NON-HUMAN PRIMATE HEART/LUNG TRANSPLANTATION TOLERANCE

RELEASE DATE: August 20, 2004

RFA Number:  RFA-AI-04-049 (This RFA has been reissued, see RFA-AI-09-041)

(This RFA has been reissued, see RFA-AI-06-018)

EXPIRATION DATE:  December 22, 2004

Department of Health and Human Services (DHHS) 

PARTICIPATING ORGANIZATION:
National Institutes of Health (NIH) 
(http://www.nih.gov)

COMPONENT OF PARTICIPATING ORGANIZATION:
National Institute of Allergy and Infectious Diseases (NIAID) 
(http://www.niaid.nih.gov)

CATALOGUE OF FEDERAL DOMESTIC ASSISTANCE NUMBERS:
No. 93.855, Immunology, Allergy, and Transplantation Research
No. 93.856, Microbiology and Infectious Diseases Research

LETTER OF INTENT RECEIPT DATE: November 22, 2004
APPLICATION RECEIPT DATE: December 21, 2004  

THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanisms of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements 
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Supplementary Instructions
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS RFA 

The National Institute of Allergy and Infectious Diseases (NIAID) invites 
applications from single institutions or consortia of institutions to 
participate in the Non-Human Primate Immune Tolerance Cooperative Study Group 
(NHPCSG). The NHPCSG is a multi-center, cooperative program for research on 
non-human primate (NHP) models of kidney and islet transplantation, 
established in 1999 to evaluate preclinical safety and efficacy of existing 
and newly developed immune tolerance induction regimens and to elucidate the 
underlying mechanisms of the induction, maintenance, and/or loss of tolerance 
in these models. The long-range goal of this program is to develop and 
evaluate tolerance-induction regimens that will result in enhanced long-term 
graft survival in clinical transplantation of all organs and tissues. The 
purpose of this RFA is to expand the scope of transplantation models studied 
within the NHPCSG to include NHP models of heart and lung transplantation.

RESEARCH OBJECTIVES

Background

Organ or tissue transplantation is the preferred treatment for many end-stage 
organ diseases when other therapies have failed or are unavailable. However, 
despite significant advances in immunosuppressive medications over the past 15 
years that have led to one-year graft survival rates that approach or exceed 
90% for most organs, long-term graft survival and, in many cases, patient 
survival remains poor for all organ transplants. In addition, life-long, 
global immunosuppressive therapy results in significant morbidity and has thus 
far not significantly enhanced long-term graft survival. The overwhelming 
leading cause of graft failure, both short- and long-term, is immune-mediated 
graft rejection. Advances in immune tolerance induction will eventually 
provide valuable new therapeutic strategies, which should eliminate the need 
for life-long, global immunosuppressive therapy, increase long-term graft 
survival and life expectancy, and improve health-related quality of life. For 
purposes of this RFA, immune tolerance is defined as the lack of a pathogenic 
immune response to allogeneic organs or tissues in the absence of ongoing 
immunosuppressive therapy.

Research targeted to the induction of immune tolerance in solid organ and 
islet transplantation is a high scientific priority for the NIAID. In 1997, 
the NIAID initiated a scientific planning process designed to accelerate 
research in this area.  The 1998 broad-based, long-range plan, entitled “NIAID 
Plan for Research on Immune Tolerance”, is available at 
http://www.niaid.nih.gov/publications/immune/bookcover.htm. The NIAID Expert 
Panel for Research on Immune Tolerance enthusiastically endorsed the 
conceptual framework, scope and timeliness of the plan and encouraged the 
NIAID to take a leadership role at NIH in designing and directing major 
research programs in immune tolerance, particularly with respect to the 
application of tolerance induction strategies for the treatment of human 
disease. Two subsequent panels, the NIAID Expert Panel on Ethical Issues in 
Clinical Trials of Transplant Tolerance and the Expert Review Panel for 
NIAID's Extramural Transplantation Research Program, identified NHP tolerance 
research as an essential step to provide "...critical data on safety, toxicity 
and potential efficacy that can not be obtained ethically in human clinical 
trials." In response to these recommendations, NIAID and the National 
Institute of Diabetes and Digestive Diseases (NIDDK) formally established a 
program in NHP models of kidney and islet transplantation in 1999 (RFA AI-99-
003, http://grants.nih.gov/grants/guide/rfa-files/RFA-AI-99-003.html) and 
expanded the program in 2002 (RFA AI-01-006, 
http://grants1.nih.gov/grants/guide/rfa-files/RFA-AI-01-006.html). In 
addition, due to the rising costs and decreasing supply of specific pathogen 
free (SPF) Cynomolgus macaques and Indian Rhesus macaques, NIAID established 
breeding colonies of these monkey species to support the NHPCSG’s research 
efforts. 

The goals of the NHPCSG include: (1) development of novel donor-specific 
tolerance induction regimens; (2) assessment of the safety and efficacy of 
existing and newly developed immune tolerance regimens in preparation for 
human clinical trials; (3) definition of underlying mechanisms of action of 
the therapeutic approaches under investigation and the mechanisms of 
induction, maintenance and/or loss of tolerance; and (4) development and 
validation of biomarkers for the induction, maintenance and/or loss of immune 
tolerance. Currently, all studies within the NHPCSG are limited to NHP models 
of kidney and islet transplantation. A wide range of immune tolerance 
induction protocols are under evaluation and development. 

