Full Text AI-94-002

MECHANISM OF RESPIRATORY SYNCYTIAL VIRUS VACCINE IMMUNOPOTENTIATION

NIH GUIDE, Volume 22, Number 40, November 5, 1993

RFA:  AI-94-002

P.T. 34

Keywords: 
  0705048 
  Vaccine 
  Immunology 


National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  January 14, 1994
Application Receipt Date:  March 17, 1994

PURPOSE

The National Institute of Allergy and Infectious Diseases (NIAID)
invites applications to conduct basic research on the immunology of
Respiratory Syncytial Virus (RSV) protection and disease.
Specifically, the NIAID is interested in addressing the immune
responses associated with the exacerbation of disease in children who
had previously received formalin-inactivated RSV vaccine.

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), Mechanism of RSV Vaccine Immunopotentiation,
is related to the priority area of 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 202-783-3238).

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 or local
governments, and eligible agencies of the Federal government.
Successful applications from foreign institutions, however, are
limited to three years of support without indirect costs.
Applications from minority individuals and women are encouraged.

MECHANISM OF SUPPORT

Awards made under this RFA will use the National Institutes of Health
(NIH) individual research grant (R01) award mechanism.
Responsibility for the planning, direction and execution of the
proposed project will be solely that of the applicant.  The total
project period for applications submitted by domestic institutions
may not exceed four years; the total project period for applications
submitted by foreign institutions may not exceed three years.  The
anticipated earliest possible award date is September 1994.

Applicants are encouraged to coordinate, through the use of
consortium arrangements or subcontracts, integrated approaches with
individuals or institutions having relevant reagents and expertise in
their use, demonstrated ability in a particular area of relevant
research, or access to relevant animal or patient populations to
accelerate technical progress and clinical development of promising
prophylactics.  Because the nature and scope of the research proposed
in response to this RFA may vary, it is anticipated that the amounts
awarded will also vary.

This RFA is a one-time solicitation.  Future competing continuation
applications will compete with all unsolicited investigator-initiated
applications and be reviewed by an appropriate Study Section
according to the customary NIH referral and peer review procedures.

FUNDS AVAILABLE

The funds available for the total (direct and indirect) first year
cost of all awards under this RFA is $1.0 million.  Foreign
applications that may be funded under this RFA are not eligible for
indirect costs.  The NIAID anticipates making a minimum of three new
awards.

RESEARCH OBJECTIVES

Background

Acute respiratory infections represent a significant cause of death,
worldwide.  The most serious acute respiratory condition, pneumonia,
is the cause of four million deaths per year in children under the
age of five.  The etiology of pneumonia has been assessed in both
developed and developing countries and has been found to be
strikingly similar.  Worldwide, it has been estimated that, for
children under the age of five, over half of pneumonia deaths are of
viral or bacterial/viral origin.  Of all the respiratory viruses
associated with death due to childhood pneumonia, over 62 percent
were associated with RSV.  Within the U.S., the impact of RSV
infection is primarily through increased morbidity (hospitalization
due to pneumonia) in both normal and high risk children including low
birth weight infants and children with bronchopulmonary dysplasia
(BPD), congenital heart disease (CHD) and immunodeficiencies.  For
example, in a prospective study conducted at the University of
Colorado Hospital, BPD infants infected with RSV accounted for 10
percent of total pediatric hospital days.  Thus, the development of
successful vaccines for RSV could significantly alleviate the excess
infant morbidity and mortality.

Presently, there are no licensed RSV vaccines and only limited
efforts in the development of vaccine candidates because attempts to
develop a safe and effective vaccine have met with continued
frustration.  In the mid-1960's, a formalin inactivated RSV vaccine
was evaluated in previously unprimed (seronegative) infants.  When
these children were subsequently exposed during an RSV outbreak, the
resulting illnesses were very severe.  Specifically, children under
two years of age who received the vaccine had a much higher incidence
of pneumonia (60 percent) and hospitalization (21 percent) compared
to the children who received placebo (8 percent and 1.5 percent,
respectively).  Attempts to understand the nature of this
immunopotentiation event have relied primarily on data generated
using the cotton-rat model.  In this system, RSV challenge of animals
immunized with a formalin-inactivated RSV vaccine has been associated
with changes in lung histology.  The equation of this altered
histology in animals with the exacerbated disease in humans has been
widely debated.  Nonetheless, in the absence of definitive data to
the contrary, the cotton-rat model has been widely used to define the
preclinical safety of potential new vaccine candidates.  At a recent
NIAID/WHO/CDC RSV Workshop (May 1993) use of alternative animal model
systems for detailed studies of the immunologic mechanism of
immunopotentiation (eg., mouse model) and development of animal
models with clinical disease patterns/immunologic responses similar
to those seen in humans (eg., lamb/bovine models) were encouraged. It
was also clear that continued use of the cotton-rat model to define
safety of new experimental vaccines requires additional knowledge as
to the basis of the histologic changes observed following challenge.
Until then, a significant barrier would remain in the development of
RSV vaccines.

Scope of Research

The long-term goal of the NIAID is to facilitate the development of
an effective RSV vaccine.  However, interim objectives must be met
before candidate vaccines can be entered into clinical trials
involving seronegative infants and children.  The goal of this RFA is
to stimulate innovative new research on the complex immunology
associated with RSV disease immunopotentiation and within that
context to develop in vitro and/or in vivo assays that accurately
reflect the potential safety of RSV vaccine candidates.

