RELEASE DATE:  August 6, 2004

RFA Number:  RFA-AI-04-042  (Reissued as RFA-AI-09-035)

(See Addendum in NOT-AI-04-054)

EXPIRATION DATE:  November 23, 2004

Department of Health and Human Services (DHHS) 

National Institutes of Health (NIH) 

National Institute of Allergy and Infectious Diseases (NIAID) 
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 

No. 93.855, Immunology, Allergy, and Transplantation Research
No. 93.847, Diabetes, Endocrinology, and Metabolism Research



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


The purpose of this RFA is to solicit applications from single institutions or 
consortia of institutions to establish cooperative interdisciplinary research 
programs for development of pre-clinical, porcine to non-human primate (NHP) 
models of xenotransplantation.  The goals of this program are (1) to delineate 
the cellular and molecular mechanisms of xenograft rejection and the induction 
of tolerance and accommodation; (2) to develop effective strategies to improve 
xenograft survival; and (3) to characterize the physiological 
compatibility/limitations of xenografts.  The long-term goal of this program 
is to develop novel and efficacious strategies for broad application of 
xenotransplantation in the clinic.



Transplantation is the preferred therapy for the majority of end-stage organ 
diseases.  In 2003, more than 23,000 organ transplants were performed in the 
United States, but over 84,000 patients were still on waiting lists.  Although 
active donor recruitment and primary care education programs have resulted in 
a gradual increase in the number of donated organs, the number of patients on 
waiting lists greatly exceeds the number of available organs.  The success of 
the "Edmonton Protocol" has established pancreatic islet transplantation as a 
viable therapy for type 1 diabetes in patients whose disease cannot be 
effectively managed with exogenous insulin therapy.  As with solid organ 
transplantation however, the availability of human cadaveric islets is 
sufficient for only a small fraction of patients who could potentially benefit 
from islet transplantation.  Xenotransplantation offers a potential solution 
to the severe shortage of human organs, tissues, and cells to treat patients 
with end-stage organ diseases.  Currently, the swine is the primary species of 
interest as an unlimited source of donor organs, tissues, and cells for 
xenotransplantation due to its favorable reproductive capacity as well as 
anatomical and physiological similarities to humans.  However, 
xenotransplantation poses significant challenges, including the immune 
response of the recipient against the xenograft (i.e. hyperacute, acute 
vascular, cellular, and chronic rejection), the physiological limitations of 
organs or tissues functioning in a xenogeneic environment, and potential 
transmission of xenogeneic infectious agents, such as porcine endogenous 
retrovirus (PERV), from the graft to the recipient.  

The first and the most challenging hurdle to xenotransplantation has been 
hyperacute rejection, which is caused by preformed xenoreactive natural 
antibodies (XNA) and which can destroy the xenograft within minutes to a few 
hours of reperfusion by the recipient’s blood.  The primary target of XNA is 
the gal epitope (galactosyl alpha-(1,3)-galactosyl beta-1,4-N-acetyl 
glucosaminyl), a non-reducing trisaccharide group synthesized by New World 
monkeys and lower mammals, but not by humans, apes, and Old World monkeys.   
Over the past several years, advances made in genetic engineering of large 
animals allowed researchers to develop several lines of genetically modified 
pigs with diminished potential for hyperacute rejection.  These pig lines 
include transgenic strains expressing various human complement regulatory 
proteins [i.e., decay accelerating factor (CD55), terminal complement 
inhibitor (CD59), and monocyte chemoattractant protein (CD56)] to minimize the 
deleterious effects of the complement cascade.  Other transgenic pig strains 
express different glycosyltransferases which compete with alpha-1,3-
galactosyltransferase, the enzyme that generates the gal epitope, to decrease 
the gal antigen expression.  Additionally, transgenic pigs expressing a 
combination of a human complement regulatory protein and a glycosyltransferase 
have been developed.  These strategies dramatically, but not completely, 
reduce the frequency of hyperacute rejection and prolong the survival of some 
xenografts in porcine to nonhuman primate transplantation models from a few 
hours to a few weeks; however, the gal epitope still contributes to delayed 
acute vascular rejection.  To further reduce the risk of hyperacute rejection, 
two different strains of alpha-1,3-galactosyltransferase gene knockout pigs, 
which lack the expression of the gal epitope, were recently developed.  The 
advent of genetically modified pigs provides opportunities for the development 
of strategies to overcome hyperacute rejection; to address other immunological 
barriers to xenotransplantation, including acute vascular and cellular 
rejection as well as chronic rejection; and to pursue regimens for immune 
tolerance induction to xenografts.

