Full Text AI-94-022

BASIC RESEARCH IN HUMAN TUBERCULOSIS

NIH GUIDE, Volume 23, Number 15, April 15, 1994

RFA:  AI-94-022

P.T. 34

Keywords: 
  Pulmonary Diseases 
  Infectious Diseases/Agents 
  Pathogenesis 
  Immunology 
  Epidemiology 


National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  May 20, 1994
Application Receipt Date:  July 14, 1994

APPLICATIONS IN RESPONSE TO THIS RFA MUST BE PREPARED USING A
MODIFIED (ABBREVIATED) GRANT APPLICATION FORMAT; SPECIFIC
INSTRUCTIONS FOR COMPLETING THE APPLICATION ARE IN THE APPLICATION
PROCEDURES BELOW.

PURPOSE

The Respiratory Diseases Branch of the Division of Microbiology and
Infectious Diseases of the National Institute of Allergy and
Infectious Diseases (NIAID) invites applications to conduct
innovative basic research to elucidate the basic biology, immunology,
epidemiology, and pathogenic mechanisms of infection with
Mycobacterium tuberculosis.  To better understand tuberculosis
epidemiology, progression, treatment, and control, the NIAID wishes
to expand research in these areas with the goals of developing
rational strategies for vaccine and drug development and improving
the diagnosis, treatment, and prevention of this disease.

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), Basic Research in Human Tuberculosis, is
related to the priority areas of immunity, infectious diseases, and
HIV infection.  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 NIH individual research project
grant (R01) and the FIRST (R29) award.  The total project period for
applications submitted in response to this RFA may not exceed five
years.  The earliest anticipated award date is April 1995.

This RFA is a one-time solicitation.  Future unsolicited competing
renewal applications will compete with investigator-initiated
applications and be reviewed according to customary 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
$3,500,000.  In Fiscal Year 1995, the NIAID plans to fund
approximately 15 awards.  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

On April 23, 1993, the World Health Organization declared
tuberculosis a global public health emergency, an opprobrium never
accorded another disease.  Once believed by health officials to be
contained, tuberculosis is now recognized as out of control in many
parts of the world.  The linkage of the tuberculosis epidemic with
the AIDS epidemic and the emergence of multidrug-resistant strains of
M. tuberculosis intensify the problem and present additional
challenges to health officials.

Without substantial measures to combat the epidemic, experts foresee
a significant tragedy in both human and economic terms.  More than 30
million lives will be lost to tuberculosis during the coming decade
unless efforts to control its transmission and deliver effective
treatment in a timely fashion are improved.  Tuberculosis is
responsible for an estimated 26 percent of all avoidable deaths in
the 5 to 59 years age group.  Most of these deaths will occur in
persons aged 20 to 30 upon whom both younger and older persons rely
for their support.  This amplifies the economic burden of the
disease.

Many people in developed countries think of tuberculosis as disease
that was essentially wiped out in the 1950's.  Yet today,
tuberculosis is a worldwide problem, not limited to developing
countries nor confined by national boundaries.  Most tuberculosis
cases occur in developing countries where poor, crowded living
conditions and inadequate nutrition contribute to the spread and
susceptibility to the disease.

The disease also affects developed countries.  The World Health
Organization has identified at least 10 industrialized countries
where the number of cases of tuberculosis has increased by 5 percent
to 33 percent during recent years.  In the United States, an
estimated 15 million people are currently infected with tuberculosis.
Cases increased 20 percent during the period 1985 to 1992, and in
1992, 26,678 cases of active tuberculosis were reported to the CDC.
This trend continues.  Persons most likely to suffer the disease
include HIV-infected persons, the homeless, chronic alcohol or
drug-abusers, and those living in long-term care facilities such as
nursing homes and jails.  In developed countries, tuberculosis is
chiefly an urban disease.  Tuberculosis remains a particular burden
for the Hispanic and African-American communities located in these
areas.

The increase of tuberculosis cases in developed countries is
attributed to several causes.  The most important of these include
the link between tuberculosis and HIV infection and the emergence of
drug-resistant strains of Mycobacterium tuberculosis.