NIAID’s primary area of focus in organ and tissue transplantation research is 
the immunology of graft rejection and survival and the induction of immune 
tolerance. These immunological issues are shared across all organs and 
tissues, although specific aspects of the immunological processes involved may 
differ. Indeed, studies from each organ may offer unique insights into various 
facets of immune tolerance induction and graft rejection. Therefore, what is 
learned regarding tolerance induction and graft rejection for one organ may be 
informative to the development of therapeutic strategies for other organs and 
tissues. In FY 2004, NIAID expanded the scope of human clinical studies 
supported in tissue and organ transplantation beyond kidney and islets 
consistent with the view that graft rejection is an immunological disease. 
This first targeted research program to reflect this expansion was the 
establishment of a cooperative clinical trials and mechanistic studies program 
called the Clinical Trials in Organ Transplantation or CTOT (RFA AI-04-003, 
http://grants2.nih.gov/grants/guide/rfa-files/RFA-AI-04-003.html.), which is 
co-sponsored by the National Heart, Blood and Lung Institute (NHLBI) and the 
NIDDK. NHP transplantation studies are critical to the design of 
scientifically sound and ethically acceptable clinical trials, due, in part, 
to the close approximation of the NHP immune system and physiology to those of 
humans. NIAID intends to complement and support these human clinical trial 
efforts by expanding the scope of the NHPCSG to include models of heart and 
lung transplantation. Several aspects of heart and lung transplantation 
underscore the need for further research from an immunological standpoint. 
While three-year graft survival rates in the range of 77% in heart 
transplantation are similar to 81% graft survival seen in kidney 
transplantation, patient survival rates are more discrepant – 78% in heart, 
versus 91% in kidney – due, in part, to the availability of dialysis for those 
with a failed kidney, and the absence of a comparable life support system for 
heart recipients with a failed graft. In addition, chronic rejection in heart 
transplantation is often “silent,” with the initial presentation resulting in 
death; in contrast to kidneys, non-invasive monitoring of cardiac function is 
not sensitive to the development of chronic rejection. Lung transplantation 
has an extremely poor five-year graft survival rate of approximately 45%, with 
similarly poor patient survival rates. The lung plays a primary role in the 
host defense against airborne pathogens and, in the transplant setting, this 
unique immune environment may be related to a heightened chronic rejection in 
the lung. What is learned from studies of lung allograft rejection may prove 
to be significantly informative for the immune-mediated aspects of chronic 
rejection in multiple organs. The timely expansion of the NHPCSG will help 
meet the scientific needs of the transplantation research community and allow 
capitalization on recent and future opportunities in heart and lung 
transplantation. 

Research Objectives and Scope

This RFA solicits grant applications to expand the scope of the current NHPCSG 
to include immune tolerance induction studies in NHP models of heart and lung 
transplantation. Currently the NHPCSG is funded exclusively for studies in 
islet and kidney transplantation. Because the long-range goal of this RFA is 
to develop and evaluate candidate tolerogenic approaches for transplantation 
in humans, NIAID expects that there will be reciprocal communication between 
the NHPCSG and NIH funded clinical trials programs. In addition, this 
interaction may result in potential opportunities to develop and participate 
in initial safety and efficacy pre-clinical studies. (See the Special 
Requirements and Collaborative Responsibilities sections below for additional 
discussion of potential opportunities and policies.)

All research projects to be supported under this RFA are limited to NHP heart 
and/or lung transplantation models. Specifically, this RFA calls for the use 
of any NHP species for allogeneic studies of heart and/or lung 
transplantation. While individual research approaches may vary, the research 
scope of applications is restricted to one or more of the following areas: 

(1) Development of novel donor-specific tolerance induction regimens or 
refinement of existing regimens; 

(2) Assessment of the safety and/or efficacy existing or newly developed 
immune tolerance regimens either alone, in combination with immunosuppressive 
therapy, and/or in combination with withdrawal of immunosuppressive therapy;  

(3) Studies to define the underlying mechanisms of action of the therapeutic 
approaches under investigation, including changes in immune response and 
function, and the mechanisms of induction, maintenance and/or loss of donor-
specific tolerance; and

(4) Studies to develop, evaluate, and validate biomarkers for the induction, 
maintenance and/or loss of immune tolerance and/or for onset of acute or 
chronic graft rejection.

All U01 and U19 applications must contain at least a single tolerogenic 
approach.

This RFA will not provide support for the following:

o Studies in animal models other than non-human primates
o Xenotransplantation 
o Human studies or trials
o Preliminary development of a non-human primate model of organ 
transplantation
o Studies to improve the isolation, preservation, or supply of organs, tissues 
or cells
o Hematopoietic stem cell transplantation, unless in the context of solid 
organ transplantation (i.e. tolerance induction through bone marrow chimerism)
o Kidney or islet transplantation models
o Studies of non-immunological side effects of an immuno-modulatory agent.

