Full Text AI-94-011

BASIC BIOLOGY OF IMMUNE RESPONSES FOR VACCINE RESEARCH

NIH GUIDE, Volume 23, Number 6, February 11, 1994

RFA:  AI-94-011

P.T.


Keywords: 


National Institute of Allergy and Infectious Diseases
National Institute on Aging

Letter of Intent Receipt Date:  April 15, 1994
Application Receipt Date:  July 13, 1994

PURPOSE

The Division of Allergy, Immunology and Transplantation (DAIT) of the
National Institute of Allergy and Infectious Diseases (NIAID) and the
Biology of Aging Program (BAP) of the National Institute on Aging
(NIA) invite applications for basic studies designed to elucidate key
processes underlying immune responsiveness that will facilitate new
and improved approaches to vaccination for infectious diseases other
than AIDS.  There is increasing need to develop methods for achieving
protective immunity that depend on manipulating elements of the
immune system (e.g., the order, concentrations, and delivery of
cytokines).  There are numerous examples of potential vaccines that
are ineffective because of weak immunogenicity that could become
effective vaccines if properly presented to a prepared or modulated
immune system.  This Request for Applications (RFA) is intended to
spur the acquisition of knowledge necessary to efficaciously and
safely modulate elements of the immune system leading to protective
immunization against infectious diseases.

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,
Basic Biology of Immune Responses for Vaccine Research, is related to
the priority areas of diabetes and chronic disabling diseases, and to
immunization and infectious diseases. Potential applicants may obtain
a copy of "Healthy People 2000" (Full Report:  Stock No.
017-001-00474-0) or "Healthy People 2000" (Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (telephone 202-782-3238).

ELIGIBILITY REQUIREMENTS

Research grant applications may be submitted by domestic, for-profit
and non-profit organizations, public and private institutions, such
as universities, colleges, hospitals, laboratories, units of State or
local governments, and eligible agencies of the Federal government.
Foreign organizations are not eligible to apply.  Applications from
minority individuals and women are encouraged.

MECHANISM OF SUPPORT

The mechanism of support will be the Program Project (P01) grant.
Research that involves collaborative efforts among investigators in
the fields of basic immunology, molecular biology, cell biology,
biochemistry, and infectious disease is strongly encouraged.

The total project period for applications submitted in response to
this RFA may not exceed five years.  At this time, the NIAID and the
NIA are administratively limiting the duration of P01 grants to four
years; this administrative limitation may change in the future.  If
by the beginning of the last year of support, the NIAID and the NIA
have not announced their intention to readvertise the RFA, P01
incumbents who wish to recompete are strongly encouraged to contact
NIAID and NIA Program Staff concerning selection of an appropriate
research grant mechanism before reapplying.

FUNDS AVAILABLE

The estimated total funds (direct and indirect costs) available for
first year of support for all awards made under this RFA will be
$3,000,000.  In Fiscal Year 1995, the NIAID and the NIA plan to fund
approximately four P01 awards.  Applications may not request more
than four percent annual inflationary increases for future years.
Applications may not request budgets in excess of $750,000 total
costs (direct and indirect) in the first year.  An application with a
first year requested amount in excess of the above will require
written approval by senior NIAID and NIA officials via the program
officers for acceptance of the application for processing.  The usual
PHS policies governing grants administration and management will
apply.  This level of support is dependent on the receipt of a
sufficient number of applications of high scientific merit.  Although
this program is provided for in the financial plans of the NIAID and
the NIA, awards pursuant to this RFA are contingent upon the
availability of funds for this purpose.  Funding beyond the first and
subsequent years of the grant will be contingent upon satisfactory
progress during the preceding years and availability of funds.

RESEARCH OBJECTIVES

Background

The most effective procedure for managing human infectious diseases
is preventive immunization (vaccination).  Despite the remarkable
successes of vaccination in eradicating smallpox and soon,
poliomyelitis, and preventing illness and death of many millions of
children, there remain many infectious diseases that have not yielded
to vigorous attempts to develop vaccines.  Furthermore, it is
increasingly evident that successful vaccination of elderly humans is
a special problem that needs to be addressed due to the declining
competence of the immune system with age.

The generation of protective immunity depends upon a responsive
immune system.  During the last 10 years, there has been a flood of
new information in the field of immunology.  Much has been learned
about the mechanisms of defined, protein antigen processing and
presentation of key epitopes in a manner that engenders effective
immune responses.  Yet, very little is known about the antigens of
pathogenic microorganisms and how they could be presented to drive
desired types of immune responses. Similarly, a great deal is known
about subsets of T lymphocytes and the spectrum of cytokines each
subset produces, as well as about B lymphocytes and their responses
to cytokines.  Yet, relatively little is known about the
characteristics and generation of memory T and B cells which are
essential for long-lasting protective immunity.  Moreover, the
mechanisms responsible for the generation of cytotoxic T cells that
are efficient in attacking and neutralizing cells in the body that
are infected with viruses, bacteria and protozoa remain uncertain.

