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.
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