Examples of projects that might be responsive to this RFA include,
but are not limited to:

1.  Detailed analysis of the immune pathways stimulated following:

o  immunization with experimental RSV vaccines that have been
previously associated with immunopotentiation;
o  immunization with experimental RSV vaccines that have been
associated with protection but not immunopotentiation;
o  natural infection;

2.  Development of in vivo models that closely mimic the clinical
disease/immunopotentiation event seen in humans;

3.  Development of immunologically defined reagents for valid in vivo
models;

4.  Development of in vitro models to assess the immunopotentiation
effect of candidate RSV vaccines;

5.  Definition of the properties of vaccine preparations which have
been associated with immunopotentiation.

SPECIAL REQUIREMENTS

NIAID Program Staff will organize annual meetings in Bethesda that
Principal Investigators and other key members (as designated by the
Principal Investigators) of the projects will be requested to attend
to discuss progress.  At the discretion of the Program Staff,
clinical researchers and members of the vaccine industry may also be
invited to attend.  Funds for travel to these meetings should be
included in the budget.

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 are 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 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.  In addition, gender and
racial/ethnic issues must be addressed in developing a research
design and sample size appropriate for the scientific objectives of
the study.  This information must be included in the form PHS 398
(rev. 9/91) 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 is defined as 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 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 advises that, as a minimum, the application
should contain demographic data about the clinic and/or in-patient
population from which study subjects will be drawn: average hospital
admission 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 study sites should be
provided.

LETTER OF INTENT

Prospective applicants are asked to submit, by January 14, 1994, a
letter of intent that includes a descriptive title of the proposed
research, the names and affiliations of proposed key investigators,
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
subsequent applications, the information that it contains allows
NIAID Staff to estimate the potential review workload and to avoid
possible 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 form PHS 398 (rev. 9/91), the
standard application form for research grants.  Application kits are
available at most institutional offices of sponsored research and may
be obtained from the Office of Grants Information, Division of
Research Grants, National Institutes of Health, Westwood Building,
Room 449, Bethesda, MD 20892, telephone 301/435-0714.  Applicants
must adhere to the format and requirements specified in the PHS 398
application kit.

For purposes of identification and processing, mark "YES" in item 2a
on the face page of the application and type in the RFA number
AI-94-002 and the title "MECHANISM of RSV VACCINE
IMMUNOPOTENTIATION."  The RFA label available in the form PHS 398
must be affixed to the bottom of the face page of the original
application.  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.

The signed, typewritten original of the application, including the
Checklist, and three exact single-sided copies must be sent to:

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

At the time of submission, two additional copies must also be sent to
Dr. Olivia Preble at the address listed under INQUIRIES.

To ensure their review, applications must be received by both the
Division of Research Grants and Dr. Olivia Preble by March 17, 1994.
Applications not received by the receipt date will be considered
non-responsive and will be returned to the applicant 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 essentially 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.

REVIEW CONSIDERATIONS

Review Procedures

Applications will be reviewed by DRG staff for completeness and by
NIAID staff to determine administrative and programmatic
responsiveness to this RFA.  Those judged to be incomplete or
nonresponsive will be returned to the applicant without review.
Those considered complete and responsive may be subjected to a triage
review by an NIAID peer review group, before or during the initial
review meeting, to determine their scientific merit relative to the
other applications submitted in response to this RFA.  The NIH will
withdraw from competition those applications judged by the triage
peer review group to be noncompetitive for award and will so notify
the applicant investigator and the institutional business official.
Those applications judged 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 National Advisory Allergy and
Infectious Diseases Council.

Review Criteria

The factors to be considered in scientific review of the application
are:

1.  Scientific merit of the proposed research approach, design, and
methodology as well as the potential scientific, technical, or
medical significance of the proposed research.

2.  Research experience and competence of the Principal
Investigator(s) and other staff to conduct the proposed studies.

3.  Adequacy of the time (effort) that the Principal Investigator(s)
and staff would devote to the proposed studies.

4.  Adequacy of facilities, including, if relevant to the proposed
research, adequacy of the clinical facilities and patient
availability for clinical studies.

AWARD CRITERIA

In selecting applications for funding, while scientific merit is of
primary consideration, applications will also be evaluated for
programmatic relevance and potential for impact on the clinical
development of RSV vaccines.

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:

Dr. Carole Heilman
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
Solar Building, Room 3B-06
Bethesda, MD  20892
Telephone:  (301) 496-5305
FAX:  (301) 496-8030
E-mail:  hck@exec.niaid.pc.niaid.nih.gov

Address the letter of intent, two copies of the completed
application, and direct any questions regarding review procedures to:

Dr. Olivia Preble
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C19
Bethesda, MD  20892
Telephone:  (301) 496-8208
FAX:  (301) 402-2638

Direct inquiries regarding fiscal matters to:

Mr. Todd Ball
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B-35
Bethesda, MD  20892
Telephone:  (301) 496-7075
FAX:  (301) 480-3780

Schedule

Letter of Intent Receipt Date:  January 14, 1993
Application Receipt Date:       March 17, 1994
Scientific Review Date:         June 1994
Council Meeting Date:           September 1994
Earliest Award Date:            September 1994

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.856, Microbiology and Infectious Disease Research.
Awards are made under authorization of the Public Health Service Act,
Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158,
42 USC 241 and 285) and administered under PHS grants policies and
Federal Regulations 42 CFR 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.

.

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