Full Text PA-97-101
 
BASIC MECHANISMS OF VACCINE EFFICACY
 
NIH Guide, Volume 26, Number 29, August 29, 1997
 
PA NUMBER:  PA-97-101
 
P.T.


Keywords: 

 
National Institute of Allergy and Infectious Diseases
National Institute of Dental Research
National Institute on Aging
National Institute of Child Health and Human Development
 
PURPOSE
 
The National Institute of Allergy and Infectious Diseases (NIAID),
the National Institute of Dental Research (NIDR), the National
Institute on Aging (NIA), and the National Institute of Child Health
and Human Development, National Institutes of Health (NIH), invite
applications that utilize basic knowledge of antigen presentation
pathways, lymphocyte activation and immunoregulation to define
fundamental principles of vaccine efficacy. Innovative studies are
sought to develop vaccination strategies applicable for broad classes
of pathogens or to define approaches to direct specific immune
responses in order to enhance vaccine effectiveness for infectious
pathogens.  Applications submitted in response to Program
Announcements are assigned according to established PHS referral
guidelines.  When the subject of an application is of interest to
more than one component of NIH, dual assignments are made.
 
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 Program
Announcement (PA), BASIC MECHANISMS OF VACCINE EFFICACY, is related
to the priority areas of Immunization and Infectious Diseases, HIV
Infection and Maternal and Infant Health.  Potential applicants may
obtain a copy of "Healthy People 2000" (Full Report: Stock No.
017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through
the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-512-1800).
 
ELIGIBILITY
 
Applications may be submitted by 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.  Domestic and foreign
institutions are eligible to apply for R01 grants.  Foreign
institutions are not eligible for First Independent Research Support
and Transition (FIRST) Awards (R29). Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to
apply as Principal Investigators.
 
MECHANISMS OF SUPPORT
 
Traditional research project grant (R01) and FIRST award (R29)
applications may be submitted in response to this announcement.
Applications for R01 grants may request up to five (5) years of
support; applications for R29 grants must request five years of
support.  Responsibility for the planning, direction, and execution
of the proposed research for all applicable mechanisms of support
will be solely that of the applicant.
 
RESEARCH OBJECTIVES
 
Background
 
Vaccination has proved to be enormously successful in combating a
number of infectious diseases, yet attempts to produce effective
vaccines for certain pathogenic viruses, bacteria, fungi, or
parasites have been unsuccessful. The specific nature of the pathogen
determines the type of immune response required for successful
elimination and prevention of disease. Many currently used vaccines
elicit antibody responses that provide effective protection.
However, antibodies are not effective against certain microorganisms,
such as tuberculosis, malaria, hepatitis C or the human
immunodeficiency virus (HIV), and T cell-dependent cytotoxic
responses may be required to prevent disease.
 
Recent advances in basic immunology have demonstrated that different
antigen presentation pathways are utilized for the stimulation of CD4
and CD8 T cell subsets, which then mediate different functional
activities. Furthermore, the types of cytokines produced by activated
T cells determine the types of immune responses that will result. The
cytokine profile that is induced depends on the local cytokine
milieu, on the antigen concentration and on the types of
costimulatory signals provided by the antigen-presenting cells. A
dominance of type-2 cytokines, such as IL-4 or IL-10, results in
strong antibody responses of certain isotypes, whereas type-1
dominance, characterized by IFN-gamma or TNF-alpha, results primarily
in cell-mediated cytotoxicity. This diversity in immune functional
responses is essential for natural protection against a broad
spectrum of pathogenic agents and offers the potential for
manipulating the immune system to induce more effective immunity to
particular pathogens.
 
In conjunction with the recently enhanced ability to identify
immunogenic epitopes by molecular and biochemical techniques,
application of the basic principles of antigen presentation,
lymphocyte activation, cytokine regulation and mechanisms of
cytotoxicity should provide novel and predictable approaches for the
development of more effective vaccines.
 