MECHANISM OF SUPPORT

This RFA will use the NIH single project cooperative agreement (U01) and/or 
multi-project cooperative agreement (U19), "assistance" mechanisms, rather 
than "acquisition" mechanisms. The applicant will be solely responsible for 
planning, directing, and executing the proposed project. This RFA is a one-
time solicitation. Future unsolicited, competing-continuation applications 
based on this project will compete with all investigator-initiated 
applications and will be reviewed according to the customary peer review 
procedures. The anticipated award date is September 1, 2005.  Applications 
that are not funded in the competition described in this RFA may be 
resubmitted as NEW investigator-initiated applications using the standard 
receipt dates for NEW applications described in the instructions to the PHS 
398 application. 

The NIH U01 and U19 are cooperative agreement award mechanisms in which the 
Principal Investigator retains the primary responsibility and dominant role 
for planning, directing, and executing the proposed project, with NIH staff 
being substantially involved as a partner with the Principal Investigator, as 
described under the section "Cooperative Agreement Terms and Conditions of 
Award" At this time, the NIAID has not determined whether or how this 
solicitation will be continued beyond the present RFA. The total project 
period for applications submitted in response to this RFA may not exceed five 
years.

This RFA uses just-in-time concepts. It also uses the modular budgeting as 
well as the non-modular budgeting formats (see 
http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if 
the investigator is submitting an application with direct costs in each year 
of $250,000 or less, use the modular budget format. Otherwise follow the 
instructions for non-modular budget research grant applications. This program 
does not require cost sharing as defined in the current NIH Grants Policy 
Statement at http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part2.htm. 

Applicants for U19 grants must follow special application guidelines in the 
NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT 
AWARDS; this brochure is available via the WWW 
at: http://www.niaid.nih.gov/ncn/grants/multibron.htm. Multi-project grant 
applications must have two or more individual projects and may include 
scientific cores and an administrative core.  Scientific cores must serve at 
least two individual projects within the multi-project grant. Specific 
application details for multi-project grant applications are available at 
http://www.niaid.nih.gov/ncn/grants/multi/3aa.htm.

FUNDS AVAILABLE 

The NIAID intends to commit approximately $2,000,000 in FY 2005 to fund 2 to 3 
new grants in response to this RFA. An applicant may request a project period 
of up to five years and a budget for total first-year costs (directs and F&A) 
of up to $500,000 for U01 applications and total first-year costs (directs and 
F&A) of up to $1,000,000 for U19 applications. Because the nature and scope of 
the proposed research will vary from application to application, it is 
anticipated that the size and duration of each award will also vary. Although 
the financial plans of the NIAID provide support for this program, awards 
pursuant to this RFA are contingent upon the availability of funds and the 
receipt of a sufficient number of meritorious applications. 

At this time, the NIAID has not determined whether or how this solicitation 
will be continued beyond the present RFA.

ELIGIBLE INSTITUTIONS

The applicant may submit (an) application(s) if the institution has any of the 
following characteristics: 

o For-profit or non-profit organizations
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories
o Units of State and local governments
o Eligible agencies of the Federal government
o Domestic institutions/organizations

Foreign institutions are not eligible to apply as the applicant institution, 
but may enter into a consortium or subcontract with a domestic institution as 
the primary applicant.

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

Any individual with the skills, knowledge, and resources necessary to carry 
out the proposed research is invited to work with their institution to develop 
an application for support. Individuals from underrepresented racial and 
ethnic groups as well as individuals with disabilities are always encouraged 
to apply for NIH programs.

SPECIAL REQUIREMENTS

Applicants are encouraged to contact NIAID program staff well in advance of 
the application submission date, to discuss the proposed research program. 
These contacts help to ensure that applicants have a clear understanding of 
the goals, policies and priorities of this RFA. They also will allow staff to 
assess responsiveness to this RFA and provide appropriate guidance as needed, 
with regard to this initiative.

1. Steering Committee

The Steering Committee will be the main governing body of the NHPCSG and 
membership on the Steering Committee is determined as described below under 
Cooperative Agreement Terms and Conditions of Award. Successful applicants 
will become members of the NHPCSG and participate in the collaborative 
program. The Steering Committee will meet at least once annually in Bethesda, 
MD.  Proposed budgets should include funds to cover travel costs for these 
meetings. The Steering Committee will prioritize, develop and implement a 
scientific agenda for the group, and prioritize this agenda. All major 
scientific decisions will be determined by a majority vote of the Steering 
Committee.  In the event that additional funds for collaborative 
opportunities, pilot projects, or pre-clinical safety and efficacy evaluation 
of new therapeutic regimens are made available to the NHPCSG, participation of 
all successful applicants will be required and determined by procedures 
instituted by majority vote of the Steering Committee. The Steering Committee 
will be responsible for the approval, conduct and monitoring of studies and 
study results. Any specific collaboration involving the resources of the 
NHPCSG will require approval by the Steering Committee.  NIH will facilitate 
collaboration and coordination between the NHPCSG and the Immune Tolerance 
Network (ITN) and other clinical trials groups as needed. 