Research Objectives and Scope

The goal of this initiative is to further increase knowledge about
the basic structures and functions of the immune system that lead to
protective immunization against infectious diseases.  HIV infection
and its sequelae are not within the scope of this RFA. Examples of
relevant research topics are provided below.  However, the list of
examples is neither complete nor restrictive:

o  Elucidation of the events and factors that lead to selective
expression/expansion of morphologically and/or functionally
distinguishable T cell subsets;

o  Studies on the phenotypic and functional stability of T cell
subsets and control of the selective expression of cytokine genes by
subsets of T cells;

o  The morphological and/or functional characteristics of memory B
and T cells and clarification of mechanisms for generating specific
memory cells;

o  Analysis of the roles played by different types and functional
states of antigen processing/presenting cells and the cytokines they
secrete in determining the major type of immune response, the
effector mechanism expressed and/or isotypes of antibodies produced;
and

o  Studies on the basic mechanisms that are affected by immunological
adjuvants and examination of the immuno-enhancing properties of
adjuvants

All of the preceding examples represent central features of immune
responses to antigens in general.  However, they are particularly
important, at present, in devising new approaches to vaccination
against infectious, pathogenic organisms.  Applications submitted in
response to this RFA should focus on elucidating basic mechanisms
that qualitatively and/or quantitatively enhance immune responses,
both humoral and cell-mediated.  Improved understanding of approaches
to enhancing immune responses will be important not only to
immunization of healthy, young adults but the elderly as well.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements will be required to include minorities and
women in study populations so that research findings can be of
benefit to all persons at risk of the disease, disorder or condition
under study; special emphasis should be placed on the need for
inclusion of minorities and women in studies of diseases, disorders
and conditions which disproportionately affect them.  This policy is
intended to apply to males and females of all ages.  If women or
minorities are excluded or inadequately represented in clinical
research, particularly in proposed population-based studies, a clear
compelling rationale should be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues should be addressed in developing a research
design and sample size appropriate for the scientific objectives of
the study.  This information should be included in the form PHS 398
in Sections 1-4 of the Research Plan AND summarized in Section 5,
Human Subjects.

Applicants are urged to assess carefully the feasibility of including
the broadest possible representation of minority groups.  However,
NIH recognizes that it may not be feasible or appropriate in all
research projects to include representation of the full array of
United States racial/ethnic minority populations (i.e., Native
Americans (including American Indians or Alaskan Natives),
Asian/Pacific Islanders, Blacks, Hispanics).

The rationale for studies on single minority population groups should
be provided.

For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology,
prevention (and preventive strategies), diagnosis, or treatment of
diseases, disorders or conditions, including but not limited to
clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including
minorities.

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the
selected study population is inadequate, it will be considered a
scientific weakness or deficiency in the study design and will be
reflected in assigning the priority score to the application.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not award
grants or cooperative agreements that do not comply with these
policies.

LETTER OF INTENT

Prospective applicants are asked to submit, by April 15, 1994, a
letter of intent that includes a descriptive title of the overall
proposed research, the name, address and telephone number of the
Program Director, the number and title of this RFA, and a list of the
key investigators and their institution(s).  Although the letter of
intent is not required, is not binding, does not commit the sender to
submit an application, and does not enter into the review of
subsequent applications, the information that it contains allows
NIAID staff to estimate the potential review workload and to avoid
conflict of interest in the review.  The letter of intent is to be
sent to Dr. Mark Rohrbaugh at the address listed under INQUIRIES.

APPLICATION PROCEDURES

Applications are to be submitted on the standard research grant
application form PHS 398 (rev. 9/91).  These application forms may be
obtained from the institution's office for sponsored research or its
equivalent and from the Office of Grants Information, Division of
Research Grants, National Institutes of Health, 5333 Westbard Avenue,
Room 449, Bethesda, MD 20892, telephone (301) 710-0267.  For purposes
of identification and processing, item 2a on the face page of the
application must be marked "YES" and the RFA number and the words
"BASIC BIOLOGY OF IMMUNE RESPONSES FOR VACCINE RESEARCH" must be
typed in.

