VACCINE AND IMMUNE THERAPY FOR ALZHEIMER'S DISEASE Release Date: December 6, 2000 RFA: AG-01-003 National Institute on Aging (http://www.nih.gov/nia/) National Institute of Neurological Disorders and Stroke (http://www.ninds.nih.gov/) Letter of Intent Receipt Date: January 16, 2001 Application Receipt Date: February 20, 2001 THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE In July of 2000 it was announced that the NIH would set aside $50 million over five years to support research on new ways to treat Alzheimer's disease, an ongoing commitment, by targeting the production of disease-associated processes, such as formation of amyloid plaques and neurofibrillary tangles with a special emphasis on the development of a vaccine to prevent the disease. This RFA is intended to assist in the development of immunological preventive and treatment strategies for Alzheimer’s disease. As part of the overall initiative, several related program announcements, with set-asides, are also being developed. It has been estimated that as many as four million Americans currently suffer from Alzheimer's disease, and failure to successfully prevent and treat the disease will result in more than a tripling of its prevalence - from four to fourteen million - over the next 50 years. Thus, the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS) invite applications for research project grants (R01) that will further the understanding of the biological, immunological and immunopathological bases for the prevention or successful removal from brain of the hallmark lesions seen in individuals with Alzheimer's disease. These are beta amyloid (Abeta)-containing deposits of plaques in the extracellular space as well as tau-containing neurofibrillary tangles (NFT) within neurons. Although the cause of the disease is still unknown, new research has shown that the prevention and treatment of Alzheimer's disease (AD) might be approached through the development of a vaccine targeted at preventing, delaying, or reversing the formation of AD-associated pathologic lesions. These recent results, using a transgenic mouse model, have suggested that immunological interventions can retard and even reverse the development of at least some of the pathologic changes associated with AD. Animal models of several autoimmune and inflammatory diseases (diabetes, experimental autoimmune encephalomyelitis and arthritis) have been successfully treated in this way. Schenk et al. were the first to show that immunization with (Abeta)- amyloid prevented, and even reversed, plaque deposition in a transgenic mouse model of AD (Schenk et al., Nature 400:173-177, 1999). Since then, two additional studies in support of the findings have been published (Bard et al., Nature Medicine, 2000; Weiner et al., Annals of Neurology, 48: 567-579, 2000). Presentations at the World Alzheimer Congress, 2000 and papers in Nature (in press) showed preliminary evidence that vaccination prevents the cognitive decline seen in other plaque-producing strains of transgenic mice (Janus et al., Neurobiology of Aging 21: S61(abstract no. 275), 2000; Morgan et al., Neurobiology of Aging 21: S18 (abstract no. 83), 2000). Based on these data, there is a pressing need to understand the immunological processes involved that appear to limit the deposition of amyloid or enhance its removal from brain; to determine whether a similar approach may be useful for removal of NFT; and to determine which process, if any, prevents the related cognitive decline. 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 Request for Applications (RFA), VACCINE AND IMMUNE THERAPY FOR ALZHEIMER'S DISEASE, 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/. 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 and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) individual research grant application (R01) mechanism. The total project period for an application submitted in response to this RFA may not exceed five years. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant or awardee. This RFA is a one-time solicitation, with an anticipated award date of September 15, 2001. Future applications for the competing continuation of successful responses to this RFA will compete with all other investigator-initiated applications and be reviewed according to the customary peer review procedures. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being used by the NIH. Complete and detailed instructions and information on Modular Grant applications can be found at: http://grants.nih.gov/grants/funding/modular/modular.htm FUNDS AVAILABLE An estimated $4,500,000 will be available for the first year of support and a total of $22,500,000 will be available over 5 years. Between 10 and 14 new awards will be made. Direct costs will be awarded in modules of $25,000 up to $300,000. Awards are contingent upon availability of funds and the receipt of a sufficient number of applications of outstanding scientific and technical merit. RESEARCH OBJECTIVES Background Both early- and late-onset AD are neurodegenerative diseases marked by overproduction of (Abeta)-amyloid (Abeta) from amyloid precursor protein (APP) with subsequent deposition of (Abeta) into extracellular plaques in regions of brain responsible for memory and cognition. In addition, there is a massive accumulation of abnormal tau filaments in NFT and considerable neuronal degeneration associated with a reactive gliosis (Pratic and Trojanowski, Neurobiology of Aging 21, 441-445, 2000). The deposition of amyloid appears to be a very early, perhaps the first, event in the pathogenesis of AD (Naslund et al., JAMA 283:1571-1577, 2000), preceding any cognitive impairment. Its presence may modulate a number of biochemical pathways that result in the deposition of still other proteins, the activation of astroglia and microglia, and eventually neuronal cell death and consequent cognitive dysfunction. Although inflammatory mediators such as interleukins and tumor necrosis factor are abundant in the brains