2. Participation in a Productive Collaborative Program

The applicant must provide a written commitment to: participate in the NHPCSG; 
serve on the Steering Committee; adhere to the decisions reached by the 
Steering Committee; participate in pre-clinical safety and efficacy evaluation 
of new therapeutic regimens or collaborative or pilot projects that are 
instituted and determined by majority vote of the Steering Committee, when and 
if funds become available for these additional studies; and accept the 
participation and assistance of NIH staff in accordance with the guidelines 
outlined under “Cooperative Agreement Terms and Conditions of Award: NIH Staff 
Responsibilities”.

3. Non-human Primate Resources

Provision of NHPs from the NIAID Indian Rhesus macaque and Cynomolgus macaque 
breeding colonies is determined by availability, scientific priority, and 
recommendations by the Steering Committee. The NIAID Program Official will 
make final decisions regarding allocation of this resource. All non-human 
primates obtained from the NIAID colonies may be used only for the expressed 
purposes of the individual Cooperative Agreements funded through this RFA or 
proposals approved by the Steering Committee as discussed above under 
“Participation in a Productive Collaborative Program.” Costs for non-human 
primates from the NIAID breeding colonies will be assumed by the NIAID, but 
all shipping, handling, and special testing fees will be the responsibility of 
the grantee. It is possible that in future years NIAID will institute a 
partial cost recovery program for the NIAID non-human primate breeding colony 
monkeys for research use. However, for purposes of budget preparation, assume 
that non-human primates will not be provided by the NIAID breeding facility. 
Therefore, budgets will include the costs of non-human primate purchases for 
the proposed studies. 

The Steering Committee provides scientific advice and recommendations to the 
NIAID regarding breeding strategies and other considerations to assure the 
optimum long-range value of this resource to the research community. 

COOPERATIVE AGREEMENT TERMS AND CONDITIONS OF AWARD

The following terms and conditions will be incorporated into the award 
statement and provided to the Principal Investigator as well as the 
institutional official at the time of award.

These special Terms of Award are in addition to, and not in lieu of, otherwise 
applicable OMB administrative guidelines, HHS Grant Administration Regulations 
at 45 CFR part 74 and 92, and other HHS, PHS, and NIH Grant Administration 
policy statements.

The administrative and funding instrument used for this program is the NIH 
cooperative agreement (U01) or multi-project cooperative agreement (U19), 
"assistance", rather than an "acquisition", mechanisms, in which substantial 
NIH scientific and/or programmatic involvement with the awardee is anticipated 
during the performance of the activity. Under the cooperative agreement, the 
NIH purpose is to support and/or stimulate the recipient's activity by 
involvement in and otherwise working jointly with the award recipient in a 
partner role, but it is not to assume direction, prime responsibility, or a 
dominant role in the activity. Consistent with this concept, the dominant role 
and prime responsibility for the activity resides with the awardees for the 
project as a whole, although specific tasks and activities in carrying out the 
research will be shared among the awardees and the NIAID Scientific 
Coordinator.

1. Awardee Rights and Responsibilities

Awardees will have primary responsibility for defining the research 
objectives, approaches and details of the projects within the guidelines of 
the RFA and for performing the scientific activity. Specifically, awardees 
have primary responsibility as described below.

The Principal Investigators will determine and coordinate the project 
activities scientifically and administratively; set project goals and 
timelines to achieve the proposed goals; accept and implement common 
guidelines and policies set forth and approved by the Steering Committee; 
attend Steering Committee meetings; participate in all Steering Committee 
activities; and serve as a voting member of the Steering Committee, as 
outlined below under Collaborative Responsibilities; and participate in the 
cooperative nature of the group. Awardees will retain custody of and have 
primary rights to the data developed under these awards, subject to Government 
rights of access consistent with current HHS, PHS, and NIH policies. Data 
sharing requirements are presented under Required Federal Citations below.

NIAID intends to support the peer-reviewed studies proposed in the awarded 
grant applications.  However, under special circumstances (e.g. duplicative or 
overlapping specific aims between two awardees), the Steering Committee will 
establish guidelines and review procedures, and will evaluate and determine 
redirection or modification of the peer-reviewed proposals or provide 
recommendations to the NIH when applicable and necessary. All NHPCG 
institutions, upon acceptance of an award, agree to participate in studies as 
specified by majority vote of the Steering Committee, if and when additional 
funds for these studies become available, including those studies that involve 
collaborations with biotechnology and pharmaceutical companies. In addition, 
the Steering Committee will establish guidelines for proposal and review 
procedures for new pilot or collaborative projects when applicable and 
necessary, if and when funds for such projects are available. These policies 
are in keeping with the terms and conditions of the cooperative agreement 
mechanism.

2. NIAID Staff Responsibilities

An NIAID Program Official will be responsible for the normal program 
stewardship, including monitoring program progress and approving changes. The 
Government, via the NIAID Program Official, will have access to data generated 
under this Cooperative Agreement and may periodically review the data and 
progress reports.  NIAID staff may use information obtained from the data for 
the preparation of internal reports on the activities of the study.  However, 
awardees will retain custody of and have primary rights to all data developed 
under these awards.

