Release Date:  March 14, 2001
RFA:  RFA-AI-01-009

National Institute of Allergy and Infectious Diseases (NIAID)

National Heart, Lung, and Blood Institute (NHLBI)

Letter of Intent Receipt Date:  June 16, 2001
Application Receipt Date:       July 16, 2001




The objective of this Request for Applications (RFA) is to stimulate 
investigator-initiated research to elucidate the mechanisms underlying 
persistent, asymptomatic infection (also referred to as “latency”) with 
Mycobacterium tuberculosis.  Of the 1.86 billion persons infected with 
M. tuberculosis worldwide, 90% harbor the bacterium but do not display 
symptoms.  However, these latent infections may convert to active 
tuberculosis that renders patients infectious and capable of 
transmitting M. tuberculosis to others.  The rate of conversion from 
latent to active tuberculosis depends on the immune status of the 
patients and may be as high as 10% per year in HIV co-infected persons, 
who constitute about 0.18% of the world population and 8% of all TB 
cases.  The increased rate of conversion to active TB in HIV/TB co-
infected persons also increases the potential for spread of 
tuberculosis and clearly contributes to the global threat from this 
disease.  (The prevalence of HIV/TB co-infection is as high as 1194 
cases per 100,000 individuals in some high burden countries.)  In the 
US alone, it is estimated that 10-15 million people are infected with 
M. tuberculosis.  A better understanding of persistent infection is an 
essential step toward developing improved intervention strategies to 
eliminate tuberculosis as a public health problem.


The Public Health Service (PHS) is committed to achieving the health 
promotion and disease prevention objectives of "Healthy People 2010," a 
PHS led national activity for setting priority areas.  This Request for 
Applications (RFA), “Response to the Presidential Vaccine Initiative - 
Overcoming the Tuberculosis Latency Challenge”, is related to one or 
more of the focus areas.  Potential applicants may obtain a copy of 
"Healthy People 2010" at


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 and 
local governments; and eligible agencies of the Federal government.  
Although foreign institutions are not eligible to apply for Program 
Project (P01) grants, they are permitted as subprojects.  Racial/ethnic 
minority individuals, women, and persons with disabilities are 
encouraged to apply as Principal Investigators.


This RFA is being co-sponsored by NIAID and NHLBI.  The mechanisms of 
support will be the individual research project grant (R01), 
Exploratory/Developmental Research Project Grant (R21) and the Program 
Project Grant (P01) for NIAID.  NHLBI will support only R01 and R21 
grant applications received in response to this RFA.  The total 
requested project period for an application submitted in response to 
this RFA may not exceed five years for an R01, two years for an R21, 
and five years for a P01 grant.  

Responsibility for the planning, direction, and execution of the 
proposed project will be solely that of the applicant.

NIAID and NHLBI use R21 grants to provide short-duration support for 
preliminary studies of a highly speculative nature, which are expected 
to yield, within this time frame, sufficient information upon which to 
base a well-planned and rigorous series of further investigations.  R21 
applications in response to this RFA may not request more than $150,000 
direct costs per year and the total requested project period may not 
exceed two years. 

P01 grant applications may be accepted by NIAID, but not by NHLBI in 
response to this RFA.  The P01 grants are used to support broadly based 
multidisciplinary research programs that have a well-defined central 
research focus or objective.  An important feature is that the 
interrelationships among the individual scientifically meritorious 
projects will result in a greater contribution to the overall program 
goals than if each project was pursued individually.  The program 
project grant consists of a minimum of three interrelated individual 
research projects that contribute to the program objective.  The award 
also can provide support for certain common resources termed cores.  
Such resources should be utilized by two or more projects within the 
award. A P01 application should be prepared using the guidance and 
instruction provided in the NIAID Information Brochure for Program 
Projects and Grants, available at:  A P01 application in 
response to this RFA may not request more than $750,000 total costs 
without prior program staff approval (contact information listed in 
INQUIRIES section).  