Physiological incompatibility between organs, tissues, and cells and the 
xenogeneic environment is another potentially critical challenge to successful 
xenotransplantation.  Initial observations in studies using solid organs from 
transgenic pigs transplanted into nonhuman primates (NHP) indicate that the 
xenografts may have basic physiological functions that are compatible with the 
recipient as long as the grafts survive.  However, it is possible that some 
proteins produced by the xenograft, such as the liver, will not function or 
will be incompatible and thus interfere with normal metabolic processes in the 
recipient.  Furthermore,  although porcine insulin has been used to 
effectively treat diabetic patients, porcine islets transplanted into not only 
xenogeneic but also heterotopic environments (i.e. liver in human and under 
the kidney capsule and muscle in some NHP studies) may not function in a  
physiologically compatible manner.  Therefore, each organ/tissue/cell 
xenograft is likely to face unique obstacles.  Additionally, issues related to 
the longevity, growth, and development of xenografts remain to be addressed.  
While the heart or kidney of a juvenile miniature swine is of suitable size 
for transplant into human, the rate and extent of graft growth as well as the 
lifespan of the xenograft beyond the pig’s natural lifespan of 15 years, are 
undetermined.  Successful strategies to overcome hyperacute rejection and 
prolong the survival of xenografts will also allow opportunities to 
investigate any physiological obstacles to xenotransplantation and the 
development of novel therapeutic approaches to address those limitations.  

The third major barrier to xenotransplantation is potential transmission of an 
infectious agent from the xenograft to the recipient and then more broadly to 
the general population.  The animals used as the source of xenografts can be 
bred in specific pathogen-free conditions, vaccinated, caesarian derived, 
medicated, and routinely screened to eliminate most, if not all, known 
zoonotic agents.  However, endogenous retroviruses (e.g. PERV), whose DNA is 
integrated into the donor genome, or new and yet unidentified infectious 
agents may not be removed by conventional means.  Although the patients 
transplanted with porcine cells or tissues show no evidence of PERV infection 
thus far, the effects of long-term exposure to xenografts, especially in 
immunosuppressed recipients, are unknown.  In the last few years, 
investigators have made significant progress in assessing the risk of PERV 
infection.  Polytropic (PERV-A, B, and A/C) and ecotropic (PERV-C) classes of 
PERV and human receptors for PERV-A have been identified.  These findings 
provide the basis for additional investigations critical to determine 
susceptibility to and pathogenic consequences of PERV infection, the most 
serious known risk of zoonoses following xenotransplantation.  While insights 
gained from such studies would increase understanding of the infectious risks 
of xenotransplantation, such studies are beyond the scope of this RFA.

In 2003, the National Center for Research Resources established the National 
Swine Research and Resource Center (NSRRC;, 
which is co-sponsored by the National Institute of Allergy and Infectious 
Diseases and the National Heart, Lung, and Blood Institute.  The purpose of 
the NSRRC is to provide the biomedical research community enhanced access to 
critically needed swine models for studies involving human health and diseases 
including xenotransplantation.  The recent scientific advances in 
xenotransplantation and the advent of new and novel resources underscore the 
timeliness of research efforts focused on the vital issues facing 
xenotransplantation.  Understanding cellular and molecular mechanisms of 
xenograft rejection and physiological compatibility between xenografts and 
recipients will facilitate the development of novel and efficacious strategies 
for broad clinical application of xenotransplantation.

