Full Text AI-93-03


NIH GUIDE, Volume 21, Number 45, December 18, 1992

RFA:  AI-93-03

P.T. 34

  Diagnosis, Medical 
  Infectious Diseases/Agents 
  Clinical Medicine, General 
  Biomedical Research, Multidiscipl 

National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  January 22, 1993
Application Receipt Date:  March 23, 1993


The Respiratory Diseases Branch of the Division of Microbiology and
Infectious Diseases and the Developmental Therapeutics Branch of the
Division of AIDS of the National Institute of Allergy and Infectious
Diseases (NIAID) invite applications for research on the basic
structural and functional biology and pathogenic mechanisms of
Mycobacterium tuberculosis.


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 Biology and Pathogenesis of 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 202-783-3238).


Domestic and foreign non-profit and for-profit organizations and
institutions, governments and their agencies, are eligible to apply.
Minorities and women are encouraged to apply.  Foreign institutions
are not eligible for the First Independent Research Support and
Transition (FIRST) (R29) award.  Applications from or involving
minority institutions or women's institutions are encouraged.


This RFA will use the National Institutes of Health (NIH) individual
research project grant (R01), and the FIRST (R29) award.
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 in response to this RFA may
not exceed five years.

This RFA is a one-time solicitation.  Future unsolicited competing
applications will compete with investigator-initiated applications
and be reviewed according to customary review procedures.


The estimated total funds (direct and indirect costs) available for
the first year of this program will be $1,000,000.  In fiscal year
1993, the NIAID plans to fund at least four R01s and/or R29s.  This
level of support is dependent on the receipt of a sufficient number
of applications of high scientific merit.



A century ago, tuberculosis (TB) was a leading cause of death in the
United States.  Through the efforts of researchers, physicians, and
public health officials, as well as through improvements in living
conditions and the introduction of effective drug therapy, the number
of TB cases and deaths in the United States declined steadily for 40
years.  This trend stopped in 1985.  The number of cases is now
increasing.  The new cases of TB in the U.S. reported to the Centers
for Disease Control were 22,517 in 1987, 23,495 in 1989 and 26,283 in
1991.  This resurgence of TB is a matter of grave concern.  In the
United States TB is responsible for about 2,000 deaths annually.  An
estimated 10 million persons in the United States are presently
infected with the TB organism and have the potential to develop
clinical TB (active disease) at some time in their lives.  Globally,
TB is an even more serious threat.  An estimated 8 million new TB
cases and 2.9 million TB deaths occur each year. (Science, Vol. 21,
p1055-1064, Aug. 21, 1992).

The recent rise in tuberculosis cases reported in the United States
and elsewhere is attributed, at least in part, to the heightened
susceptibility to TB infections of HIV-positive persons.  Other
factors, including intravenous drug abuse, the increased influx of
immigrants from less developed nations, and poor socio-economic
status, also contribute to this rise.  The concern of health
officials about the number of cases is intensified by the recent
growth in the number of isolates of multi-drug-resistant M.
tuberculosis (MDRTB).  The background to these developments is
documented in publications of the Centers for Disease Control (e.g.,
Morbidity and Mortality Weekly Reports, March 1, 1991, Vol. 40, No. 8
and June 19, 1992,  Vol. 41, No. RR-11).

Despite advances in diagnosis and treatment made during the 100 years
since the identification of M. tuberculosis, serious problem areas
remain.  A clearer understanding of the structural and functional
biology of the organism could provide insight into both pathogenic
mechanisms and the immunologic responses evoked in the infected host.
 Sensitive and specific methods for rapid, reliable diagnosis of
tuberculosis are urgently needed.  Treatment of active tuberculosis
also remains an area of interest.  The means to shorten the treatment
course and hence improve both patient compliance and lower costs is
an important goal.  The emergence of resistant organisms is a matter
of particular concern to health officials.  The case fatality rate
for TB resistant to two or more drugs (MRDTB) is 40 to 60 percent and
the overall costs of treatment of these cases is five times higher.
Patients often fail to complete the long term drug treatments needed
to cure TB infections, an action that encourages both relapse and the
emergence of resistant organisms.  In conjunction with this,
methodologies for the rapid, reliable identification of MDRTB in
clinical specimens and in laboratory cultures are needed.

Progress in all areas of clinical tuberculosis research is contingent
upon an improved understanding of the basic structural and molecular
biology of M. tuberculosis.  Studies of the immunology, pathogenesis,
virulence factors, and molecular bacteriology of this organism are
thus of great importance if we are to achieve our clinical research

Research Objectives and Scope

Applications are encouraged that involve a coordinated
multi-disciplinary approach to investigate M. tuberculosis and/or its
interactions with its host (including animal models).  Applications
that involve an integration of basic and clinical sciences will be
given favorable consideration.  The aim of these efforts should be a
greater understanding of mechanisms of pathogenesis, immune evasion,
virulence factors or host response and/or lead to improvements in the
diagnosis, treatment or prevention of tuberculosis.  These areas may
include, but are not limited to, the following:

o  Identify and characterize virulence factors important in the
pathogenesis of tuberculosis.

o  Characterize the role(s) of tumor necrosis factor and other
cytokines and soluble factors that affect the course of the disease.

o  Develop improved in vitro or animal models for basic and applied

o  Characterize cell surface antigens and describe their interactions
with components of the host immune system.

o  Characterize the response of the host to natural infection and
define the correlates of protective immunity.

o  Characterize immune mechanisms underlying successful inhibition of
growth and persistence of tubercle bacilli in the body.  Define the
mechanisms by which M. tuberculosis persists in a quiescent state,
and conditions under which reactivation of infection may occur.

o  Characterize mechanisms underlying drug resistance, particularly

o  Develop improved methods for rapid, reliable identification of
drug-sensitive and drug-resistant strains of M. tuberculosis,
including MDRTB, in clinical specimens and in laboratory cultures.