NIAID staff assistance will be provided by the Chief, Transplantation Basic 
Sciences Section, DAIT or his/her designee, who will serve as the NIAID 
Scientific Coordinator. The NIAID Scientific Coordinator will have substantial 
scientific/programmatic involvement during the conduct of this activity 
through technical assistance, advice and coordination above and beyond normal 
program stewardship for grants, as described below. An NIAID Program Official 
will be assigned to perform normal program stewardship responsibilities for 
this award. The Program Official may serve as the Scientific Coordinator. The 
NIAID Scientific Coordinator will serve as a voting member of the Steering 
Committee and will participate in all Committee activities.

During performance of the award, the NIAID Scientific Coordinator, with 
assistance from other scientific program staff who are designated based on the 
research topic and their relevant expertise, may provide appropriate 
assistance, advice, and guidance by: participating in the design of the 
activities; advising in the selection of sources or resources; advising in 
management and technical performance; or participating in the preparation of 
publications for collaborative programs when and if applicable. The NIAID 
Scientific Coordinator will serve as a liaison/facilitator between the 
awardee, pharmaceutical and biotech industries, and other government agencies 
and will serve as a resource of scientific and policy information related to 
the goals of the awardee's research. However, the role of NIH will be to 
facilitate and not to direct the activities. It is anticipated that decisions 
in all activities will be reached by consensus and the NIH staff will be given 
the opportunity to offer input into this process. The manner of reaching this 
consensus and the final decision-making authority will rest with the Steering 
Committee.

3. Collaborative Responsibilities

The Steering Committee

The NHPCSG Steering Committee serves as the governing board for the 
cooperative group. Each member of the Steering Committee will have one vote.  
At a minimum, voting membership of the Steering Committee will include the 
NIAID Scientific Coordinator, the Program Officials for other participating 
ICs, each U01/U19 Principal Investigator, one sub-project investigator from 
each U19 award, and selected scientists other than the awardees when 
additional expertise is required for committee breadth and balance. The 
Steering Committee will appoint additional members by majority vote.  In 
addition, the NIAID may appoint up to two members of an NIAID scientific 
advisory panel to the Steering Committee as non-voting members. Federal voting 
membership cannot exceed 25% of the total voting members. A Chairperson was 
selected from among the non-federal Committee members by majority vote of the 
current NHPCSG Steering Committee. When or if a new Chairperson is selected, 
the selection will also be from the non-federal Committee members determined 
by majority vote of the Steering Committee. Subcommittees of the Steering 
Committee may be established as necessary. Each Steering Committee member will 
be expected to participate in all meetings and activities, e.g., conference 
calls and special subcommittees as required, and will be required to accept 
and implement common guidelines and procedures approved by the Steering 
Committee. 

The Steering Committee or a designated subcommittee will prepare an annual 
report containing the following information: progress of ongoing and newly-
initiated projects; manuscripts published, in press, and in preparation; 
presentations at regional, national, and international meetings; other 
activities of the group; data submitted to databases; and future plans. The 
first such report will be submitted to the NIAID Scientific Coordinator not 
later than 13 months after the initial notice of award, or a time agreed upon 
by the NIAID Scientific Coordinator and yearly thereafter.

The NIAID Scientific Coordinator will schedule the meetings of the Steering 
Committee and actively assist the Chair in developing the meeting agendas. The 
NIAID Scientific Coordinator will ensure coordination of the Steering 
Committee’s activities and implementation of the group’s recommendations. In 
order to most efficiently utilize research resources and exchange scientific 
information to rapidly respond to new pre-clinical opportunities, it is 
anticipated that collaborations with other NIH funded programs, such as the 
Cooperative Clinical Trials in Organ Transplantation or the ITN, will be 
initiated in future years. These collaborations will be coordinated and 
facilitated by the NIAID Program Official.

The Steering Committee will:

o serve as the main governing board;
o establish protocols and subcommittees, as needed, for the receipt, review, 
development and evaluation of potential new, pilot, or collaborative projects, 
if additional funds are provided and available for such projects;
o advise NIAID on scientific opportunities, emerging needs, and impediments; 
o advise NIAID on maximizing the value of the NIAID macaque breeding colonies;
o ensure the timely release of data through publication and/or release of data 
to public databases;
o develop guidelines for publication of collaborative project results;
o prepare annual reports; and
o collaborate when appropriate with NIH clinical trials programs. 

4. Organizational Changes

Certain organizational changes require the prior written approval of the NIAID 
Program Official.  These changes include the addition or replacement of a 
scientific investigator, affiliate, component, or research base that is 
associated with this study.  A change in the Principal Investigator, or in any 
key personnel identified on the Notice of Award, must have the prior written 
approval of the NIAID Grants Management Specialist in consultation with the 
NIAID Program Official.

5. Arbitration:

Any disagreement that may arise on scientific/programmatic matters (within the 
scope of the award), between award recipients and NIAID may be brought to 
arbitration. An arbitration panel will be composed of three members – one 
chosen by Steering Committee (with the NIH representation not voting) or one 
selected by the individual awardee in the event of an individual disagreement, 
a second member selected by NIAID, and the third member selected by the two 
prior selected members. This special arbitration procedure in no way affects 
the awardee's right to appeal an adverse action that is otherwise appealable 
in accordance with the PHS regulations at 42 CFR Part 50, Subpart D and HHS 
regulation at 45 CFR Part 16.