Research Scope

This RFA will establish a cooperative research program to develop pre-
clinical, porcine to NHP models of xenotransplantation to address 
immunological and physiological issues critical to the engraftment, survival, 
and function of xenografts.  The research focus may include: (1) elucidation 
of cellular and molecular mechanisms of xenograft rejection, accommodation, 
and/or tolerance induction; (2) development of effective strategies to prolong 
xenograft survival, including immune tolerance induction; and (3) 
characterization of the biology of the xenograft post-transplantation. 

Examples of research topics may include, but are not limited to the following:

o  Elucidation of the mechanisms of acute vascular and cellular rejection as 
well as chronic rejection of xenografts
o  Characterization of the host innate and adaptive immune responses to the 
xenograft post-transplantation
o  Evaluation of the immune responses to xenografts from the same animal 
source but in different stages of development, e.g. neonatal islet-like 
clusters vs. adult islets
o  Approaches to immune tolerance induction 
o Approaches to reducing host toxicity (i.e. hepatosteatosis) in 
xenotransplantation models
o  Delineation of the mechanisms of accommodation and/or tolerance induction
o  Development and characterization of life-supporting models of 
o  Development of effective strategies, including genetic modifications of 
organs/tissues/cells or utilization of encapsulation, to prolong xenograft 
survival and to eliminate or minimize the use of immunosuppressive drugs
o  Characterization of physiological interactions between the xenograft and 
the host and development of strategies to overcome physiological 

This RFA will not support: 

o  Studies on zoonotic agents or strategies to circumvent zoonoses
o  Small animal models of xenotransplantation, such as rodent models, unless a 
novel rodent animal model(s) is proposed only as an in vivo bioassay of large 
animal immune function (e.g. trans in vivo DTH assay)
o  Clinical trials or clinical studies on xenotransplantation


This RFA will use the NIH cooperative agreement (U01) and/or the NIH multi-
project cooperative agreement (U19), "assistance" mechanisms, rather than an 
"acquisition" mechanism. 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 June 30, 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/U19 is a cooperative agreement award mechanism 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 

The total project period for applications submitted in response to this RFA 
may not exceed five years.

This RFA uses just-in-time concepts. 
Applicants for U19 grants must follow special application guidelines in the 
AWARDS; this brochure is available via the WWW at  

The NIH intends to commit approximately $4M in FY2005 to fund 2 to 6 new 
and/or competitive continuation grants in response to this RFA. An applicant 
may request a project period of up to 5 years. 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 and the NIDDK 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, it is not known if this RFA will be reissued.

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


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
o Foreign institutions are not eligible to apply but are eligible for 
inclusion as collaborators or subcontracts with sufficient justification.


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.


Applicants are encouraged to contact NIH Program staff well in advance of the 
application submission date to discuss the proposed research program. This 
contact allows staff to assess responsiveness to this RFA and provide 
appropriate guidance as needed.

1.  Description of Research Projects

Applications must propose a 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 studies responsive to this RFA.

2.  Development of a Productive Collaborative Program

Each U01 or U19 application must demonstrate the organization’s ability to 
participate effectively in the NIH Immunobiology of Xenotransplantation 
Cooperative Research Program.  The applicant must include a written commitment 
to: participate in the NIH Immunobiology of Xenotransplantation Cooperative 
Research Program; serve on the Steering Committee; adhere to the decisions 
reached by the Steering Committee; 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.” 

