Full Text AI-93-023

TUBERCULOSIS DIAGNOSTICS

NIH GUIDE, Volume 22, Number 34, September 24, 1993

RFA:  AI-93-023

P.T. 34

Keywords: 
  Pulmonary Diseases 
  Diagnosis, Medical 
  Chemistry, Clinical 
  Biological Markers 
  Disease Model 
  Immunology 


National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  January  7, 1994
Application Receipt Date:  February 18, 1994

PURPOSE

The Respiratory Diseases Branch, Division of Microbiology and
Infectious Diseases (DMID), National Institute of Allergy and
Infectious Diseases (NIAID) invites applications for innovative basic
or applied research leading to the development of diagnostics for
tuberculosis.   It is anticipated that new and improved diagnostic
tools to assist in the detection, prevention, and treatment of
tuberculosis will improve the speed, sensitivity, specificity, and/or
reliability of existing diagnostic procedures.

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), Tuberculosis Diagnostics, 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).

ELIGIBILITY REQUIREMENTS

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

MECHANISM OF SUPPORT

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.  The earliest anticipated award date is
September 1994.

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.

FUNDS AVAILABLE

The estimated minimum total funds (direct and indirect costs)
available for the first year of this program will be $2,000,000.  In
fiscal year 1994, the NIAID plans to fund at least eight R01s and/or
R29s.  This level of support is dependent on the receipt of a
sufficient number of applications of high scientific merit.

RESEARCH OBJECTIVES

Background

On April 23, 1993, the World Health Organization declared
tuberculosis a global public health emergency, a distinction 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 London School of Hygiene and Tropical
Medicine estimates that tuberculosis will claim more than 30 million
lives during the coming decade unless efforts to control its
transmission and deliver treatment in a timely fashion are improved.
Most of these deaths will occur in persons aged 20 to 30 upon whom
both younger and older persons rely for their support.  Tuberculosis
is responsible for an estimated 26 percent of all avoidable deaths in
the 5 to 59 years age group.  This increases the economic burden of
the disease that remains the world's leading cause of death from any
infectious agent.  Most tuberculosis cases occur in developing
countries where poor, crowded living conditions and inadequate
nutrition prevail, and where public health programs are limited.
Yet, the disease is not confined by national boundaries.

In the United States, after decades of successful control and
decreasing rates of disease, tuberculosis is making a comeback.
About 10 million people in the U.S. are infected by the tuberculosis
bacillus.  The vast majority of these individuals are not sick and
they are not infectious but remain at risk to develop active disease.
During 1992, 26,678 cases of active tuberculosis were reported to the
Centers for Disease Control up 20 percent from 1985 when resurgence
of the disease began.  This trend continues, among those with AIDS,
the homeless, chronic alcohol or drug-abuse, those living in
long-term care facilities (nursing homes, jails, etc.) and especially
among certain  minorities.  During 1991, more than 56 percent of the
active cases of tuberculosis were reported among Hispanic or African
Americans.

The resurgence of tuberculosis is a matter of grave concern for
physicians and other health care workers, especially those charged
with care of patients with active disease.  These workers must treat
the patient and limit transmission of an airborne infectious agent.

Role of HIV Epidemic and the Emergence of Multiple-Drug-Resistant
Disease

The difficulties associated with early diagnosis and successful
treatment of tuberculosis are compounded by two evolving
developments:  (1) the impact of the HIV epidemic on tuberculosis and
(2) the recent accumulation in the number of isolates of
multi-drug-resistant Mycobacterium tuberculosis (MDRTB).

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 have been identified as synergistic.  HIV
infection increases the chance of primary tuberculosis and 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.

Among HIV-infected persons, tuberculosis can result in death during
the first month of treatment or even before diagnosis.  Finally,
HIV+, TB+ patients may remain infectious due to difficulties in
diagnosing tuberculosis.  This increases the likelihood of
transmission and poses additional challenges for public health
authorities.

The transmission of MDRTB poses a major threat, especially to health
care workers, social workers, prison personnel, and other contacts at
risk. Treatment of MDRTB infections is difficult, expensive, and
often unsuccessful.  Successful treatment of tuberculosis, especially
MDRTB, 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.

Treated effectively, both HIV+ and HIV- tuberculosis patients rapidly
become non-infectious.  MDRTB response to appropriate treatment is
markedly improved by early diagnosis.  These circumstances support
the need for urgent development of more rapid diagnostic testing in
M. tuberculosis infections.

The skin test, also called the Mantoux test, is used to determine
primary infection by M. tuberculosis.  This test will show a positive
result for most people who have been exposed to tuberculosis.  Other
tests are required to determine the presence of active disease.  A
recent conversion to a positive skin test suggests the start of a new
infection.  Yet this test is not reliable for HIV infected persons.
Patients with dual HIV and tuberculosis infections often do not
respond to the skin test.  This may delay diagnosis and treatment of
newly infected patients, prolonging the period of infectivity.  Chest
X-rays of HIV infected tuberculosis patients are unreliable as well.