These special Terms of Award are in addition to and not in lieu of otherwise 
applicable OMB administrative guidelines, HHS Grant Administration Regulations 
at 45 CFR Parts 74 and 92, and other HHS, PHS, and NIH Grant Administration 
policy statements.

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA and welcome the opportunity to 
answer questions from potential applicants. Inquiries may fall into three 
areas: scientific/research, peer review, and financial or grants management 
issues:

o Direct questions about scientific/research issues to:

Kristy Kraemer, Ph.D.
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
Room 3043, MSC-6601
6610 Rockledge Drive
Bethesda, MD 20892-6601
(FedEx: Bethesda, MD 20817)
Telephone: 301-496-5598
Fax: 301-480-0693
e-mail: kk187y@nih.gov

o Direct questions about peer review issues to: 

Madelon Halula, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 3116, MSC-7616
6700-B Rockledge Drive
Bethesda, MD 20892-7616
Telephone: (301) 402-2636
FAX:  (301) 402-2638
Email: mh30x@nih.gov

o Direct questions about financial or grants management matters to:

Ann Devine
Division of Extramural Activities 
National Institute of Allergy and Infectious Diseases
Room 2114, MSC-7614
6700-B Rockledge Drive
Bethesda, MD 20892-7614
Telephone: (301) 402-5601
FAX:  (301) 480-3780
Email: ad22x@nih.gov

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes 
the following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel
o Participating institutions
o Number and title of this RFA

Although a 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 IC staff to estimate the potential review workload and plan 
the review.

The letter of intent is to be sent by the date listed at the beginning of this 
document. The letter of intent should be sent to:

Madelon Halula, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 3116, MSC-7616
6700-B Rockledge Drive
Bethesda, MD 20892-7616
Bethesda, MD 20817 (for express mail or courier service)
Telephone: (301) 402-2636
FAX:  (301) 402-2638
Email: mh30x@nih.gov

SUBMITTING AN APPLICATION

Applicants for U19 grants must follow special application guidelines in the 
NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT 
AWARDS; this brochure is available via the WWW at: 
http://www.niaid.nih.gov/ncn/grants/multibron.htm. 

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001). Applications must have a DUN and 
Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the 
Universal Identifier when applying for Federal grants or cooperative 
agreements. The D&B number can be obtained by calling (866) 705-5711 or 
through the web site at http://www.dunandbradstreet.com/. The D&B number 
should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 
document is available at 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive 
format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, 
Email: GrantsInfo@nih.gov.

SUPPLEMENTARY INSTRUCTIONS: 

1.  All applications must include a broad-based research program designed to 
evaluate the safety and efficacy of tolerogenic approaches in non-human 
primate models of heart and/or lung transplantation with the goal of inducing 
immunosuppression-free immune tolerance and delineating the mechanisms 
involved in the induction, maintenance and loss of tolerance as an integral 
part of the treatment protocols.  All U19 and U01 applications must contain at 
least a single tolerogenic approach.  The research plan must include the 
following:

a) A discussion of the state-of-the-art of research focused on elucidating the 
underlying mechanisms of immune tolerance and on evaluating tolerogenic 
approaches in non-human primate studies and human clinical trials.

b) A description of gaps in knowledge and scientific opportunities relevant 
for the application of tolerogenic approaches to non-human primate studies and 
human clinical trials.

c) A plan to accelerate research on immune tolerance in non-human primate 
models of lung and/or heart transplantation, including:
o A conceptual framework delineating approaches to tolerance induction and 
their relevance to human transplantation, priorities among the various 
approaches and the rationale for such priorities, including potentially 
promising reagents and molecules in development;
o A description of promising non-human primate treatment protocols, including 
the rationale for the selection of tolerogenic approaches and overall study 
design; 
o A description of promising mechanistic studies to be incorporated as an 
integral part of the non-human primate treatment protocols, including the 
rationale for the selection of the mechanistic studies, proposed techniques, 
and the overall design of such studies; and
o A plan detailing the acquisition and preparation, if applicable, of the 
solid organs, tissues or cells to be used in the studies. All related costs 
required should be included in the application and fully justified.

2. All applications must propose clear research plan(s) and project goal(s) to 
be completed during the award period.  The applicant must clearly state the 
interim objectives to be achieved during the project, identify impediments or 
critical decision points that could require a revision in the work plan, and 
provide a detailed timeline for the attainment of each goal.  The application 
must also demonstrate the scientific and technical expertise required to 
design, conduct and analyze NHP studies responsive to this RFA.

3.  All applications must also include a 1-2 page synopsis (to be included as 
appendices) of the proposed treatment protocol(s) to assess safety and 
efficacy and incorporating the proposed mechanistic studies. Budget requests 
should reflect and fully justify all costs associated with the conduct of the 
above studies.

4.  Any application may include, in addition to the tolerogenic approach(s) 
and mechanistic project(s), the development, evaluation and validation of 
sensitive immune and/or surrogate biomarkers of the induction, maintenance, or 
loss of tolerance. Proposed tolerance assay studies should include: 
identification of and rationale for the immune and/or surrogate markers 
selected, including published data from in vitro or in vivo studies; 
description of and rationale for the proposed source, quantity and number of 
samples required; methodologies proposed to collect and analyze samples; and a 
discussion of how the results of the proposed studies will contribute to 
improvements in the capacity to utilize immune and/or surrogate biomarkers to 
predict the induction, maintenance or loss of tolerance.  Use of new 
technologies, including minimally and non-invasive approaches, is encouraged.  
All costs required for the proposed tolerance and biomarker assays must be 
included in the application and must be fully justified.  