The areas outlined above are not intended to be all-inclusive, nor
are they all required.  All research strategies designed to improve
markedly the understanding of the pathogenic mechanisms operative in
tuberculosis, or with the potential for improving current diagnosis,
treatment, and prevention modalities, are encouraged.


NIAID program staff will organize annual meetings that Principal
Investigators and other key members (as designated by the Principal
Investigators) of the projects will be encouraged to attend to
discuss progress.  This will facilitate overall program planning and
development, evaluation of the feasibility of planned approaches, and
will promote productive interactions among the awardees.  Funds for
travel to these meetings should be included in the budget.  NIAID
program staff will also ensure and arrange for the participation in
these meetings of investigators from other relevant NIAID-supported
tuberculosis research projects, if appropriate, in order to further
promote productive interactions.



NIH policy is that applicants for NIH clinical research grants and
cooperative agreements will be 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 should 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 should be provided.

The composition of the proposed study populations must be described
in terms of gender and racial/ethnic group, together with a rationale
for its choice.  In addition, gender and racial/ethnic issues should
be addressed in developing a research design and sample size
appropriate for the scientific objectives of the study.  This
information should be included in the form PHS 398 (rev. 9/91) in
Sections 1-4 of the Research Plan AND summarized in Section 5, Human

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 includes 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 populations
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 will be 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 support
applications that do not comply.


Prospective applicants are asked to submit, by January 22, 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 the
participating institution, 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 allows
NIAID staff to estimate the potential review workload and 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.


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 or business offices and
from the Office of Grants Inquiries, Division of Research Grants,
National Institutes of Health, Westwood Building, Room 449, Bethesda,
MD 20892, telephone 301/496-7441.  The deadline for receipt of
applications in response to this RFA is March 23, 1993.  Applicants
for FIRST (R29) awards 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.

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center of 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 should be included in the application material.

The RFA label available in the application form 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.  In addition, the "Yes" box
must be marked and the RFA title (Basic Biology and Pathogenesis of
Human Tuberculosis) and number (AI-93-03) must be typed on line 2a of
the face page of the application.

Submit a signed, typewritten original of the application, including
the Checklist and three signed 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 to DRG, two additional exact copies must be
sent to Dr. Olivia Preble at the address listed under INQUIRIES.

Applications received after the deadline will be returned without

The Division of Research Grants (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 exclude
the submission of substantial revisions of application already
reviewed.  These applications must, however, include an introduction
addressing the previous critique.


Upon receipt, applications and supporting material will be reviewed
by the DRG for completeness and by NIAID staff for responsiveness to
the RFA.  Incomplete applications will be returned without further
consideration.  If the application is not responsive to the RFA,
NIAID staff will contact the applicant to determine whether to return
the application or submit it for review in competition with
unsolicited applications at the next review cycle.

Applications may be triaged by an NIAID peer review group on the
basis of relative competitiveness.  The NIH will withdraw from
further competition those applications judged to be non-competitive
for award and notify the applicant Principal Investigator and
institutional official.  Those applications that are complete and
responsive will be evaluated in accordance with the criteria stated
below for scientific/technical merit by an appropriate peer review
group convened by the NIAID.  The second level of review will be
provided by the National Advisory Allergy and Infectious Diseases

Review criteria for applications received in response to an RFA are
the same as those for unsolicited applications, namely:

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.


The anticipated date of award is September 30, 1993.

The primary criterion for award is technical and scientific merit as
judged by peer review and reflected in the priority score.
Additional criteria are availability of funds and the number of
meritorious applications received in response to this RFA.


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

Direct inquiries regarding programmatic issues to:

Dr. John Foulds
Tuberculosis Program Officer
Respiratory Diseases Branch
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
Solar Building, Room 3A31
Bethesda, MD  20892
Telephone:  (301) 496-5305
FAX:  (301) 496-8030

Direct inquiries regarding the review of applications to:

Dr. Olivia Preble
Chief, Microbiology and Immunology Review Section
Scientific Review Branch
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C20
Bethesda, MD  20892
Telephone:  (301) 496-8208
FAX:  (301) 402-2638

Direct inquiries regarding fiscal matters to:

Mr. Todd Ball
Chief, MID Grants Management Section
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

The mailing address for sending applications, letters of intent, or
other correspondence to NIAID staff in the Solar Building is the
central mailing address for the NIH.  Applicants who use express mail
or a courier service are advised to follow the carrier's requirements
for showing a street address.  The address for the Solar Building is:

6003 Executive Boulevard
Rockville, Maryland  20852


Letter of intent date:     January 22, 1993
Application receipt date:  March 23, 1993
Scientific review date:    July 1993
Advisory Council date:     September 1993
Earliest award date:       September 30, 1993


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.


Return to RFAs Index

Return to NIH Guide Main Index

Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy

Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.