of individuals with AD, AD pathology is unlike that seen in other diseases, such as multiple sclerosis, that are marked by the classical criteria of neuroinflammation (Raine, Neurobiology of Aging 21: 437-440, 2000). It is unclear whether or not the upregulation and localization of inflammatory mediators in or near AD plaques are solely part of a vicious cycle contributing to progression of AD pathology or whether some components may be part of a protective or reparative response. The recent evidence that an (Abeta)- elicited immune response can virtually eliminate plaque development in a mouse model of AD suggests that an immunotherapeutic approach to the treatment of AD is a possibility. Thus, the development of therapies for Alzheimer's disease that use a vaccine approach and research aimed at understanding the immunological bases for this approach are being solicited in this RFA. Based upon the limited results available thus far in an animal model of AD or in an ex vivo assay of AD brain sections, the removal of (Abeta)/amyloid from brain in response to immunization against amyloid peptide has been achieved by circulating antibody, at least in part through induction of an Fc receptor-mediated uptake and clearance of the (Abeta) by activated microglia or CNS macrophages (Bard et al., Nature Medicine 6: 916-919, 2000; Walker, Journal of Neuroimmunology 94: 127- 133, 1999). However, some role for cell-mediated immunity in this clearance process cannot be ruled out. Understanding just how closely the (Abeta)-rich plaques or other AD pathologies that develop in animal models mirror the human condition, especially with respect to the presence of inflammatory modulators, is important because the closer the model, the better the results obtained can be translated to humans. For example, circulating, local and plaque-bound cytokines, chemokines, complement and complement inhibitors (Murphy et al., Amer. J. Path. 157:895-904, 2000) have not been well studied in any of the models. For the development of truly effective AD vaccines, there is also a need to know more about the factors that control the activation and proliferation of the key cell types involved with the immune response to AD target antigens, and their effects on amyloid and NFT clearance as well as on brain and cognitive function. Thus, the widespread amyloid deposition, activation of microglia and presence of NFT in AD might be amenable to a therapeutic vaccination stratagem that is designed to prevent the deposition of (Abeta) in plaques or tau in NFT in the first place or, once present, to rid the brain parenchyma of extracellular amyloid and intracellular NFT. In this way, there may be a role for both humoral and cell-mediated immune mechanisms in the prevention and treatment of AD. Answers to the questions of exactly how the vaccine works are of paramount importance: The answers obtained through such studies will be of value both in the context of vaccine development and in providing further insight into the relationship between the immunological processes in brain and the etiology, pathogenesis, treatment and prevention of AD. They may also shed light on age-related cognitive deficits. Research Objectives and Approaches o It is anticipated that most applications submitted in response to this RFA would utilize animal model systems of AD. Any one of a number of mouse transgenic (tg) models might be used (reviewed in Emilien et al., Arch Neurol 57: 176-181, 2000). Other mouse and animal models (for example rat, dog, guinea pig or miniature pig) also could be considered. Animal models having a full range of AD pathology (plaques, tangles, neuritic dystrophy and cell death) and which also show cognitive decline would be the ideal. Applicants are encouraged to contact program staff concerning sources for in vivo models. A well-justified rationale for whatever model is selected will be essential. Analyses using any of the models could be either in vivo, ex vivo, or in vitro. Studies involving living human subjects will be considered non- responsive to this announcement. However, studies that use human autopsy materials are allowed. o The most effective protocol for induction of an effective immune response, for example route of administration, schedule of immunization, and antigen dose, as well as the means by which immunogen is delivered and, where appropriate, the choice of adjuvants o The effect of vaccination on the major outcome measures, including different behavioral tests of learning and memory that are both appropriate and adequate for a given cognitive domain o The minimal epitopes in a given antigen (e.g. (Abeta)-amyloid, tau, or other plaque constituents) to elicit cell-mediated or humoral effects o The potential role of cell-mediated immunity in protection from AD pathology o Identification of subtype and time course of humoral or cell- mediated effects o The immune-mediated mechanisms that account for inhibiting plaque deposition or facilitating its removal o The effect of age-related changes in the functional competency and constitution of the immune system, with particular emphasis on factors relevant to human subjects o In addition to protein antibodies, the development and use of novel immuno-therapeutics, for example DNA and RNA vaccines and bifunctional chimeric antibodies o Monitoring the removal of plaques or NFT and/or their constituents by in vivo imaging, brain PET tracers, CSF/serum/plasma/urine ELISAs, or mass spectrometry measures o Localization and extent of immune activation response in different brain regions, and its effects o The possible induction of tolerance in response to repeated immunization o The possible development of sensitization and autoimmune disease with non-specific effects in organ systems and other cell types o Interference with the normal function of APP or amyloid precursor-like proteins or tau o Possible negative effects of immunization and development of an immune response in brain o Effects on other tissues and intracellular pathways 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. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. LETTER OF INTENT Prospective applicants are asked to submit 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. 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 IC staff to estimate the potential review workload and to plan the review. The letter of intent is to be sent to the program staff listed under INQUIRIES by the letter of intent receipt date listed in the heading of this RFA. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. These forms are available at most institutional offices of sponsored research; from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: grantsinfo@nih.gov; and on the internet at: http://grants.nih.gov/grants/funding/phs398/phs398.html. The RFA label available in the PHS 398 (rev. 4/98) 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 sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note that this sample label is in pdf format. 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. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules. 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: PHS 398 o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to $300,000) in the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. This is not a Form page. o Under Personnel, list all project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals and organizations with whom consortium or contractual arrangements have been made, the percent effort of all personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by reviewers in the assessment of each individual's qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm - Complete the educational block at the top of the form page; - List position(s) and any honors; - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years; - List selected peer-reviewed publications, with full citations. o CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o 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. Submit a signed, original of the application 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, send two additional copies of the application to: Mary Nekola, Ph.D. Chief, Scientific Review Scientific Review Office National Institute on Aging 7201 Wisconsin Avenue, Room 2C212 Bethesda, MD 20892-9205 It is important to send these copies at the same time as the original and three copies are sent to the Center for Scientific Review. These copies are used to identify conflicts and to help ensure the appropriate and timely review of the application. 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. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by CSR and responsiveness by NIA and NINDS staff. Incomplete applications will be returned to the applicant. If the application is not responsive to the RFA, CSR staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next review cycle. 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 NIA in accordance with the review criteria stated below. As part of the initial merit review, a process may be used by the initial review group in which applications receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the National Advisory Council on Aging and the National Advisory Neurological Disorders and Stroke 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 the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. 1. Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? 2. Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? 3. Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 4. Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? 5. Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? The adequacy of the proposed protection for animals or the environment, to the extent they may be adversely affected by the project proposed in the application should be addressed. 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. Schedule: Letter of Intent Receipt Date: 01/16/2001 Application Receipt Date: 02/20/2001 Date of Initial Review: 05/07/2001 Review by Advisory Council: 08/25/2001 Anticipated Award Date: 09/15/2001 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 INQUIRIES Inquiries concerning this RFA are encouraged. Additional information, including sample budget narratives and biographical sketch, may be found at this site: http://grants.nih.gov/grants/funding/modular/modular.htm. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: D. Stephen Snyder, Ph.D. Neuroscience and Neuropsychology of Aging Program National Institute on Aging 7201 Wisconsin Avenue, Suite 3C307 MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-9350 FAX: (301) 496-1494 Email: ss82f@nih.gov Diane D. Murphy, Ph.D. Program Director Neurodegeneration Program National Institute of Neurological Disorders and Stroke Neuroscience Center, Room 2223 6001 Executive Boulevard Bethesda, MD 20892-9525 Telephone: 301/496-5680 FAX: 301/480-1080 E-mail: murphyd@ninds.nih.gov Direct inquiries regarding fiscal matters to: Ms. Linda Whipp Acting Grants Management Officer Grants and Contracts Management Office National Institute on Aging 7201 Wisconsin Avenue, Suite 2N212, MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: lw17m@nih.gov Kimberly Pendleton Grants Management Specialist Grants Management Branch, DEA Neuroscience Center, Room 3254 6001 Executive Boulevard Bethesda, MD 20892-9525 Telephone: (301) 496-9231 FAX: 301-402-0219 EMAIL: kp33e@nih.gov AUTHORITY AND REGULATIONS The NIA and NINDS programs are described in the Catalog of Federal Domestic Assistance Nos. 93.866 and 93.853. 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 and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 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.


Weekly TOC for this Announcement
NIH Funding Opportunities and Notices



NIH Office of Extramural Research Logo
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy
NIH... Turning Discovery Into Health®



Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.