5.  U19 multi-project applications only must provide: a clear, concise plan, 
in narrative and diagrammatic form, that depicts the interrelationships among 
the research projects and the scientific and technical staff, their relevant 
experience/expertise, and the contribution of each to fulfillment of the 
objectives of this RFA; and an organizational chart of the consortium showing 
the name, organization, and scientific discipline of the PI and of all key 
scientific, technical and administrative personnel.

6.  All applications must also include a written commitment to: participating 
in the cooperative study group; serving on the Steering Committee and adhering 
to the decisions reached by that Committee, including following the consensus 
treatment protocols and adjunct studies; and accepting the participation and 
assistance of NIH staff in accordance with the guidelines outlined under 
"Terms and Conditions of Award: NIH Staff Responsibilities." 

7. All applications must include a written commitment to design and conduct 
non-human primate research, in addition to the studies funded in the initial 
application, under circumstances in which such additional research is of 
significant importance to further the field of immune tolerance and if  and 
when funds become available.  Such circumstances include the evaluation of 
safety and efficacy and studies of underlying mechanisms for: existing 
tolerance induction treatment strategies in non-human primate models to 
produce data of critical importance to the design and conduct of 
scientifically sound and ethically acceptable human clinical trials; and newly 
discovered molecular targets for the induction of immune tolerance identified 
through fundamental research in small animal models.  This written commitment 
must also include the awardee’s willingness and agreement to:  (1) prepare 
scientific proposals for the design, conduct and analysis of such additional 
studies and budget requests for all associated costs; (2) submit proposals for 
scientific evaluation by NIH staff, the NHPCSG Steering Committee, and, when 
appropriate, non-Federal experts identified by the sponsors of this research 
program; and (3) accept additional funding from NIH and non-Federal 
organizations to support such additional investigations.  The time frame 
within which such additional projects can be initiated and completed will be 
negotiated and agreed upon jointly between the awardees and the sponsors.

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) 
application form must be affixed to the bottom of the face page of the 
application. Type the RFA number on the label. 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 and number 
must be typed on line 2 of the face page of the application form and the YES 
box must be marked. The RFA label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the Checklist, and three signed, photocopies, in 
one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710
Bethesda, MD 20817 (for express/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:

Madelon Halula, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 3116, MSC-7616
6700-B Rockledge Drive
Bethesda, MD 20892-7616
BETHESDA, MD 20817 (for express mail or courier service)

Applications that are not received as a single package on or before the 
December 21, 2004 or that do not conform to the instructions contained in PHS 
398 (rev. 5/01) Application Kit (as modified in, and superseded by, the NIAID 
BROCHURE ENTITLED "INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS" for 
U19s), will be judged non-responsive and will be returned to the applicant.

SPECIAL INSTRUCTIONS FOR COMPLETION OF U19 APPLICATIONS IN RESPONSE TO THIS 
RFA:

Applicants for U19 cooperative agreements must follow special application 
guidelines in the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR 
MULTI-PROJECT AWARDS; this brochure is available from NIAID listed under 
INQUIRIES via the WWW at: http://www.niaid.nih.gov/ncn/grants/multibron.htm.

This brochure presents specific instructions for sections of the PHS 398 (rev. 
5/01) application form that should be completed differently than usual. For 
all other items in the application, follow the usual instructions in the PHS 
398.

APPLICATION PROCESSING: 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.

The NIH will not accept any application in response to this RFA that is 
essentially the same as one currently pending initial review, unless the 
applicant withdraws the pending application. However, when a previously 
unfunded application, originally submitted as an investigator-initiated 
application, is to be submitted in response to an RFA, it is to be prepared as 
a NEW application. That is the application for the RFA must not include an 
Introduction describing the changes and improvements made, and the text must 
not be marked to indicate the changes from the previous unfunded version of 
the application. While the investigator may still benefit from the previous 
review, the RFA application is not to state explicitly how.

CONCURRENT SUBMISSION OF AN R01 AND A COMPONENT PROJECT OF A MULTI-PROJECT 
APPLICATION: Current NIH policy permits a component research project of a 
multi-project grant application to be concurrently submitted as a traditional 
individual research project (R01) application. If, following review, both the 
multi-project application and the R01 application are found to be in the 
fundable range, the investigator must relinquish the R01 and will not have the 
option to withdraw from the multi-project grant. This is an NIH policy 
intended to preserve the scientific integrity of a multi-project grant, which 
may be seriously compromised if a strong component project(s) is removed from 
the program. Investigators wishing to participate in a multi-project grant 
must be aware of this policy before making a commitment to the Principal 
Investigator and awarding institution.

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and funding 
assignment within 8 weeks.

PEER REVIEW PROCESS

Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NIAID. 

