Full Text AI-94-001

IMMUNOLOGIC ENHANCEMENT OF VACCINE IMMUNOGENICITY

NIH GUIDE, Volume 22, Number 42, November 19, 1993

RFA:  AI-94-001

P.T. 34

Keywords: 
  Immunogenetics 
  Vaccine 


National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  January 15, 1994
Application Receipt Date:  March 15, 1994

PURPOSE

The Division of Allergy, Immunology and Transplantation (DAIT) and
the Division of Microbiology and Infectious Diseases (DMID) of the
National Institute of Allergy and Infectious Diseases (NIAID) invite
applications for basic, applied, or preclinical studies of molecular
immunologic methods to enhance protective responses to the antigens
of infectious pathogens of man to develop new and improved vaccines.
The NIAID seeks studies that utilize advances in immunology to
develop new targeting molecules, immunologic adjuvants, or other
technology to improve existing vaccines by making them safer or more
immunogenic and to develop new vaccines where none exist for
microbial pathogens.  Of special interest are those studies that
demonstrate the feasibility of new ideas or novel approaches and show
promise for clinical application.

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 Request
for Applications (RFA), Immunologic Enhancement of Vaccine
Immunogenicity, is related to the priority areas of diabetes and
chronic disabling diseases, and 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 and foreign,
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 institutions are not
eligible to apply for First Independent Research Support and
Transition (FIRST) (R29) Awards.  Applications from minority
individuals and women are encouraged.

MECHANISM OF SUPPORT

The mechanisms of support will be the individual research project
grant (R01) and the FIRST (R29) grant.  Multidisciplinary approaches
that involve collaborative efforts among investigators in the fields
of basic immunology, molecular biology, cell biology, biochemistry,
and infectious disease are strongly encouraged.  The total project
period for applications submitted in response to this RFA may not
exceed five years.

This RFA is a one-time solicitation.  Future competing renewal
applications will compete with all investigator-initiated
applications and will be reviewed according to customary referral and
review procedures.

FUNDS AVAILABLE

The estimated total funds (direct and indirect costs) available for
the first year of support for all awards made under this RFA will be
$2,000,000.  In Fiscal Year 1994, the NIAID plans to fund
approximately 10 R01s/R29s.   Applications may not request more than
four percent annual inflationary increases for future years.  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,
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 area of vaccine research and development has been, and continues
to be, a major priority for the NIAID, and it is the lead agency
within the National Institutes of Health (NIH) for such efforts.
Vaccines are probably the best tools ever developed for the
prevention of disease, and they are important for both disease
control and control of health care costs.  A Blue Ribbon Panel on
Vaccine Research convened by the NIAID in 1993 emphasized the
priorities of improving the safety and effectiveness of current
vaccines, as well as the development of new vaccines for diseases
where none exist including emerging infectious diseases.

Major advances in our understanding of the immune system and its
response to infectious agents have occurred in recent years. These
advances include:  characterization of the structure and function of
the T lymphocyte receptor for antigen and the numerous accessory
molecules involved in the initial signal transduction events;
identification and characterization of the numerous cytokines that
regulate immune responses; delineation of the steps involved in
antigen processing and presentation; definition and characterization
of adhesion molecules and their roles in interactions between cells
of the immune system; identification of genes that regulate the
expression and function of many immune system molecules; and, in
several infectious diseases, elucidation of the role (protective vs.
pathogenic) played by different arms of the immune response.

