Full Text AI-93-06


NIH GUIDE, Volume 21, Number 44, December 11, 1992

RFA:  AI-93-06

P.T. 34

  Infectious Diseases/Agents 

National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  January 11, 1993
Application Receipt Date:  March 11, 1993


Measles recently reemerged as a public health problem in the U.S. and
measles continues to be a deadly disease in the developing world.  The
purpose of this Request for Application (RFA) is to acquire the
information needed for the development of safe new measles vaccines
that are highly efficacious when administered in early infancy and that
will aid in the control and eventual eradication of measles.  An
expanded research effort is needed for the rational development and
evaluation of new vaccines and immunization strategies.  The National
Institute of Allergy and Infectious Diseases (NIAID) requests
investigator-initiated research grant applications focused on the study
of measles virus and the host's response to infection as it relates to
the safe induction of long-lasting protective immunity in individuals,
and the reduction of measles disease and infant deaths in populations.


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,
Research Leading to Improved Measles Vaccine, 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


Research grant 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 and
local governments, and eligible agencies of the Federal Government.
Foreign institutions are not eligible for the First Independent
Research Support and Transition (FIRST) (R29) award.  Applications from
minority individuals and women are encouraged.


This RFA will use the National Institutes of Health (NIH) individual
research grant (R01) and the FIRST award (R29) programs (if
interinstitutional collaborations are anticipated, please contact Dr.
James M. Meegan at the address listed under INQUIRIES).  The total
project period for applications submitted in response to the present
RFA may not exceed five years.  Because the nature and scope of the
research proposed in response to this RFA may vary, it is anticipated
that the size of the award will vary also.  This RFA is a one-time
solicitation.  Future unsolicited competing continuation applications
will compete with all unsolicited investigator-initiated applications
and be reviewed according to the customary peer-review procedures.


There are $1.5 million available in total support (direct plus indirect
costs) for this RFA for the first year.  It is anticipated that six to
eight new awards will be made, none to exceed $200,000 in total annual
direct costs.  If the proposed budget exceeds $200,000, the Principal
Investigator must obtain a written waiver from Dr. James Meegan to
submit with the grant application.



In the U.S. from 1981 to 1988, approximately 3,000 cases of measles
occurred each year.  This represents a reduction of more than 99
percent from the annual number of cases reported before the
introduction of measles vaccine in 1963.  However, a major epidemic of
measles occurred in 1989-90, and measles reemerged as a significant
health problem in the U.S.  In 1990, there were 27,672 cases, which
represented the largest number of cases since 1977, and included the
largest number of deaths (89) since 1971.  Fifty-five percent of the
deaths occurred in children less than five years old.  Of the reported
cases, 22.7 percent experienced complications and 21.1 percent required

The major cause of the reemergence of measles in the U.S. was the
failure to vaccinate children at the appropriate age, rather than
failure of vaccine efficacy.  However, currently licensed vaccines do
have some deficiencies as public health tools, particularly in regard
to efficacy in very young infants.

The U.S. program in response to the reemergence of measles includes
increasing vaccine coverage rates by recommending immunization against
measles using the measles, mumps and rubella vaccine (MMR) at 15 months
of age, followed by a booster MMR immunization as the child enters
school.  The vaccine used in the U.S. has a primary failure rate of
about five percent, but this rate is higher if the vaccine is given to
children less than 15 months of age because residual,
maternally-derived measles antibody interferes with infant immunization
rates.  In developing countries, measles continues to be a deadly
disease, causing over one and a half million deaths each year.  In
those areas, infants also are at greatest risk during the interval
between loss of maternal antibody and receipt of vaccine.  Thus, both
internationally and domestically, there is an urgent need for an
efficacious vaccine that can be safely administered at six-nine months
of age or earlier in infancy.  This need was underscored in the 1990
U.S. epidemic in which 17 percent of cases and 16.9 percent of deaths
occurred in infants under one year of age.  Furthermore, future
programs aimed at increasing immunization coverage will emphasize
administration at earlier ages in infancy of current, as well as new,
combinations of vaccines.

With regard to safety, it is important to note that the use of
inactivated measles vaccine in the 1960s was followed by atypical
measles in some individuals naturally exposed to measles in later life.
Moreover, recent studies of some candidate live virus vaccines raise
concerns about possible immunosuppression-associated adverse
consequences.  The goal is to avoid similar problems with future
vaccines, through research to understand the biological factors that
underlie these observations.