The link between HIV and tuberculosis is anticipated to be a major
factor in the spread of tuberculosis.  It is the only AIDS-associated
infection readily transmitted to non-HIV-infected persons.
Tuberculosis and HIV are synergistic. HIV infection increases the
chance of primary tuberculosis and of activation of latent
tuberculosis infections.  Recent reports show HIV-infected
tuberculosis patients may become super-infected with a second,
drug-resistant tuberculosis strain, reducing the potential for cure
and increasing both treatment costs and the chance of further
transmission.  HIV infection also accelerates the progression of
tuberculosis.  Tuberculosis may also be difficult to diagnose in HIV-
infected persons.  Thus, these individuals may remain infectious due
to delayed diagnosis.

The tuberculosis crisis is sharpened by the emergence of disease
caused by multidrug-resistant organisms (MDR-TB). These strains may
result in an essentially incurable form of the disease, capable of
spread by casual contact.  Outbreaks of disease caused by virulent
organisms resistant to two or more of the major anti-tuberculosis
drugs have occurred at several sites in the United States.  These
outbreaks emphasize the importance of efforts to limit spread of the
disease.  In 1992 in New York City, more than one-third of the
strains tested were resistant to one drug and nearly one-fifth were
resistant to both isoniazid and rifampin.  These strains are as
contagious as drug-susceptible strains. Drug-resistant tuberculosis
is more difficult and vastly more expensive to treat.  Patients with
drug-resistant tuberculosis may remain infectious longer due to
inadequate treatment.

Treatment of MDR-TB infections is difficult, expensive, and often
unsuccessful.  Successful treatment of tuberculosis, especially
MDR-TB, depends upon early diagnosis.  At present, it may take as
long as 13 weeks to diagnose tuberculosis and determine the
antibiotic susceptibility of the organism.  This information is
critical to development of an effective treatment plan.  Treated
effectively, almost all tuberculosis patients, including HIV
co-infected patients, rapidly become non-infectious.  MDR-TB response
to appropriate treatment is markedly improved by early diagnosis.

The resurgence of tuberculosis, especially MDR-TB, poses special
problems for health care workers, social workers, prison personnel,
and other contacts at risk.  Particularly exposed are those charged
with care of patients with active disease.

Research Objectives and Scope

The objective of this RFA is to encourage established investigators
and investigators new to TB research to pursue innovative new
research in the following representative, areas:

o  Epidemiology of tuberculosis infection, reactivation, and
reinfection to improve understanding of disease transmission

o  Improved understanding of genetic mechanisms (recombination,
repair and replication) and of the molecular basis by which
Mycobacterium tuberculosis invades target cells, avoids host defense
mechanisms, causes tissue damage, and ultimately kills the host

o  Mycobacterium tuberculosis antigens: identification of antigens
expressed within infected macrophages, and their role in enhanced
cell-mediated immunity and reduced delayed-type hypersensitivity

o  Development of a human in vitro model system that can predict, or
help to identify, potentially protective Mycobacterium tuberculosis
antigens

o  Immunologic mechanisms and other host factors that contribute to
development of primary tuberculosis

o  Immune modulators in regulation of T-cell response in protection,
granuloma formation, and macrophage Mycobacterium tuberculosis
interactions

o  Design of drugs for latent Mycobacterium tuberculosis infections

o  Characterization of molecular or metabolic targets with potential
for design of new treatment and/or prophylactic agents.

o  Preparation of attenuated strains of Mycobacterium tuberculosis as
candidate vaccines

The areas outlined above are not intended to be all-inclusive.  All
research strategies designed to markedly improve our understanding of
tuberculosis infection and pathogenesis and with the potential for
improving current diagnosis, treatment, and prevention modalities
will be considered.

STUDY POPULATIONS

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 sub-populations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations) which
have been in effect since 1990.  The new policy contains some new
provisions that are substantially different from the 1990 policies.
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 9, 1994 (FR 59 11146-11151), and reprinted
in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume
23, Number 11.

