ORAL MUCOSAL VACCINATION AGAINST HIV INFECTION AND HIV-RELATED OPPORTUNISTIC PATHOGENS RELEASE DATE: October 3, 2002 RFA: DE-03-003 National Institute of Dental and Craniofacial Research (NIDCR) (http://www.nidcr.nih.gov) LETTER OF INTENT RECEIPT DATE: December 15, 2002 APPLICATION RECEIPT DATE: January 14, 2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations: PURPOSE OF THIS RFA Substantial advances have been made in understanding the immunology of oral and nasopharyngeal mucosal tissues. To capitalize on this research in the fight against AIDS, the National Institute of Dental and Craniofacial Research (NIDCR) invites applications to investigate the use of oral and nasopharyngeal mucosal immune system as a route for vaccination against HIV and associated opportunistic infections. RESEARCH OBJECTIVES Background Recent advances in the understanding of the pathogenesis of HIV and AIDS opportunistic infections provide scientific motivation that a vaccine can be developed to block or at least substantially reduce the risk or severity of disease. This is encouraging at a time when the spread of HIV occurs in approximately 40,000 people in the United States each year, and the rates of infection are climbing in certain subpopulations of individuals such as women, racial and ethnic minorities, young homosexual men, individuals with addictive disorders, and people over 50 years of age. In response to this AIDS pandemic, the NIDCR wishes to capitalize on over 50 years of support for molecular and cellular research on the immunology of oral and nasopharyngeal mucosal (ONM) tissues in order to develop vaccines against HIV and AIDS associated opportunistic oral infections. In this regard, the ONM tissues provide exceptionally easy access and have been shown to be a portal for successful delivery of vaccines against oral, respiratory, gut and systemic pathogens. Depending on route and dose, the responses to antigen delivery to the ONM tissues include local as well as systemic increases in mucosal antibodies (for example, secretory IgA in ONM fluids) and cell mediated reactions. The capacity to boost the immune responses through vaccination against opportunistic pathogens would be a medical achievement and could greatly reduce the morbidity and mortality associated with AIDS. However, the complexity of the immune response that would be needed for effective clinical protection against infection has hindered vaccine development. The basis for this RFA is derived directly from the NIH Fiscal Year 2003 Plan for HIV-Related Research, Section V, Vaccines: http://www.nih.gov/od/oar/public/pubs/fy2003/v_vaccines.pdf. Specifically, the objectives are to: i) increase scientific knowledge through basic research on protective immune responses and host defenses against HIV to facilitate the development of vaccines and other biomedical intervention strategies to prevent and or control HIV and opportunistic infections, and ii) design antigens, adjuvants, immunomodulators, and vaccine delivery methods that elicit long-lasting protective immune responses against a broad range of HIV isolates by applying findings from basic, epidemiological, and clinical research; facilitate development and preclinical evaluation of vaccine strategies in laboratory studies and animal models; and foster early and continued collaboration between academicians, other government agencies, non- government organizations, and industry in the research and development of candidate vaccines to test a broad array of vaccine concepts and combinations of different approaches for development of potential HIV and opportunistic pathogen vaccine products, including vaccines for particular populations. Applications from both individuals and groups interested in oral AIDS research are encouraged. However, team approaches to these efforts are especially encouraged in the belief that a synergistic blend of expertise and resources could advance the science more quickly. Scope Applicants are urged to review the numerous proposed strategies outlined in the NIH Fiscal Year 2003 Plan for HIV-Related Research (http://www.nih.gov/od/oar/public/pubs/fy2003/v_vaccines.pdf), and to consider approaches specifically for the development of a ONM vaccine. Some examples of research include: o Develop vectors to deliver HIV antigens directly to ONM tissues; o Develop adjuvants to improve the HIV immune response to ONM vaccines; o Define the immunogenicity of various HIV proteins in ONM tissues and characterize the pathways of antigen processing in these tissues; o Characterize the humoral and cellular immune components induced by ONM immunization that provide the greatest amount of protection against HIV or opportunistic infections; o Identify the sites (e.g., mouth, rectum, vagina) at which HIV infection is blocked following ONM immunization; o Characterize immunological memory and long-term protection following ONM immunization; o Develop passive immunization approaches to protect against oral infection and invasion of HIV or opportunistic pathogens; o Study the protective response induced by ONM immunization in conjunction with viral mutation and variation; o Determine whether clades of HIV are differentially neutralized by ONM vaccination; o Compare the immune protection and cross-protection conferred from immunization by the