In preparing the application in response to this RFA, the applicant
should bear in mind the research objectives of this RFA.  P01
applications should be prepared using the guidance and instructions
provided in the NIAID Information Brochure on Program Project Grants
and Multiproject Cooperative Agreements, available from the program
staff listed under INQUIRIES.  Failure to follow these instructions
may result in delays in the review or in an incomplete application.
It is highly recommended that the program staff listed under
INQUIRIES be contacted in the early stages of preparing the
application.  Applications must be received by July 13, 1994.
Applications that do not conform to the instructions contained in PHS
398 (rev. 9/91) application kit, will be judged non-responsive and
will be returned to the applicant.

The RFA label available in PHS 398 must be affixed to the bottom of
the face page.  Failure to use this label could result in delayed
processing of the application such that it may not reach the review
committee in time for review.

Applications received after the receipt date will be returned without
review.  If the application submitted in response to this RFA is
substantially similar to a grant application already submitted to the
NIH for review, but has not yet been reviewed, the applicant will be
asked to withdraw either the pending application or the new one.
Simultaneous submission of identical applications will not be
allowed, nor will essentially identical applications be reviewed by
different review committees.  Therefore, an application cannot be
submitted in response to this RFA that is essentially identical to
one that has already been 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.

Submit a signed, typewritten original of the application, including
the checklist, and three signed, exact, single-sided photocopies, in
one package to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892

At the time of submission, two additional exact copies of the grant
application and all five sets of the appendix must also be sent to
dr. Mark Rohrbaugh at the address listed under INQUIRIES.

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the GCRC as a resource for conducting
the proposed research.  If so, a letter of agreement from either the
GCRC program director or Principal Investigator could be included
with the application.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by
the Division of Research Grants (DRG) and for responsiveness
by NIAID staff; those judged to be incomplete will be returned to
the applicant without review.  Those considered to be non-responsive
may be returned without review.

Those applications that are complete and responsive may be subjected
to a triage by an NIAID peer review group to determine their
scientific merit relative to other applications received in response
to this RFA.  The NIAID and the NIA will withdraw from competition
those applications judged to be non-competitive for award and will
notify the applicant and institutional business officials.  Those
applications judged by the reviewers to be competitive for award will
be reviewed for scientific and technical merit by a review committee
convened by the Division of Extramural Activities, NIAID.  The second
level of review will be provided by the Advisory Councils of the
NIAID and the NIA.

The factors to be considered in the evaluation of scientific merit of
each application will be those used in the review of traditional
research project grant applications, including:  the novelty,
originality, and feasibility of the approach; the training,
experience, and research competence of the investigators; the
adequacy of the experimental design; and the adequacy and suitability
of the facilities.  For program project applications, additional
review criteria are used, which are outlined in the NIAID Information
Brochure on Program Project Grants and Multiproject Cooperative
Agreements.

While the following review factors do not usually influence the
priority score, they are nonetheless carefully considered by the
initial review group:  the appropriateness of the requested budget to
the work proposed; the adequacy of protection of human subjects
and/or animals in research; and the adherence to NIH guidelines
concerning adequate representation of women and minorities in
clinical research.  Any documented concerns expressed by the initial
review group about any of these factors on a given application may
influence the recommendation of the Advisory Council concerning
funding of that application.

AWARD CRITERIA

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.

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcome.

Direct inquiries regarding programmatic issues to:

M. Michele Hogan, Ph.D.
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4A22
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-7551
FAX:  (301) 402-2571

Anna M. McCormick, Ph.D.
Biology of Aging Program
National Institute on Aging
Gateway Building, Suite 2C231
Bethesda, MD  20892
Telephone:   (301) 496-6402
FAX:  (301) 402-0010

Direct inquiries regarding review issues, address the letter of
intent to, and mail two copies of the application and the five sets
of appendices to:

Mark Rohrbaugh, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C22
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-8424
FAX:  (301) 402-2638

Direct inquiries regarding fiscal matters to:

Mr. Jeffrey Carow
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B29
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-7075

Schedule

Letter of Intent Receipt Date:  April 15, 1994
Application Receipt Date:       July 13, 1994
Scientific Review Date:         October 1994
Advisory Council Date:          February 1995
Earliest Award Date:            April 1995

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance, No. 93.855 - Immunology, Allergy and Transplantation
Research and No. 93.866 - Aging Research.  Awards will be made under
the authority of the Public Health Service Act, Title III, Section
301 (Public Law 78-410, as amended; 42 USC 241) and administered
under PHS grants policies and Federal Regulations 42 CFR Part 74.
This program is not subject to the intergovernmental review
requirements of Executive Order 12372 or Health Systems Agency
review.

.

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