Investigators may obtain copies from these sources or from Dr. Foulds
(listed in INQUIRIES below) who may also provide additional relevant
information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by May 20, 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

Note:  See Special Instructions below for Completion of Grant
Applications in response to this RFA.

Applications are to be submitted on the standard research grant
application form PHS 398 (rev. 9/91).  For purposes of identification
and processing, item 2a on the face page of the application must be
marked "YES" and the RFA number "AI-94-022" and the words "BASIC
RESEARCH IN HUMAN TUBERCULOSIS" 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) 710-0267.

Applications must be received by July 14, 1994.  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. 9/91)
Application Kit (as modified in, and superseded by, the special
instructions below, for the purposes of this RFA), 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 that 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 and all five sets of any appendix material must 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 should be included
with the application.

SPECIAL INSTRUCTIONS FOR COMPLETION OF APPLICATIONS IN RESPONSE TO
THIS RFA

The NIH has recently been designated a "reinvention laboratory" by
the Public Health Service.  One NIH reinvention objective is to
simplify and improve each stage in the grant process:  application,
review, award, and administration.

An experiment is being conducted to determine how to reduce the
administrative burden in applying for an NIH grant without
compromising the information needed by the initial scientific peer
review group to assess the scientific merit of the application and
the reasonableness of the proposed budget.

The following are specific instructions for sections of the PHS 398
(rev. 9/91) application form, which should be completed differently
than usual.  Some sections are modified and others in the application
should not be completed for the submission of the application, but
will be requested if the application receives a score in the fundable
range.  For all other items in the application, follow the usual
instructions on pages 9-32 of the PHS 398 booklet.

Form AA, Face Page:

o  Item 10.  Inventions and Patents:  Do not complete.

Form DD, Page 4.  Detailed Budget Page for Initial Budget Period:
Complete only selected portions of the Personnel section; do NOT
complete balance of this page (see Form EE, page 5 below).

o  Personnel.  Enter Names; and for each named person, enter Role on
Project and percent effort on project.  Do NOT complete remainder of
columns for personnel.

Form EE, Page 5.  Budget for Entire Proposed Project Period and
Justification:

o   Budget.  Complete the budget section for all requested years of
support for all budget categories including total direct costs by
year and for all years.

o   Justification.  For the INITIAL BUDGET PERIOD, provide brief
justifications only for budget items that exceed the following dollar
amounts and/or meet the following criteria:

-  Consultant Costs:  Exceeds $10,000 and/or consultant(s) are key
personnel.
-  Equipment:  Exceeds $15,000.
-  Supplies:  Exceeds $15,000 independent of animal care costs.  All
animal unit purchase prices and animal care costs must be itemized.
-  Travel:  Exceeds $5,000.
-  Patient Care:  Exceeds $15,000.
-  Other Expenses:  Exceeds $5,000.
-  Consortium/Contractual:  Exceeds $10,000.

o  Justification.  For ADDITIONAL YEARS OF SUPPORT REQUESTED, briefly
justify annual changes that are more than or less than four percent
increases from the preceding years.

Form FF - Page 6 - Biographical Sketch:  For each key investigator
provide a biographical sketch that does not exceed TWO PAGES and
includes the following information:

o  Name, Position Title, Education.  Complete these sections as
instructed in the PHS 398 booklet.

o  Research and Professional Experience.  This section should be used
to highlight the investigator's scientific background and experience
relevant to the research proposed in this application.  Completing
this section in the following sequence will facilitate review of this
application:

-  Previous research position(s) relevant to this application

-  Honors including:  title and funding sources for all current and
relevant completed research on which investigator was Principal
Investigator, Co-Investigator, or Project Leader; and, membership on
NIH review groups, councils, or program advisory committees and
length of service on each.

-  Complete references including titles and all authors for peer
reviewed publications representative of the investigator's research
career or pertinent to the research proposed in this application.

Form GG - Page 7 - Other Support:  Do not complete.  Information on
specific levels of support will be requested by the NIAID only from
applicants being considered for funding.

Form HH - Page 8 - Resources and Environment:  Complete selected
item(s) only if proposed research requires specialized unique
resources for which availability must be documented.