oral, rectal, vaginal and parenteral routes; o Develop high-throughput technology to quantify HIV or opportunistic pathogens in saliva, gingival crevicular fluid or nasal secretions to assess the effectiveness of vaccines to lower pathogen load and interrupt transmission or prevent disease progression; and, o Develop in vitro correlates of an in vivo protective immune response induced by ONM immunization as a prelude to subsequent clinical research studies. The examples listed are illustrative and not meant to be inclusive. Investigators are encouraged to propose other studies related to vaccine development in ONM tissues and to contact the research/science staff listed below to determine whether the project would be responsive to this RFA. Research on "oral" vaccines that are given by mouth and immunize other mucosal tissues, for example the intestines, is not responsive to this RFA. MECHANISM OF SUPPORT This RFA will use the NIH individual research project grant (R01) and the exploratory/developmental research grant (R21) award mechanisms. As an applicant you will be solely responsible for the planning, direction, and execution of the proposed project. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. This RFA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (see https://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. Otherwise follow the instructions for non-modular research grant applications. R21 Applications. R21 proposals should have the potential for truly groundbreaking impact. Use of this mechanism by investigators experienced in immunology who wish to explore new approaches to address basic and applied research questions related to host immunity to HIV or opportunistic pathogens is encouraged. Investigators with expertise in fields other than immunology who wish to establish new research programs in this area are also encouraged to apply. Applicants are encouraged to contact program staff for advice about choosing the appropriate grant mechanism. The objective of the R21 mechanism is to support innovative, high risk/high impact research requiring preliminary testing or development; exploration of the use of approaches and concepts new to AIDS/HIV infection; research and development of new technologies, techniques or methods; or initial research and development of data upon which significant future research may be built. Applications will be considered as high impact if they demonstrate the potential for ground- breaking, precedent-setting significance, and high risk because they either lack sufficient preliminary data to ensure their feasibility, or involve using a new model system or technique. While the R21 mechanism is intended to support innovation and high impact research, and while minimal preliminary data are expected to be described in the application, applications should clearly indicate that the proposed research and/or development is scientifically sound, that the qualifications of the investigators are appropriate, and that resources available to the investigators are adequate. FUNDS AVAILABLE The NIDCR intends to commit a total of $2,000,000 in FY2003 to fund approximately six to ten new and/or competitive continuation grants in response to this RFA. An R01 applicant may request a project period of up to four years. An R21 applicant may request a project period of up to 2 years and a budget for direct costs of up to $150,000 per year. This R21 cap may be exceeded by $25,000 to accommodate costs associated with collaborative research at another institution. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NIDCR provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if this RFA will be reissued. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. SPECIAL REQUIREMENTS Grantees will meet annually at or near NIH, Bethesda, MD, to share results, to ensure that the NIDCR has a coherent view of the advances in the field, and to have an opportunity for collective problem solving among investigators. Applicants should budget for travel in their requested budget for the principal investigator and one additional young investigator to attend this annual meeting. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: Dennis F. Mangan, Ph.D. Division of Basic and Translational Sciences National Institute of Dental and Craniofacial Research Building 45, Suite 4AN-18 Bethesda, MD 20892-6402 Telephone: (301) 594-2421 Fax: (301) 480-8318 Email: Dennis.Mangan@nih.gov o Direct your questions about peer review issues to: H. George Hausch, Ph.D. Division of Extramural Activities National Institute of Dental and Craniofacial Research National Institutes of Health Building 45, Room 4AN-44F Bethesda, MD 20892-6402 Telephone: (301) 594-2904 FAX: (301) 480-8303 Email: George.Hausch@nih.gov o Direct your questions about financial or grants management matters to: Robert L. Tarwater Division of Extramural Activities National Institute of Dental and Craniofacial Research Building 45, Room 4AN32A 45 Center Drive Bethesda, Maryland 20892-6402 Telephone: (301) 594-4800 FAX: (301) 480-8303 Email: NIDCRGMB@mail.nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NIDCR staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to Dr. Hausch at the address listed above. SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. SUPPLEMENTAL INSTRUCTIONS: R21 Applications: All application instructions outlined in the PHS 398 application kit are to be followed with the following modifications for R21 applications: 1. FACE PAGE, Item 6: Up to a total of two years of support may be requested. 