Specific application instructions have been modified to reflect 
"MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined 
by the NIH.  Complete and detailed instructions and information on 
Modular Grant applications can be found at

A notice of modification and update (OD-00-046) regarding modular 
grants was released on 7/24/00 and can be found at

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


The estimated total funds (direct and Facilities and Administrative 
(F&A) Costs) available for the first year, fiscal year 2002, of this 
RFA will be $1.5 million from NIAID and $0.5 million from NHLBI, a 
total of $2.0 million.  In Fiscal Year 2002 the NIAID plans to fund 
approximately two to four grants and NHLBI plans to fund one to two 
grants (three to six grants total). The usual NIH policies governing 
grants administration and management will apply.  Although this program 
is provided for in the financial plans of the NIAID and NHLBI, awards 
pursuant to this RFA are contingent upon the availability of funds for 
this purpose and the receipt of a sufficient number of applications of 
high scientific merit.  Funding beyond the first and subsequent years 
of the grant will be contingent upon satisfactory progress during the 
preceding years and availability of funds.



As a response to the Presidential Millennium Vaccine Initiative, 
national and international agencies have committed to further 
development of TB, malaria and HIV vaccines.  This RFA is part of the 
NIAID and NHLBI response to the vaccine initiative.  Both NIAID and 
NHLBI intend to support research to increase our understanding of the 
biological mechanisms underlying human M. tuberculosis infection and 
host response.  Persistent infection and reactivation of disease is an 
important, but poorly understood aspect of human TB.  Understanding 
these aspects of TB is critical to developing new diagnostic tools and 
identifying potential new vaccine and/or therapeutic targets.

The recent NIAID Workshop “Addressing the Presidential Challenge”, held 
May 22-23, 2000, identified the lack of appropriate animal models that 
accurately reflect human tuberculosis infection as a significant 
technical barrier to developing new or improved TB vaccines.  The TB 
working group convened by NHLBI in September of 1999 and an NHLBI RFA 
grantees meeting in September of 2000 also emphasized the need for 
better animal models and more in vivo research to improve our 
understanding of host-mycobacterial interactions and the pathogenesis 
of tuberculosis, both for latency and reactivation.  This type of 
research is an important aspect of vaccine development and testing.  
New and improved animal models not only would be instrumental in the 
early evaluation of vaccine and drug candidates before efficacy studies 
in humans are undertaken, but also would allow further characterization 
of latent mycobacterial infection in a nonhuman host.  Previous 
attempts by NIAID and NHLBI to stimulate interest and opportunities in 
this research area have not been very successful due to the technical 
challenges and inherent slow pace of this research.  However, the 
availability of the M. tuberculosis genome sequence has opened new 
avenues to exploring gene and protein expression during persistent 
infection and reactivation, and progress has begun in a number of 
laboratories towards developing and validating improved models of human 
“latency”.  The primary goal of this RFA is to engage investigators in 
innovative pursuits that will further our understanding of “latency” 
and reactivation through the development of consistent, reliable animal 
models of persistent, asymptomatic human M. tuberculosis infection and 
Research Objectives and Scope

To pursue the above-described goal, we encourage applications in the 
following research areas:

o Novel approaches, to characterizing mycobacterial physiology and gene 
expression patterns, as well as host response during persistent, 
asymptomatic human M. tuberculosis infection.  These approaches should 
be based on human tissues and/or M. tuberculosis isolated from these 
tissues, whenever possible, take advantage of new genomic-, proteomic-, 
and/or nano-technologies, and potentially lead to development of 
surrogate microbiologic or immunologic markers for persistent infection 
in humans.  The use of theoretical or mathematical models could be 
considered as a possible component of the proposed projects.

o Development of consistent, reliable animal models that mimic 
persistent, asymptomatic human M. tuberculosis infection and 
reactivation.  These models, once developed, should be useful for 
furthering our understanding of the mechanisms underlying these 
phenomena and/or serve as screening models for potential TB vaccines or 
drug candidates.  Methods for validating these models should also be 
proposed where possible, including, for example, comparison of gene 
expression patterns between mycobacteria in model animal tissues and in 
tissues from humans with “latent” infection.

Any investigators interested in developing drug therapies against 
persistent and/or reactivated tuberculosis may find the following 
program of interest: NIH Inter-Institute Pilot Program for the 
Development of AIDS-Related Therapeutics


NIAID and NHLBI plan to sponsor an annual meeting to encourage the 
exchange of information among investigators supported under this RFA, 
foster collaborative efforts, and identify resources that would enhance 
the productivity of this research program.  For this purpose, travel 
funds for an annual one to two day meeting, to be held in the 
Washington DC area, should be included in the budget request.