Research Objectives and Scope

The goal of this initiative is to increase knowledge of the cellular,
molecular, and immunologic basis of immunogenicity and to promote the
application of this knowledge to the development of new approaches,
not only to improve existing vaccines (e.g., render them safer, more
immunogenic), but also to develop new vaccines for pathogens or
diseases for which no vaccines currently exist. Studies that involve
relevant animal models of human diseases, including appropriate in
vivo testing of immunoenhancers, and studies that involve human
tissues and cells are especially encouraged.  Some examples of
relevant research topics are given below; these examples, however,
are not intended to be all-encompassing or limiting.

o  Incorporation of antigen or antigenic peptides into targeting
molecules that will more efficiently deliver them to antigen
presenting cells and/or specific lymphoid tissue

o  Manipulation of antigen processing and presentation pathways to
enhance immunogenicity

o  Modification of cytokine structure to enhance potency of the
adjuvant properties and/or to reduce undesirable or deleterious
aspects of cytokine function(s)

o  Concomitant administration of appropriate cytokines and antigens
to elicit specific effector arms (e.g., TH1 vs. TH2 lymphocytes,
immunoglobulin isotypes) of the immune system

o  Prolongation of antigen exposure by immunization with cells into
which microbial genes have been transferred.

STUDY POPULATIONS

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

NIH policy requires that applicants for NIH clinical research grants
and cooperative agreements 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 must 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 MUST be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group, together with a rationale
for its choice.  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 items 1-4 of
the Research Plan AND summarized in item 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, (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,
clinical samples which may be coded for use by the applicant but
could be identified by another source are not excluded.  Every effort
should be made and documented 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 U.S. 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.

NOTE:  Peer review groups need adequate information about the
composition of proposed study populations in all applications
involving human subjects.  To avoid delays in review of such
applications, the NIAID therefore requires that, at a minimum, the
application must contain demographic data about the clinic and/or
in-patient population from which study subjects will be drawn:
average hospital admissions per year; percentage distribution of
black/hispanic/other minority/non-minority populations; gender; etc.
Studies using non-hospital populations, such as community-based
studies, should provide similar data about populations in the area or
region from which the study subjects will be drawn.  In the absence
of current data, historical demographic information and/or previous
recruitment data for similar studies from the proposed sites should
be provided.

LETTER OF INTENT

Prospective applicants are asked to submit, by January 15, 1994, a
letter of intent that includes a descriptive title of the overall
proposed research, the name, address and telephone number of the
Principal Investigator, and the number and title of this RFA.
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. Olivia Preble at the address listed under
INQUIRIES.

APPLICATION PROCEDURES

Applications are to be submitted on the standard research grant
application form PHS 398 (rev. 09/91).  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
"IMMUNOLOGIC ENHANCEMENT OF VACCINE IMMUNOGENICITY" must be typed in.

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) 435-0714.

It is highly recommended that the Chief of the Clinical Immunology
Branch be contacted in the early stages of preparation of the
application.  (See program contact in INQUIRIES below.)

Applications must be received by March 15, 1994.  indicated in the
RFA heading and in "SCHEDULE" below.  Applications that are not
received as a single package on the receipt date or that do not
conform to the instructions contained in PHS 398 (rev. 09/91)
Application kit, will be judged non-responsive and will be returned
to the applicant.  The RFA label available in the application form
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.
FIRST (R29) applications must include at least three sealed letters
of reference attached to the face page of the original application.
FIRST (R29) applications submitted without the required number of
reference letters will be considered incomplete and 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 must also be sent to Dr. Olivia Preble 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
NIH 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 will be either returned without
review or will be referred to the DRG as unsolicited applications, to
be scheduled for initial review at the next DRG review cycle.

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 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 further 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 National
Advisory Allergy and Infectious Diseases Council.

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 investigator(s); the
adequacy of the experimental design; and the adequacy and suitability
of the facilities.

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, whenever appropriate,
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 priorities, 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:

Howard B. Dickler, M.D.
Division of Allergy, Immunology & Transplantation
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4A19
6003 Executive Boulevard
Bethesda, MD  20892
Telephone: (301) 496-7104
FAX:  (301) 402-2571

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

Olivia Preble, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C19
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-8208
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:  January 15, 1994
Application Receipt Date:       March 15, 1994
Scientific Review Date:         July 1994
Advisory Council Date:          September 1994
Earliest Award Date:            September 1994

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance, No. 93.855 - Immunology, Allergy and Transplantation
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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