Research Objectives and Scope
 
Innovative research applications are sought that use the current
wealth of knowledge of the immune system to define basic and general
principles of vaccine efficacy. This PA is NOT intended to support
the identification of specific pathogen antigens or descriptive
studies on protection against particular pathogens. Rather, the
emphasis is focused on studies to elucidate basic mechanisms of
immune protection by vaccination protocols that may be applied to a
variety of antigen systems.  Projects should address key issues at
the basis of vaccine function; accordingly, employment of relevant
microbial systems and utilization of models that will facilitate
application of principles to eventual clinical studies in humans are
especially encouraged.  Examples of research topics of interest
include, but are not limited to, the following:
 
o  The mechanistic basis of adjuvant activity, and the design of
novel adjuvants based upon functional principles;
o  Elucidation of the basic causes of vaccine failure, such as T cell
receptor antagonism and age-related deficiencies in responses; and
novel approaches to counteract these problems;
o  Immunological memory related to vaccine composition, form, and
delivery; for example, memory responses to different microbial
polysaccharides;
o  Basic mechanisms of epitope dominance and their impact on vaccine
design;
o  Methodologies to target immunogens to specific antigen presenting
cells and antigen-processing pathways for enhancement of protective
responses;
o Genetic basis for variability in immune responsiveness to vaccines;
o  Mechanisms of unique antigenic and immunogenic properties of novel
vaccine vectors, including nucleic acid, viral or microbial vectors;
and
o  Design of effective vaccination approaches for non-peptide
immunogens, including lipids, carbohydrates, and other types of
antigens not readily addressable by genetic vectors.
 
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS
 
It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification are
provided that inclusion is inappropriate with respect to the health
of the subjects or the purpose of the research.  This policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43).
 
All investigators proposing research involving human subjects should
read the "NIH Guidelines for Inclusion of Women and Minorities as
Subjects in Clinical Research", which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513) and the NIH
Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994.
 
Investigators may obtain copies from these sources or from the
program staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.
 
APPLICATION PROCEDURES
 
Applications are to be submitted on the grant application form PHS
398 (rev. 5/95) and will be accepted on the standard application
deadlines as indicated on the application kit.  Application kits are
available at most institutional offices of sponsored research and may
be obtained from the Division of Extramural Outreach and Information
Resources, National Institutes of Health, 6701 Rockledge Drive, MSC
7910, Bethesda, MD 20892-7910, telephone (301) 435-0714, email:
asknih@odrockm1.od.nih.gov.
 
For purposes of identification and processing, item 2 on the face
page of the application must be marked "YES".  The PA number and the
PA title, "BASIC MECHANISMS OF VACCINE EFFICACY," must also be typed
in section 2.
 
The completed, signed original and five (5) legible, single-sided
copies of the application must be sent or delivered to:
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817-7710 (for express/courier service)
 
R29 APPLICANTS ONLY.  R29 applications must include at least three
(3) sealed letters of reference attached to the face page of the
original application.  FIRST applications submitted without the
required number of reference letters will be considered incomplete
and will be returned without review.
 
GCRC INSTITUTIONS
 
Applicants from institutions that have a General Clinical Research
Centers (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the Center as a resource for
conducting the proposed research.  If so, a letter of agreement from
the GCRC Program Director must be included in the application
material.
 
REVIEW CONSIDERATIONS
 
Review Procedures
 
Applications will be assigned on the basis of established PHS
referral guidelines. Upon receipt, applications will be reviewed for
completeness by the NIH Division of Research Grants. Incomplete
applications will be returned to the applicant without further
consideration.
 
R01 and R29 applications will be reviewed for scientific and
technical merit by study sections of the Division of Research Grants,
NIH, in accordance with the standard NIH peer review procedures.  As
part of the initial merit review, all applications will 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
appropriate national advisory council.
 
Review Criteria
 
The five criteria to be used in the evaluation of grant applications
are listed below.  To put those criteria in context, the following
information is contained in instructions to the peer reviewers.
 
