Full Text PA-97-097
NIH GUIDE, Volume 26, Number 28, August 22, 1997
PA NUMBER:  PA-97-097


National Institute on Aging
National Institute of Allergy and Infectious Diseases
The National Institute on Aging (NIA), and the
National Institute of Allergy and Infectious Diseases NIAID,
National Institutes of Health (NIH), invite applications to
evaluate control measures (i.e., vaccines and therapeutic agents)
for infectious diseases in the elderly and to enhance the
understanding of the immune response to infection and
immunizations in this at risk population.  In addition to the
clinical evaluation of candidate vaccines and therapeutic agents,
there is a special emphasis on defining the mechanisms that lead
to the decline in immune function and responsiveness (i.e.,
immunosenescence) with age.  Innovative studies are sought
that will develop vaccination strategies applicable for the
elderly or that define approaches that direct specific types of
immune responses which may lead to enhanced vaccine
effectiveness towards various infectious agents.  When
assessing the immune response to immunization in aged
populations, possible approaches may include incorporating
established vaccines that may be used in this population such as
pneumococcal, influenza, varicella, and hepatitis b.
This Program Announcement solicits applications for research
designed to enhance the overall understanding of mechanisms
that account for the differential sensitivity to vaccines of young
and older adult populations.  Through the use of clinical
research comparing younger and elderly adults  using licensed
vaccines and therapeutic agents, studies can be conducted to
examine differences in:  a) vaccine safety/reactogenicity; b)
optimal dose and schedule; c) immunogenicity; d)
transmissibility of infections from younger and older adults to
uninfected individuals and how this is effected by
immunization; e) resistance to infection and colonization; f)
efficacy; and g) duration of immunity and protection.
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), ?THE IMPACT OF
related to the priority areas of Immunization and Infectious
Diseases, and Immunosenescence.  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) through the Superintendent of Document,
Government Printing Office, Washington, DC 20402-0325
(telephone 202-512-1800).
Applications may be submitted by domestic and foreign, for-profit and
organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State and local governments, and
eligible agencies of the Federal government.Foreign institutions are
not eligible for
First Independent Research Support Transition (FIRST) R29)
awards.  Racial/ethnic minority individuals, women, and
persons with disabilities are encouraged to apply as Principal
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 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.
An investigator planning to submit an application requesting
$500,000 or more in direct costs for any budget period is
advised that he or she must contact Institute program staff listed
under INQUIRIES before submitting the application to obtain
agreement from program staff that the Institute or Center will
accept the application for consideration of award.  An
application of such a size received without prior staff
concurrence and identification of that contact will be returned to
the applicant without review.  Investigators are referred to the
policy update notice in the NIH Guide for Grants and Contracts,
Volume 25, Number 14, May 3, 1996.  Applicants proposing
human intervention studies are referred to the NIA policy notice
in the NIH Guide for Grants and Contracts, Volume 25, Number
33, October 4, 1996.
Over the past 50 years, the widespread use of vaccines has been
a major factor in improving the health of people worldwide.
Immunizations are among the most cost-effective means of
protecting the public?s health.  Children in particular, have
benefited from immunization programs to such an extent that
diseases like paralytic poliomyelitis have been eliminated and
the incidence of others, including rubella and measles, has been
significantly reduced.  However, in the U.S., the immunization
of adults does not receive the same priority as the immunization
of children, even though deaths from vaccine preventable
diseases such as influenza and pneumococcal infections occur
predominantly in adults, especially the elderly.  It is estimated
that in the U.S., there are approximately 300,000-500,000
hospital discharges annually for pneumococcal pneumonia
alone.  For pneumococcal pneumonia, pneumonia in general,
and pneumonia occurring during influenza outbreak periods, the
risks of hospitalization are increased substantially in patients
with chronic cardiopulmonary disease, stroke, diabetes mellitus,
and cancer.  Mortality caused by influenza and pneumococcal
infections is substantial; an estimated 40,000 deaths from
pneumococcal infections and 10,000 to 40,000 excess
influenza-associated deaths occur each year.  Of these deaths,
85% or more are among persons 65 years or older.
Studies show that elderly adults are at increased risk of disease
caused by encapsulated bacteria including Haemophilus
influenzae and Streptococcus pneumoniae.  The ability of the
elderly to mount a substantial antibody response to
polysaccharide antigens is dependent, in part, on their health
status.  Studies have shown healthy elderly individuals to
respond in a normal fashion to  pneumococcal polysaccharides
when compared to healthy young controls, while those with
chronic illness or high-risk conditions such as chronic
obstructive pulmonary disease, chronic cardiac disease,
alcoholism, diabetes, and renal failure respond poorly and are
not protected.  Furthermore, some serotypes associated with S.
pneumoniae may be less immunogenic in the elderly than in
younger adults.
In a prospective, case-controlled study, the protective efficacy
of polysaccharide pneumococcal vaccine progressively declined
with advancing age and time since vaccination, falling from an
aggregate efficacy of 93% in individuals less than 55 years of
age within three years of vaccination, to 32% among those over
age 75 who were last vaccinated more than five years earlier.
These results highlight the concept that the response of older
adults to current polysaccharide vaccines may be suboptimal,
and that the duration of immunity provided by the
polysaccharide vaccine is uncertain.  Thus, the immune system
at the extremes of life appears less efficient at mounting an
effective antibody response to encapsulated pathogens, as
evidence by the increased susceptibility of infants and the
elderly to these pathogens including the pneumococcus.