When clinical studies or trials are a component of the research 
proposed, NIAID policy requires that studies be monitored commensurate 
with the degree of potential risk to study subjects and the complexity 
of the study.  Terms and Conditions of Award will be included with 
awards.  NIAID policy was announced in the NIH Guide on February 24, 
2000 and is available at:  
he full policy, including terms and 
conditions of award, is available at:

Policies and guidance for clinical research funded by NHLBI can be 
found on the Institute web site located at:


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, compelling rationale, and justification are provided 
that inclusion is inappropriate with respect to the health of the 
subjects or the purpose of the research.  This policy results from the 
NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43).

All investigators proposing research involving human subjects should 
read the UPDATED "NIH Guidelines For Inclusion of Women and Minorities 
as Subjects in Clinical Research," published in the NIH Guide for 
Grants and Contracts on August 2, 2000 
(; a 
complete copy of the updated Guidelines are available at:  
The revisions relate to NIH-defined Phase III clinical trials and 
require:  a) all applications or proposals and/or protocols to provide 
a description of plans to conduct analyses, as appropriate, to address 
differences by sex/gender and/or racial/ethnic groups, including 
subgroups if applicable; and b) all investigators to report accrual, 
and to conduct and report analyses, as appropriate, by sex/gender 
and/or racial/ethnic group differences.


It is the policy of NIH that children (i.e., individuals under the age 
of 21) must be included in all human subjects research, conducted or 
supported by the NIH, unless there are scientific and ethical reasons 
not to include them.  This policy applies to all initial (Type 1) 
applications submitted for receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should 
read the "NIH Policy and Guidelines on the Inclusion of Children as 
Participants in Research Involving Human Subjects" that was published 
in the NIH Guide for Grants and Contracts, March 6, 1998, and which is 
available at the following URL address:    

Investigators may obtain copies from these sources or from the program 
staff (listed in INQUIRIES section) who may also provide additional 
relevant information concerning the policy.


All applications and proposals for NIH funding must be self-contained 
within specified page limitations.  Unless otherwise specified in an 
NIH solicitation, Internet addresses (URLs) should not be used to 
provide information necessary to the review because reviewers are under 
no obligation to view the Internet sites.  Reviewers are cautioned that 
their anonymity may be compromised when they directly access an 
Internet site.


Prospective applicants are asked to submit, by June 16, 2001, 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, and does not enter 
into the review of a subsequent application, the information that it 
contains allows staff to estimate the potential review workload and to 
plan the review.  The letter of intent is to be sent to Dr. Edward 
Schroder at the address listed under INQUIRIES.


Applicants are strongly encouraged to call NIAID and NHLBI program 
staff with any questions regarding the responsiveness of their proposed 
project to the goals of this RFA.  

The research grant application form PHS 398 (rev. 4/98) is to be used 
in applying for these grants. Application kits are available at most 
institutional offices of sponsored research and may be obtained from 
the Division of Extramural Outreach and Information Resources, National 
Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 
20892-7910, telephone 301/710-0267, email: In 
addition, the application kits can be found on the following URL:

For purposes of identification and processing, item 2a on the face page 
of the application must be marked "YES" and the RFA number AI-01-009 
and the words "Response to the Presidential Vaccine Initiative – 
Overcoming the Tuberculosis Latency Challenge" must be typed in.

The RFA label and line 2 of the application should both indicate the 
RFA number.  The RFA label 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.

The sample RFA label available at: has been 
modified to allow for this change.  Please note this is in pdf format.

Applications must be received by July 16, 2001.  Applications not 
received as a single package on the receipt date or not conforming to 
the instructions, including page limitations and font size, contained 
in PHS 398 (rev. 4/98) Application Kit (as modified in, and superseded 
MULTI-PROJECT AWARDS”), will be judged non-responsive and will be 
returned to the applicant. 

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 that is 
essentially identical to one that has already been reviewed cannot be 
submitted in response to this RFA.  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:

6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express mail or courier service)

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. Edward Schroder
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room Number 2151, MSC-7616
6700-B Rockledge Drive
Bethesda, MD  20892-7616

Applications must be received by the application receipt date listed in 
the heading of this RFA.  If an application is received after that 
date, it will be returned to the applicant without review.

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 


Applicants for P01 grants must follow special application guidelines in 
PROJECT AWARDS (August 2000); this brochure is available via the WWW 

The brochure presents specific instructions for sections of the PHS 398 
(rev. 4/98) application form that should be completed differently than 
usual.  For all other items in the application, follow the usual 
instructions in the PHS 398.  A P01 application in response to this RFA 
may not request more than $750,000 total costs without prior program 
staff approval (contact information listed in INQUIRIES section).
Concurrent submissions of a component research project of a multi-
project (P01) grant application as a traditional individual research 
project (R01) to this RFA is prohibited.


