Full Text AI-93-02

TUBERCULOSIS VACCINE DEVELOPMENT

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

RFA:  AI-93-02

P.T. 34

Keywords: 
  Diagnosis, Medical 
  Infectious Diseases/Agents 
  Immunology 
  Clinical Medicine, General 
  Biomedical Research, Multidiscipl 
  Bioassay 


National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  January 19, 1993
Application Receipt Date:  March 18, 1993

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 for basic research
that will lead to the development of effective new vaccines for the
prevention and control of tuberculosis.  At present, a live
attenuated strain of Mycobacterium bovis, Bacillus Calmette Guerin
(BCG), is the only vaccine available for protecting humans from
tuberculosis.  Protection elicited by BCG in controlled clinical
trials has been variable  Applications that feature improvements to
BCG will not be considered responsive to this Request for
Applications (RFA).  However, applications that use BCG components in
the development of a novel vaccine(s) are encouraged.

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 RFA,
Tuberculosis Vaccine Development, is related to the priority areas
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

Domestic and foreign non-profit and for-profit organizations and
institutions, governments and their agencies, are eligible to apply.
Foreign institutions are not eligible for First Independent Research
Support and Transition (FIRST) (R29) awards.  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.

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

FUNDS AVAILABLE

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 and the availability of
funds.

RESEARCH OBJECTIVES

Background

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 had declined steadily for
40 years.  This trend stopped in 1985.  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 an
estimated 2000 deaths annually.  Approximately 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 contributed 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 (see,
for instance, Morbidity and Mortality Weekly Reports, March 1, 1991,
Vol. 40, No. 8 and June 19, 1992, Vol. 41, No. RR-11).  The case
fatality rate for TB resistant to two or more drugs (MRDTB) is 40 to
60 percent, and the overall costs for treatment of these cases is
five times higher than for drug-susceptible TB patients.

While treatment of drug-responsive tuberculosis infections is
generally effective, the treatment regimen is lengthy, and many
patients do not complete therapy.  This interruption in treatment not
only increases the likelihood of relapse but also is believed to
promote the emergence of drug-resistant Mycobacterium tuberculosis
strains.  These problems continue, mainly because of the lack of a
safe and efficacious vaccine to control tuberculosis.

An effective vaccine will likely induce responses in the host similar
to those induced by natural infection.  Ordinarily, persons are
infected after exposure to an infected patient.  Tuberculosis is
transmitted through airborne droplets containing the bacillus.  The
transmission is difficult to control through behavior modification
for the principal risk factor is breathing.  Inhaled bacilli are
typically ingested by phagocytes in the lung where they may either be
killed or grow to a limited extent.   Usually, cell-mediated immunity
develops with a few weeks and the infection is controlled.  A clear
understanding of this immunity and of other aspects of the host
response to natural infection could serve as the basis for the
development of a safe, effective vaccine.  Identification of
protective antigens and epitopes could provide insight into both
pathogenic mechanisms and the immunologic responses evoked in the
infected host.

At present, a live attenuated strain of Mycobacterium bovis, Bacillus
Calmette-Guerin [BCG], is the only vaccine available for protection
of humans from tuberculosis.  Protection elicited by BCG in
controlled clinical trials has been variable; therefore, the efficacy
of this vaccine has been seriously questioned.  Moreover, there is no
single BCG vaccine.  It is produced at dozens of sites located
throughout the world, each site maintaining its individual seed
strain.  This potential for diversity is a cause for concern among
some health care personnel.  Because BCG is a live vaccine, it may be
unsuitable for HIV-positive individuals; it is contraindicated for
AIDS patients.  A new, more effective vaccine that prevents primary
and/or reactivation tuberculosis would be of great benefit.

Research Objectives

The long term goal of this initiative is to promote efforts to
develop new, more effective vaccines, not based on BCG, to prevent
and control tuberculosis.  This will require innovative research
approaches to develop candidate vaccine preparations that will elicit
appropriate and protective functional responses.  In order to achieve
this objective, a focused effort on the basic biology of the
mycobacterium and an understanding of the host response to natural
infection is needed.  Consistent with this, applicants are encouraged
to develop innovative projects that address any of, though not be
limited to, the following areas:

o  Identification and characterization of components of M.
tuberculosis that are immunogenic.

o  Identification and characterization of immunogens that elicit
responses by the host during natural infection.

o  Isolation and characterization of relevant immunogen-coding
sequences and their products.

o  Characterization of the host response to natural infection and
definition of the correlates of protective immunity.

Should an applicant have access to, or have already identified and
prepared a novel candidate vaccine, this RFA would also encourage
research in the area of:

o  Enhancement of the immunogenicity of candidate vaccine immunogens.

o  Development of animal model(s) for testing candidate vaccine
immunogens.

The areas outlined are not intended to be all-inclusive nor are they
all required.

SPECIAL REQUIREMENTS

NIAID program staff will organize annual meetings that Principal
Investigators and other key members (as designated by the Principal
Investigators) of the projects are 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 may 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
fruitful 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.

LETTER OF INTENT

Prospective applicants are asked to submit, by January 19, 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.
Although a letter of intent is not required, is not binding, and does
not enter into the review of subsequent applications, the information
it contains 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.

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 for 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 18, 1993. Applications
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 must 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 RFA title
"Tuberculosis Vaccine Development" and number (AI-93-02)  must be
typed on line 2a of the face page of the application and the "Yes"
box marked.

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 to the Division of Research Grants (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
review.  Alternatively, the late applicant will be contacted and
given the choice of having the application returned or of having it
submitted for review in competitition with unsolicited applications
at the next 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 exclude
the submission of substantial revisions of 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 complete but not responsive to
the RFA, NIAID staff will contact the applicant and present the same
options for handling the application as in late applications, above.

Applications may be triaged by an NIAID peer review group on the
basis of relative competitiveness among the applications responsive
to the RFA.  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 review committee convened by the 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, 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.

AWARD CRITERIA

The anticipated date of award is September 30, 1993.

The primary criterion for award is the scientific and technical merit
of the application as judged by peer reviewers and reflected in the
priority score. Additional award criteria are the availability of
funds and the receipt of a sufficient number of scientifically
meritorious applications that are responsive to the RFA.

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
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, Microbiology and Infectious Diseases Grants Management Section
Grants Management Branch
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Bldg., 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, MD  20852

SCHEDULE

Letter of intent date:     January 19, 1993
Application receipt date:  March 18, 1993
Scientific review date:    July 1993
Advisory Council date:     September 1993
Award date:                September 30, 1993

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.

.

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	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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