The world's elderly population (65 and over) in 1991 numbered
nearly half a billion persons and is expected to exceed one
billion by the year 2020.  In most countries, the elderly
population is growing faster than the population as a whole.  In
at least 30 countries, 15% or more of the entire population is
age 60 or over and 57% live in developing countries.  The
oldest old segment (85 and over) of the world's elderly
population numbers approximately 50 million, representing
one-tenth of all elderly.  Unlike the elderly as a whole, the
oldest old today are more likely to reside in developed (54%)
than in developing countries.  The numerical growth of older
populations around the world poses challenges to national
public health care policies.  This increasing number of elderly
persons poses even more of a problem in light of the fact that
various disease rates have increased, or at least have remained
stable, in addition to the increasing and serious clinical problem
associated with antimicrobial drug resistance.
Research Objectives and Scope:
Innovative research applications are sought that expand the
current knowledge of senescence as it applies to the immune
system and its expression following immunization and natural
infection.  The emphases of this PA are on: 1) identifying the
determinants of the relative non-responsivity to vaccination in
the elderly as compared to younger individuals; and 2)
development of approaches to enhance immune responsiveness
in the elderly. Studies proposed should address not only the
differences in immune response between younger and older
persons but also the variation observed within the older
population. This should help explain differences among older
persons in susceptibility to infection and protection conferred by
immunization. Examples of research topics of interest include,
but are not limited to, the following:
o  Age-related deficiencies in response to vaccine-related
antigens; discovering the basic causes of vaccine failure such as
T cell receptor antagonism, alterations in antigen-processing
pathways, memory responses to different microbial
polysaccharides, and the influence of previous infections and
pathogen exposures on inducing protective immune responses;
o Effect of aging on functional antibody activity,isotype
responses, IgG subclass activity, cell-mediated immunity
cytotoxic lymphocytes in particular), antibody affinity, avidity,
and V-region expression, and their relative importance for
predicting clinical outcome;
o Changes in the colonization, transmission, and response
to antimicrobial treatment for pathogenic and drug
resistant forms of microorganisms;
o Effect of age on clinical presentation, severity and
course of disease, as well as the effects of stress,
nutrition, and co-morbidities, and concurrent medication
on the immune response (with special attention to the
response on priming and boosting)and clinical course;
o Approaches to modulating the immune response in the elderly
including the use of adjuvants, conjugate formulations, immune
modulators, regimens for administering multiple doses etc.;
o Clinical and epidemiological studies of infectious
diseases in nursing homes and retirement facilities where
immune senescence, transmission, and exposure may
complicate immune intervention;
o Studies of varicella vaccines in older individuals to limit
reactivation of herpes zoster and to reduce the occurrence and
severity of zoster infection and post-herpetic neuralgia.
o The relation between colonization and invasive disease in the
o Gender differences in response to various types of vaccines;
o Response to mucosal immunization using different licensed
and new candidate vaccines (e.g., DNA vaccines).
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 of the
purpose of the research.  This policy results from the NIH
Revitalization Act of 1993 (Section 492B of Public Law
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.
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)
710-0267, email: asknih@odrockm1.nih.gov.
For purposes of identification and processing, item 2 on the face
page of the application must be marked "YES" and the PA
number and the PA title, ?The Impact of Immune Senescence
and Maturation on Vaccine Responsiveness in the Elderly,?
2.  The completed, signed original and five legible,
single-sided copies of the application must be sent or delivered
BETHESDA, MD 20892-7710
BETHESDA, MD 20817-7710 (for express/courier service)
FIRST (R29) awards  applications must include at
least three 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.
FIRST (R29) award applications must also be prepared
according to the requirements of Just-In-Time procedures, as
announced in the NIH Guide for Grants and Contracts, Volume
25, Number 10, March 29, 1996.  There may be a significant
delay in the processing and review of a FIRST award
application that has not been prepared according to the
instructions in the NIH Guide notice.
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 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 Procedures:
Applications will be assigned on the basis of established PHS
referral guidelines.
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:
 (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
 (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 group will also examine the provisions for the
protection of human and animal subjects and the safety of the
research environment.
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, and availability of funds.
Written and telephone inquiries are encouraged.  The
opportunity to clarify any issues or questions from potential
applicants is welcome.
Inquiries regarding programmatic (research scope, eligibility
and responsiveness) issues may be directed to:
Stanley Slater, M.D.
Deputy Associate Director for Geriatrics
Geriatrics Program
National Institute on Aging
Gateway Building, Room 3E327
7201 Wisconsin Avenue
Bethesda, Maryland 20892-9205
Telephone:  (301) 496-6761
Fax:   (301) 402-1784
EMAIL:   slaters@gw.nia.nih.gov
David L. Klein, Ph.D.
Bacterial Respiratory Diseases Program Officer
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
Solar Building, Room 3B03
6003 Executive Blvd.
Bethesda, MD 20892-7640
Telephone: (301) 496-5305
Fax:   (301) 496-8030
EMAIL:  dk27a@nih.gov
Direct inquiries regarding fiscal matters to:
Cynthia Riddick
Grants Management Office
National Institute on Aging
Gateway Building, Room 2C
7201 Wisconsin Avenue
Bethesda, Maryland 20814
Telephone:  (301) 496-1472
Fax:  (301) 402-3672
William Powell
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B26
6003 Executive Blvd.
Bethesda, MD 20892-7610
Telephone: (301) 496-7075
Fax:   (301) 480-3780
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. 93.866 - Immunology, Allergy, and
Transplantation Research.
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
The Public Health Service strongly encourages all grant
recipients to provide a smoke-free workplace and promote the
non-use of all tobacco products.  This is consistent with the
PHS mission to protect and advance the physical and mental
health of the American people.

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