Scope of Research

This announcement is intended to stimulate innovative research on
measles across several research disciplines, with a strong emphasis on
studies to develop improved vaccines that can safely overcome the
maternal antibody barrier and induce long-lasting protective immunity.
Research projects are sought that investigate topics including, but not
limited to, those listed below.

o  Determination of which measles antigens are required to safely
elicit long-lasting, protective humoral and cellular immunity in the
developing immune system of the young infant.

o  Characterization of the quantitative and qualitative differences
between vaccine-induced and naturally-induced protective immunity.

o  Elucidation of the impact of maternal antibody on infant immune
response, and development of strategies to overcome maternal antibody
as a block to effective immunization in very young infants.

o  Development of an animal model of measles virus infection and
disease that parallels human disease and that could be used to study
the many host and viral factors influencing establishment of protective
immunity in the young infant.

o  Establishment of the viral correlates of virulence and attenuation.

o  Investigation of measles virus pathogenesis, including virus-induced
immune suppression.

o  Elucidation of viral and host factors contributing to
immunization-induced adverse events.

o  Pre-clinical research leading to development of highly efficient
methods for the safe delivery of measles antigens required for the
establishment of protective immunity.

o  Application of research on closely related viral systems, such as
distemper, to address specific problems related to immunization of
young infants.


Principal Investigators should budget for an annual one-day progress
review meeting at the NIH.



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

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 exempt.  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

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 the
priority score.

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.


Prospective applicants are asked to submit, by January 11, 1993, a
letter of intent that includes a descriptive title of the proposed
research, the name, address, and telephone number of the Principal
Investigator, the identities of other key personnel and participating
institutions, 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 conflict of interest in the review.

The letter of intent is to be sent to Dr. James Meegan at the address
listed under INQUIRIES.


The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research and from the Office of
Grants Inquiries, Division of Research Grants, National Institutes of
Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892, telephone
301/496-7441.  The RFA label available in the application form must be
affixed to the bottom of the face page of the 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.  In
addition, the RFA title and number must be typed on line 2a of the face
page of the application form and the "YES" box must be marked.

Submit a signed, typewritten original of the application, including the
Checklist, and five signed, photocopies, in one package to:

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

FIRST (R29) award applications must include at least three sealed
letters of reference attached to the face page of the original
application.  FIRST award applications submitted without the required
number of reference letters will be considered incomplete and will be
returned without review.

Applications must be received by the receipt date of this RFA.
Applications not received by the receipt date will be considered
non-responsive and the applicant will be contacted to determine whether
the application will be returned to the applicant or be processed as an
unsolicited application for the next Division of Research Grant (DRG)
review cycle.  The DRG will not accept any application in response to
this announcement that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending application.
The DRG will not accept any application that is essentially the same as
one already reviewed.  This does not preclude the submission of
substantial revisions of applications already reviewed, but such
applications must include an introduction addressing the previous


Upon receipt, applications will be reviewed for completeness by the DRG
and responsiveness by the NIAID.  Incomplete applications will be
returned to the applicant without further consideration.  If the
application is complete but not responsive to the RFA, it will undergo
the same process as for late applications above.  Complete and
responsive applications will be evaluated in accordance with the
criteria stated below for scientific/technical merit by an appropriate
scientific review group.  The second level of review will be provided
by the NIAID Council.

Review criteria for applications responsive to this RFA are generally
the same as those for unsolicited research grant applications:

o  scientific, technical, or medical significance and originality of
proposed research;

o  potential contribution to the development of new measles vaccines;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal Investigator
and staff, particularly but not exclusively in the area of the proposed

o  availability of resources necessary to perform the research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research;

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


The anticipated date of award is September 1993.  Awards will be made
on the basis of priority score, programmatic balance, and available


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

Send letters of intent and direct inquiries regarding programmatic
issues to:

Dr. James M. Meegan
Virology Branch, Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
Solar Building, Room 3A15
Bethesda, MD  20892
Telephone:  (301) 496-7453
FAX:  (301) 496-8030

If express mail or courier service is to be used, use the following
address for the Solar Building:  6003 Executive Blvd, Rockville, MD

Direct inquiries regarding fiscal matters to:

Mr. Todd C. Ball
Grants Management Branch, Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B35
Bethesda, MD  20892
Telephone:  (301) 496-7075


Letter of Intent Receipt Date:  January 11, 1993
Application Receipt Date:       March 11, 1993
Scientific Review Date:         July 1993
Council Meeting Date:           September 1993
Earliest Award Date:            September 1993


This program is described in the Catalog of Federal Domestic Assistance
No. 93.856, Microbiology and Infectious Diseases 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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