The goals of NIH-supported research are to advance our understanding
of biological systems, improve the control of disease, and enhance
health.  The reviewers will comment on the following aspects of the
application in their written critiques 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 by the reviewers in assigning the overall
score and 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 a 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 of 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 initial review will also examine: the appropriateness of proposed
budget and duration; the adequacy of plans to include both genders
and minorities and their subgroups as appropriate for the scientific
goals of the research and plans for the recruitment and retention of
subjects; the provisions for the protection of human and animal
subjects; and the safety of the research environment.
 
AWARD CRITERIA
 
Applications will compete for available funds with all other
favorably recommended applications.  The following will be considered
when making funding decisions: quality of the proposed project as
determined by peer review, program balance among research areas of
the announcement, and availability of funds.
 
INQUIRIES
 
Written and telephone inquiries are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.
 
Inquiries regarding programmatic (research scope and eligibility)
issues may be directed to:
 
Charles Hackett, Ph.D.
Chief, Molecular and Structural Immunology Section
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases Solar Building,
Room 4A23
6003 Executive Blvd.
Bethesda, MD 20892-7640
Telephone: (301) 496-7551
FAX:  (301) 402-2571
EMAIL:  ch187q@nih.gov
 
Dennis F. Mangan, Ph.D.
Division of Extramural Research
National Institute of Dental Research
Building 45, Room 4AN-32F
Bethesda, MD 20892-6402
Telephone: (301) 594-2421
FAX:  (301)480-8318
Email:  Dennis.Mangan@nih.gov
 
Anna McCormick, Ph.D.
Chief, Biology Branch
Biology of Aging Program
National Institute on Aging
Gateway Building, Suite 2C231
Bethesda, MD 20892
Telephone:  (301) 496-6402
FAX:  (301) 402-0010
Email:  am38k@nih.gov
 
Allen Lock, D.V.M.
Center for Research for Mothers and Children
National Institute for Child Health and Human Development 6100
Executive Boulevard, Room 4B01 MSC-7510
Bethesda, MD 20892-7510
Telephone:  (301) 496-5541
FAX:  (301) 402-4083
Email:  locka@hd01.nichd.nih.gov
 
Direct inquiries regarding fiscal matters to:
 
Celeste Kerner
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases Solar Building,
Room 4B26
6003 Executive Blvd.
Bethesda, MD 20892-7610
Telephone: (301) 402-6213
FAX:  (301) 480-3780
Email:  ckerner@mercury.niaid.nih.gov
 
Mr. Martin Rubinstein
Division of Extramural Research
National Institute of Dental Research
Natcher Building, Room 4AN-44A
Bethesda, MD 20892-6402
Telephone: (301) 594-4800
FAX:  (301) 480-8301
Email:  Martin.Rubinstein@nih.gov
 
Mr. Joseph Ellis
Grants Management Officer
Grants and Contracts Management Office
National Institute on Aging
Gateway Building, Suite 2N212
Bethesda, MD 20892
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email:  je14j@nih.gov
 
E. Douglas Shawver
Grants Management Branch
National Institute for Child Health and Human Development 6100
Executive Boulevard, Room 8A17 MSC-7510
Bethesda, MD 20892-7510
Telephone:  (301) 496-1303
FAX:  (301) 402-0915
Email:  shawverd@hd01.nichd.nih.gov
 
AUTHORITY AND REGULATIONS
 
This program is supported under authorization of the Public Health
Service Act, Sec. 301(c), Public Law 78-410, as amended.  The
Catalogue of Federal Domestic Assistance Citation is No. 93.855 -
Immunology, Allergy, and Transplantation Research, No. 93.121- Oral
Diseases and Disorders Research Awards, No. 93.366 - Aging Research,
and No. 93.865 - Research for Mothers and Children.  Awards will be
administered under PHS grants policies and Federal Regulations 42 CFR
Part 52 and 45 CFR Part 74.  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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