Current Tuberculosis Diagnostics

TB diagnostics need to be improved.  Some of the procedures commonly
used today date from the last century.  Many of these tests are too
slow and/or lack sensitivity.  Active tuberculosis is currently
diagnosed using an assortment of techniques, symptoms, and clinical
signs.  These techniques include the chest X-ray, microscopy, and
culture of the organism from clinical samples, typically sputum.
Diagnosis based on symptoms, X-ray, or even microscopy is not
definitive.  The current gold standard is culture.  A total of 6 to
13 weeks is often needed to identify the organism and determine its
pattern of antibiotic susceptibility.  Although effective
implementation of current technologies can substantially reduce the
time needed, the physician planning treatment for a suspected
tuberculosis patient vitally needs this diagnostic information.  In
the past, delays in obtaining this fundamental information were
thought to be acceptable, because the progress of the disease was
usually quite slow.  This is no longer true.  The rapid progress of
the disease in HIV infected individuals and the continued emergence
of drug-resistant disease underscore the need for new rapid and
sensitive diagnostics.  Thus, some of the current widely used
diagnostics are not effective for use in immune-suppressed persons,
those most in need.

Research Objectives and Scope

Rapid, reliable, sensitive, and specific diagnostic tests are not
available.  A positive tuberculin skin test provides only a
presumptive diagnosis.  It does not distinguish between latent and
active disease and has only limited value for those co-infected with
HIV.  Acid-fast sputum samples indicate only that some species of
mycobacteria are present.  Isolation and identification of M.
tuberculosis using culture often requires six to eight weeks.
Antibiotic susceptibility determinations often require additional
time.  Antigens and metabolites specific for M. tuberculosis for use
in serodiagnostic tests are greatly needed.  Development or
improvement of diagnostics tests that would be effective for use in
both normal and immunocompromised persons are encouraged.

The purpose of this RFA is to stimulate and encourage high quality
innovative research leading toward a greater understanding of
microbiological and immunological response to infection and advancing
to improvements in the diagnosis of tuberculosis.  These areas may
include, but are not limited to, studies to:

o  Develop improved methods for rapid, sensitive, specific, and
reliable identification of M. tuberculosis in clinical samples,
especially samples containing limited numbers of organisms, i.e.,
paucibacillary disease.

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.

o  Develop rapid methods for reliable identification of M.
tuberculosis, including MDRTB, in clinical specimens other than
sputum, including blood and spinal fluid.

o  Develop methods to distinguish latent and active tuberculosis
infections.

o  Identify low molecular weight compounds or metabolites that may
serve as specific markers for active or latent tuberculosis infection
and/or reflect the extent of the bacterial burden.

o  Develop improved in vitro or animal models for evaluation of
diagnostics.

o  Characterize cell surface antigens, including those expressed
exclusively, or primarily, during intracellular growth and develop
their use for diagnosis of active disease.

o  Define and characterize immune mechanisms associated with latent
tuberculosis infections and the mechanisms by which M. tuberculosis
persists in a quiescent state, and develop for use in the diagnosis
of latent infection.

The areas outlined above are not intended to be all-inclusive, nor
are they all required.  All research strategies designed to improve
knowledge anticipated to lead directly toward improved tuberculosis
diagnostics, or with the potential for improving current diagnosis
are encouraged.

SPECIAL REQUIREMENTS

NIAID program staff will organize annual meetings that Principal
Investigators and other key members (as designated by the Principal
Investigators in consultation with the program staff) of the projects
will be invited to attend to discuss progress.  Funds for travel to
these meetings should be included in the budget.  NIAID program staff
will also arrange for the participation in these meetings of
investigators from other relevant NIAID-supported tuberculosis
research projects, if appropriate, in order to further promote
relevant interactions.

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 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
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 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.

NOTE:   Peer review groups need adequate information about the
composition of proposed study populations is all applications
involving human subjects.  To avoid delays in review of such
applications, the NIAID therefore requires that, at a minimum, the
application must contain demographic data about the clinic and/or
in-patient population from which the study subjects will be drawn:
average hospital admissions 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 sites should
be provided.

LETTER OF INTENT

Prospective applicants are asked to submit, by January 7, 1994, 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.  A letter of intent is not
required, is not binding, and does not enter into the review of
subsequent applications.  It will be used to assist NIAID staff in
estimating the potential review workload and avoiding 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

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 Information, Division of Research Grants, National Institutes
of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone
301/710-0267.  Applicants for FIRST (R29) awards must attach three
reference letters (in sealed envelopes) to the face page of the
original application.

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 must be included in the application material.

The RFA label available in the PHS 398 (rev. 9/91) of 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 RFA title (Tuberculosis Diagnostics) and number
(AI-93-023) must be typed on line 2a of the face page of the
application.

The typed and signed original application and three exact
single-sided photocopies must be sent or delivered 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 must be sent
to Dr. Olivia Preble at the address listed under INQUIRIES.

Applications received after the receipt date will be returned without
review.  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 an
application already reviewed.  These applications must, however,
include an introduction addressing the previous critique.

REVIEW CONSIDERATIONS

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 application at the next review cycle.

Those applications that are complete and responsive may be subjected
to 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 the institutional business officials.

Those applications judged by the reviewers to be competitive for
award will be further 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 an 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 nor 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.

AWARD CRITERIA

The anticipated date of award is September 1994.

The NIAID will consider for funding all R01s and R29s rated by peer
review as having significant and substantial scientific merit.
Awards are subject to the availability of funds.

INQUIRIES

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
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
Solar Building, Room 3B10
Bethesda, MD  20892
Telephone:  (301) 496-5305
FAX:  (301) 496-8030
E-Mail:  [email protected]

Direct letters of intent and inquiries regarding the review of
applications 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 4B35
Bethesda, MD  20892
Telephone:  (301) 496-7075

Schedule

Letter of Intent Receipt Date:  January 7, 1994
Application Receipt Date:       February 18, 1994
Scientific Review Date:         June 15, 1994
Advisory Council Date:          September 1994
Earliest Award Date:            September 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 grant 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.

.

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