Research Plan (Booklet Pages 19-24):  Note:  Items 1 - 4 may not
exceed twenty (20) pages.

o  Item 1- Specific Aims (typically less than one page):  List in
priority order the broad, long range objectives of the proposed
project and describe concisely and realistically the hypothesis to be
tested and what the specific research described in this application
is intended to accomplish.

o  Item 2- Background and Significance (typically 1 page):  The
background and significance has been established by the NIAID in
setting aside funds for the release of this RFA.  Use this section to
describe how the proposed research will contribute to meeting the
goals and objectives of the RFA and explain the rationale for the
selection of the general methods and approaches proposed to
accomplish the specific aims.

o  Items 3 - 4:  Complete as instructed on pages 21-23 of the PHS 398
booklet, noting the reduced page limit stated above.  The following
is general guidance for information to be presented in this section:

-  preliminary studies pertinent to the application.
-  rationale for each particular set of experiments.
-  general methods that will be utilized.  Provide specific details
ONLY for those techniques that are unique, or where a significant
departure from a generally accepted technique is important for the
reviewers to know.
-  outcome measures that will be used to assess the success or
failure of each set of experiments.
-  potential pitfalls in the experimental design and alternative
studies that will be done if the proposed experiments fail.

o  Items 5 - 6:  Complete as described on pages 22-23 of PHS 398
booklet.

o  Item 7 - Consultants/Collaborators:  Biographical sketches should
conform to the brief format described for Form FF, above.

o  Item 8 - Consortium, Contractual Arrangements (1 page only):
Provide brief explanation (not to exceed one page) of the scientific,
fiscal, and administrative arrangements made with collaborating
organizations.

Appendix (PHS 398 Booklet - Page 24) A maximum of five publications,
manuscripts, submitted or accepted for publication, patents,
invention reports may be included.  Other than this change, complete
as instructed.

Forms II and JJ - Checklist:  Do not complete.  Information will be
requested by NIAID only from applicants being considered for funding.

If you or your business office has any questions regarding these
special instructions, call, FAX, or write Dr. McGowan at the address
listed under INQUIRIES.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness and
adherence to the Special Instuctions above 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 returned without review.

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.  For
non-competitive applications, summary reports will be very brief and
will generally highlight the major reason(s) for the non-competitive
rating.

Those applications judged by the reviewers 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 for applications received in response to this RFA are
generally the same as those for unsolicited applications:

o  Scientific, technical, or medical significance and originality of
the proposed research.

o  Appropriateness and adequacy of the experimental approach and
methodology proposed to accomplish the research.

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

o  Availability of resources to carry out the proposed research.

o  Appropriateness of the proposed budget and duration of the project
in relation to the proposed research.

o  Adherence, whenever appropriate, to NIH guidelines concerning
adequate representation of women and minorities in clinical research.

Although the following review factors do not influence the priority
score, they are nonetheless carefully considered by the initial
review group:

o  Adequacy of protection of human subjects and/or animals in
research.

o  Biohazard issues relevant to handling infectious mycobacteria.

Concerns expressed by the initial review group about any of these
factors 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 balance, and
the availability of funds.  The earliest anticipated date of award is
April 1, 1995.

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. John Foulds
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
Solar Building, Room 3B10
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-5305
FAX:  (301) 496-8030
E-Mail:  jf32v@nih.gov
E-Mail (alternate):  Jfoulds@exec.niaid.pc.niaid.nih.gov

Direct inquiries regarding the special instructions for preparation
of the grant application to:

Dr. John J. McGowan, Director
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 3C20
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-7291
FAX:  (301) 402-0369
E-Mail:  jm80c@nih.gov
E-Mail (alternate):  JMcGowan@exec.niaid.pc.niaid.nih.gov

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
E-Mail:  op2t@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Catherine Walker
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B32
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-7075

Schedule

Letter of intent receipt date:  May 20, 1994
Application receipt date:       July 14, 1994
Scientific review date:         October 1994
Advisory Council date:          February 1995
Earliest award date:            April 1, 1994

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 Sec. 93.856,
Microbiology and Infectious Diseases 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 review.

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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