2. Items a-d of the Research Plan for the R21 application may not exceed ten (10) pages, including tables and figures. The following information should be taken into account for items a, b and c: o Item a, SPECIFIC AIMS--The instructions for this section suggest that the applicant state "the hypotheses to be tested". Since some applications submitted in response to this RFA may also be design- or problem-driven (e.g., development of novel technologies), or need- driven (initial research to develop a body of data upon which future research will build), hypothesis testing per se may not be the driving force in developing such a proposal and, therefore, may not be applicable. The application should state the hypotheses, design, problem and/or need which will drive the proposed research. o Item b, BACKGROUND AND SIGNIFICANCE--In this section, it is important to identify clearly how the application addresses the specific objectives of this RFA and the purpose of the R21 mechanism. Item c, PRELIMINARY STUDIES/PROGRESS REPORT—Minimal preliminary data are required for an R21 application. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: R01 applications requesting up to $250,000 per year in direct costs and all R21 applications must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at https://grants.nih.gov/grants/funding/phs398/phs398.html includes step- by-step guidance for preparing modular grants. Additional information on modular grants is available at https://grants.nih.gov/grants/funding/modular/modular.htm. R21 Applications: Applicants may request direct costs in $25,000 modules up to a total of six modules ($150,000). This cap may be exceeded by one module ($25,000) to accommodate the facilities and administrative (F&A) costs associated with collaborative research at another institution. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. 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. The RFA label is also available at: https://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SUBMITTING AN APPLICATION TO THE NIH: Submit a signed original copy of the application, including the Checklist, and three signed, 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 copies of the application must be sent to: H. George Hausch, Ph.D. Division of Extramural Activities National Institute of Dental and Craniofacial Research National Institutes of Health Building 45, Room 4AN-44F, MSC 6402 Bethesda, MD 20892-6402 APPLICATION PROCESSING: Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) 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 CSR 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. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIDCR. 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 appropriate peer review group convened by the NIDCR in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique o 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 and assigned a priority score o Receive a second level review by the NIDCR National Advisory Council. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Your application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, you 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 your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? What will be the effect of these studies on the concepts or methods that drive this field? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your 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? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: o PROTECTIONS: The adequacy of the proposed protection for human and animals subjects, or the environment, to the extent they may be adversely affected by the project proposed in the application. o INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. o R21 APPLICATIONS: The potential for ground-breaking, precedent- setting research, with particular emphasis on novel and innovative approaches; and the potential to stimulate new concepts or approaches regarding important biomedical/behavioral problems, or provide a technique/system of wide applicability. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: December 15, 2002 Application Receipt Date: January 14, 2003 Peer Review Date: March 2003 Council Review: June 16, 2003 Earliest Anticipated Start Date: July 2003 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities. REQUIRED FEDERAL CITATIONS MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: https://grants.nih.gov/grants/guide/notice-files/not98-084.html). INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH- defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at https://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at https://grants.nih.gov/grants/stem_cells.htm and at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.121, Oral Diseases and Disorders Research and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies described at https://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke- free workplace and discourage the 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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