R01 and R21 applications in response to this RFA should use the modular 
grant format.  R21 applications in response to this RFA may not request 
more than $150,000 direct costs per year and the total requested 
project period may not exceed two years. 
Modular Grant applications will request direct costs in $25,000 
modules, up to a total direct cost request of $250,000 per year. 
Applications that request more than $250,000 direct costs in any year 
must follow the traditional PHS 398 application instructions.  For 
grants at $250,000 and below, the total direct costs must be requested 
in accordance with the program guidelines and the modifications made to 
the standard PHS 398 application instructions, which are described 

o FACE PAGE: Items 7a and 7b should be completed, indicating Direct 
Costs (in $25,000 increments up to a maximum of $250,000) and Total 
Costs (Modular Total Direct plus Facilities and Administrative  (F&A) 
costs) for the initial budget period Items 8a and 8b should be 
completed indicating the Direct and Total Costs for the entire proposed 
period of support.

Page 4 of the PHS 398. It is not required and will not be accepted with 
the application.

the categorical budget table on Form Page 5 of the PHS 398. It is not 
required and will not be accepted with the application.

o BUDGET NARRATIVE JUSTIFICATION - Prepare a Modular Grant Budget 
Narrative page. (See for sample 
pages.) At the top of the page, enter the total direct costs requested 
for each year.  This is not a Form page.

Under Personnel, provide budget narrative for ALL personnel by 
position, role and level of effort.  This includes consultants and any 
“to be appointed” positions.  No individual salary information should 
be provided. However, the applicant should use the NIH appropriation 
language salary cap and the NIH policy for graduate student 
compensation in developing the budget request.

For Consortium/Contractual costs, provide an estimate of total costs 
(direct plus facilities and administrative) for each year, each rounded 
to the nearest $1,000. List the individuals/organizations with whom 
consortium or contractual arrangements have been made, the percent 
effort of all personnel, and the role on the project. Indicate whether 
the collaborating institution is foreign or domestic. The total cost 
for a consortium/contractual arrangement is included in the overall 
requested modular direct cost amount.  Include a Letter of Commitment 
or Intent if there is or is to be a subcontract/consortium.

Provide an additional narrative budget justification for any variation 
in the number of modules requested.

o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information 
used by  reviewers in the assessment of each individual's 
qualifications for a specific role in the proposed project, as well as 
to evaluate the overall qualifications of the research team. A 
biographical sketch is required for all KEY personnel, including 
consultants, following the instructions below. No more than three pages 
may be used for each person. A sample biographical sketch may be viewed 
- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on 
research projects ongoing or completed during the last three years;
- List selected peer-reviewed publications, with full citations.

o CHECKLIST - This page should be completed and submitted with the 
application. Applicant institutions should calculate the Facilities and 
Administration (F&A) costs using the current negotiated F&A rate, less 
exclusions, for the initial budget period and all future budget 
periods.  It is not necessary to list the exclusions on the Checklist 
nor anywhere in the application.  If the F&A rate agreement has been 
established, indicate the type of agreement and the date. All 
appropriate exclusions must be applied in the calculation of the F&A 
costs for the initial budget period and all future budget years.

o The applicant should provide the name and phone number of the 
individual to contact concerning fiscal and administrative issues if 
additional information is necessary following the initial review. 


Review Procedures

Upon receipt, applications will be reviewed for completeness by Center 
for Scientific Review and for responsiveness by NIAID and NHLBI staff.  
Incomplete and/or non-responsive applications will be returned to the 
applicant without further consideration.

Review Considerations

Applications that are complete and responsive to the RFA will be 
evaluated for scientific and technical merit by an appropriate peer 
review group convened by the Division of Extramural Activities, NIAID 
in accordance with the review criteria stated below. As part of the 
initial merit review, all applications will receive a written critique 
and undergo a process in which only those applications deemed to have 
the highest scientific merit, generally the top half of the 
applications under review, will be discussed, assigned a priority 
score, and receive a second level of review provided by the National 
Advisory Allergy and Infectious Diseases Council and the National 
Heart, Lung and Blood Advisory Council.