Incomplete and/or nonresponsive applications will be returned to the applicant 
without further consideration.  
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 NIAID in accordance with the review criteria stated below. As part of the 
initial merit review, all applications will:

o Undergo a selection process in which only those applications deemed to have 
the highest scientific merit, generally the top half of applications under 
review, will be discussed and assigned a priority score
o Receive a written critique
o Receive a second level review by the National Advisory Allergy and 
Infectious Diseases Council

REVIEW CRITERIA

Review Criteria for U19 Applications:

The general review criteria for U19 multi-project cooperative agreement 
applications are presented in the NIAID brochure entitled "INSTRUCTIONS FOR 
APPLICATIONS FOR MULTI-PROJECT AWARDS” at 
http://www.niaid.nih.gov/ncn/grants/multibron.htm.

Review Criteria for U01 Applications:

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments, reviewers will be asked to evaluate the application in 
order to judge the likelihood that the proposed research will have a 
substantial impact on the pursuit of these goals. The scientific review group 
will address and consider each of the following criteria in assigning the 
application’s overall score, weighting them as appropriate for each 
application.

o Significance
o Approach
o Innovation
o Investigator
o Environment
   
   The scientific review group will address and consider each of these criteria 
in assigning the application’s overall score, weighting them as appropriate 
for each application. The application does not need to be strong in all 
categories to be judged likely to have major scientific impact and thus 
deserve a high priority score. For example, an investigator may propose to 
carry out important work that by its nature is not innovative but is essential 
to move a field forward.

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?

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?

INNOVATION: Does the project employ novel concepts, approaches or methods? Are 
the aims original and innovative? Does the project challenge existing 
paradigms or develop new methodologies or technologies?

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)?

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?

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following 
items will be considered in the determination of scientific merit and the 
priority score:

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to 
be used in the project, the five items described under Section f of the PHS 
398 research grant application instructions (rev. 5/2001) will be assessed.

ADDITIONAL REVIEW CONSIDERATIONS

SHARING RESEARCH DATA: Applicants requesting $500,000 or more in direct costs 
in any year of the proposed research are expected to include a data sharing 
plan in their application. The reasonableness of the data sharing plan or the 
rationale for not sharing research data will be assessed by the reviewers. 
However, reviewers will not factor the proposed data-sharing plan into the 
determination of scientific merit or priority score. (See instructions and URL 
to policy in the Federal Citations, below.)

BUDGET: The reasonableness of the proposed budget and the requested period of 
support in relation to the proposed research.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date:         November 22, 2004
Application Receipt Date:              December 21,2004
Peer Review Date:                        April, 2005
Council Review:                            June, 2005
Earliest Anticipated Start Date:        September, 2005

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o Scientific merit of the proposed project as determined by peer review
o Availability of funds
o Programmatic priorities.

REQUIRED FEDERAL CITATIONS

ANIMAL WELFARE PROTECTION:  Recipients of PHS support for activities involving 
live, vertebrate animals must comply with PHS Policy on Humane Care and Use of 
Laboratory Animals 
(http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf), as 
mandated by the Health Research Extension Act of 1985 
(http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA 
Animal Welfare Regulations 
(http://www.nal.usda.gov/awic/legislat/usdaleg1.htm), as applicable.

SHARING RESEARCH DATA: Investigators submitting an NIH application seeking 
$500,000 or more in direct costs in any single year are expected to include a 
plan for data sharing or state why this is not possible 
http://grants.nih.gov/grants/policy/data_sharing. Investigators should seek 
guidance from their institutions, on issues related to institutional policies, 
local IRB rules, as well as local, state and Federal laws and regulations, 
including the Privacy Rule. Reviewers will consider the data sharing plan but 
will not factor the plan into the determination of the scientific merit or the 
priority score.

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The 
Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances. Data that are (1) first produced in a project 
that is supported in whole or in part with Federal funds and (2) cited 
publicly and officially by a Federal agency in support of an action that has 
the force and effect of law (i.e., a regulation) may be accessed through FOIA. 
It is important for applicants to understand the basic scope of this 
amendment. NIH has provided guidance at 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this RFA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time. If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the application. 
In addition, applicants should think about how to structure informed consent 
statements and other human subjects procedures given the potential for wider 
use of data collected under this award.

URLs IN NIH GRANT APPLICATIONS OR APPENDICES: 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. Furthermore, we 
caution reviewers that their anonymity may be compromised when they directly 
access an Internet site.

HEALTHY PEOPLE 2010: 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 RFA is 
related to one or more of the priority areas. Potential applicants may obtain 
a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

AUTHORITY AND REGULATIONS

This program is described in the Catalogue of Federal Domestic Assistance at 
http://www.cfda.gov/ in the following citations: No. 93.855, Immunology, 
Allergy, and Transplantation Research and No. 93.856, Microbiology and 
Infectious Diseases Research. 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 and 92. This program is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.

The NIH Grants Policy Statement is available at 
http://grants.nih.gov/grants/policy/policy.htm. This document includes general 
information about the grant application and review process; information on the 
terms and conditions that apply to NIH Grants and cooperative agreements; and 
a listing of pertinent offices and officials at the NIH. All awards are 
subject to the terms and conditions, cost principles, and other considerations 
described in the NIH Grants Policy Statement. 

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the 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.


Weekly TOC for this Announcement
NIH Funding Opportunities and Notices


H H S Department of Health
and Human Services

 
  N I H National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892