct costs budget request will be reviewed for consistency with the proposed methods and specific aims. Any budgetary adjustments recommended by the reviewers will be in $25,000 modules. The duration of support will be reviewed to determine if it is appropriate to ensure successful completion of the requested scope of the project. AWARD CRITERIA The anticipated date of award is September 1997. Funding decisions will be made on the basis of scientific and technical merit as determined by peer review, program needs and balance, and the availability of funds. Awards in response to this RFA will be made to foreign institutions only for research of very unusual merit, need, and promise, and in accordance with PHS policy governing such awards. Designated funding levels are subject to change at any time prior to award, due to unforeseen budgetary, administrative and/or scientific developments. INQUIRIES Inquiries concerning this RFA are encouraged. Potential applicants may request a copy of sample budget pages. The opportunity to clarify any issues or questions from potential applicants is welcome. Inquiries regarding programmatic issues may be directed to: Dr. Luiz H. Barbosa Division of Blood Diseases and Resources National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 10146 Bethesda, MD 20892-7950 Telephone: (301) 435-0075 FAX: (301) 480-0868 Email: lb30o@nih.gov Direct inquiries regarding fiscal matters to: Ms. Jane R. Davis Section Grants Management Officer National Heart, Lung, and Blood Institute 6701 Rockledge Drive, MSC 7926 Bethesda, MD 20892-7926 Telephone: (301) 435-0166 FAX: (301) 480-3310 Email: jane_davis@nih.gov AUTHORITY AND REGULATIONS The programs of the Division of Blood Diseases and Resources, NHLBI, are described in the Catalog of Federal Domestic Assistance No. 93.839. Awards will be made under the authority of the Public Health Service Act, Section 301 (42 USC 241) and administered under PHS grant policies and Federal regulations, most specifically 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. 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. .
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