The initial review group will examine: the appropriateness of the 
proposed project budget and duration; the adequacy of plans to include 
children and both genders and minorities and their subgroups as 
appropriate for the scientific goals of the research and plans for the 
recruitment and retention of subjects; the provisions for the 
protection of human and animal subjects; and the safety of the research 

Review Criteria for P01 Grant Applications

The general criteria for P01 grant applications are presented in the 
AWARDS (August 2000).  

Review Criteria for R01 and R21 grant applications

The criteria to be used in the evaluation of R01 and R21 grant 
applications are listed below.  To put those criteria in context, the 
following information is contained in instructions to the peer 

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  
The reviewers will comment on the following aspects of the application 
in their written critiques in order to judge the likelihood that the 
proposed research will have a substantial impact on the pursuit of 
these goals.  Each of these criteria will be addressed and considered 
by the reviewers in assigning the overall score weighting them as 
appropriate for each application.  Note that the application does not 
need to be strong in all categories to be judged likely to have a major 
scientific impact and thus deserve a high priority score.  R21 
applications should be evaluated based more on innovation and/or 
potential significance for moving a field forward, than feasibility; 
preliminary data are not required for R21 applications.

1.  Significance.  Does this study address an important problem? If the 
aims of the application are achieved, how will scientific knowledge be 
advanced?  What will be the effect of these studies on the concepts or 
methods that drive this field?

2.  Approach.  Are the conceptual framework, design, methods, and 
analyses adequately developed, well-integrated, and appropriate to the 
aims of the project?  Does the applicant acknowledge potential problem 
areas and consider alternative tactics? 

3.  Innovation.  Does the project employ novel concepts, approaches or 
method?  Are the aims original and innovative? Does the project 
challenge existing paradigms or develop new methodologies or 

4.  Investigator.  Is the investigator appropriately trained and well 
suited to carry out this work?  Is the work proposed appropriate to the 
experience level of the principal investigator and other researchers 
(if any)?

5.  Environment.  Does the scientific environment in which the work 
will be done contribute to the probability of success?  Do the proposed 
experiments take advantage of unique features of the scientific 
environment or employ useful collaborative arrangements?  Is there 
evidence of institutional support?


Letter of Intent Receipt Date:    June 16, 2001 
Application Receipt Date:         July 16, 2001
Scientific Peer Review Date:      October, 2001
Advisory Council Date:            February, 2002
Earliest Anticipated Award date:  April, 2002 

Funding decisions will be made on the basis of scientific
and technical merit as determined by peer review, programmatic 
priorities, and the availability of funds. The earliest anticipated 
date of award is April, 2002.

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 (research scope and 
eligibility) issues to:  

Christine Sizemore, Ph.D.  
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases  
Room 3131, MSC- 7630
6700-B Rockledge Drive
Bethesda, MD  20892-7630
Telephone:  (301) 496-5305
FAX:        (301) 496-8030
Hannah H. Peavy, M.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 10018, MSC 7952
Bethesda, MD  20892-7952
Telephone:  (301) 435-0222
FAX:        (301) 480-3557

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:
Edward Schroder, Ph.D.  
Division of Extramural Activities  
National Institute of Allergy and Infectious Diseases  
Room 2151, MSC-7616
6700-B Rockledge Drive  
Bethesda, MD  20892-7616
Telephone:  (301) 435-8537
FAX:        (301) 402-2638

Direct inquiries regarding fiscal matters to:  

Ms. Ann Devine
Division of Extramural Activities  
National Institute of Allergy and Infectious Diseases  
Room 2118, MSC-7614
6700-B Rockledge Drive  
Bethesda, MD  20892-7614  
Telephone:  (301) 402-5601
Fax:        (301) 480-3780


This program is described in the Catalogue of Federal Domestic 
Assistance No. 93.856 and No. 93.361.  Awards are made under 
authorization of Sections 301 and 405 of the Public Health Service Act 
as amended (42 USC 241 and 284) and administered under NIH grants 
policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 72,and 
92.  This program is not subject to the intergovernmental review 
requirements of Executive Order 12372 or Health Systems Agency review.

The Public Health Service strongly encourages all grant and contract 
recipients to provide a smoke-free workplace and promote the non-use of 
all tobacco products. In addition, Public Law 103-227, the Pro-Children 
Act of 1994, prohibits smoking in certain facilities (or, in some 
cases, any portion of a facility) in which regular or routine 
education, library, day care, health care or early childhood 
development services are provided to children.  This is consistent with 
the PHS mission to protect and advance the physical and mental health 
of the American people.

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