For a U19 multi-project cooperative agreement, the application must provide: a 
clear and concise plan that depicts the interrelationships among the research 
groups, their relevant experience/expertise, and the contribution of each to 
fulfillment of the objectives of this RFA; an organizational chart of the U19 
cooperative group showing the name, organization, and scientific discipline of 
the PI and of all key scientific and technical personnel. If the application 
is from a consortium of institutions, the applicant must provide a plan to 
assure the maintenance of close cooperation and effective communication among 
members of the U19 cooperative group. 

In the event that additional funds for collaborative opportunities, pilot 
projects, or establishment of resources (e.g. swine islet isolation core) are 
made available to the Immunobiology of Xenotransplantation Cooperative 
Research Program, procedures for the solicitation and review of proposals will 
be instituted by majority vote of the Steering Committee.  In addition, the 
Steering Committee will establish procedures for the approval, conduct and 
monitoring of studies and study results as well as any specific collaborations 
involving the resources of the Immunobiology of Xenotransplantation 
Cooperative Research Program. 

3.  Steering Committee

The NIH will establish a Steering Committee within 60 days of award to serve 
as the governing body of the Immunobiology of Xenotransplantation Cooperative 
Research Program.  At a minimum, the Steering Committee will be composed of 
the U01/U19 Principal Investigators, one subproject investigator of each U19 
award, and the NIH Scientific Coordinators.  The Steering Committee will meet 
at least twice the first year and annually thereafter.  At least one of the 
meetings in the first year and the annual meetings will be in Bethesda, MD.  
Proposed budgets should include funds to cover travel costs for these 
meetings.  Each Steering Committee member will be expected to participate in 
all meetings and activities, e.g., conference calls and special subcommittees 
as required.

4.  Intellectual Property Rights

Institution’s rights in inventions made under this funding mechanism and the 
reporting requirements for such inventions will be governed by Public Law 96-
517 (the Bayh-Dole Act of 1980), 35 U.S.C. Secs. 200-212, 37 C.F.R. Part 401, 
and 45 C.F.R. parts 6 and 8.  Institutions and investigators are expected to 
share research resources developed under this funding agreement for research 
purposes, e.g., with other participating institutions as required to carry out 
the aims of the collaborative projects.  In the event of a joint 
invention involving multiple institutions under this funding agreement, 
the funding recipient institution is expected to cooperate with any such co-
inventor's institution(s) in developing a plan to 
achieve practical application of the technology.  Applicants are expected to 
abide by the “Principles and Guidelines for Recipients of NIH Research Grants 
and Contracts on Obtaining and Disseminating Biomedical Research Resources,” 
as published in the Federal Register December 23, 1999, Volume 64, Number 246, 
Pages 72090-72096.  The Steering Committee will develop a policy on 
publication and sharing data obtained by the collaborative efforts of the 
Immunobiology of Xenotransplantation Cooperative Research Program.


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 cooperative 
agreement (U01) and the multiproject cooperative agreement (U19), 
"assistance", rather than an "acquisition", mechanism, 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 NIH Scientific 

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 approved by the Steering Committee; attend Steering Committee 
meetings and serve as a voting member of the Steering Committee; and 
participate in the cooperative nature of the group.  It is recognized that 
goals may require revision and re-negotiation during the course of the project 
period.  Release of each funding increment by NIH will be based on a review of 
progress towards achieving the previously agreed upon research goals.  
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.

NIH 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 for modification of the peer-
reviewed or initiation of new projects, and will evaluate and determine 
opportunities for collaboration with outside investigators and redirection of 
resources when applicable and necessary. This policy is in keeping with the 
terms and conditions of the cooperative agreement mechanism.

2. NIH Staff Responsibilities

NIH staff assistance will be provided by a Program Director from the 
Transplantation Basic Sciences Section, Transplantation Immunobiology Branch, 
Division of Allergy, Immunology, and Transplantation (DAIT), who will serve as 
NIAID's Scientific Coordinator and a Program Director from the Division of 
Diabetes, Endocrinology and Metabolic Diseases (DDEM), who will serve as 
NIDDK’s Scientific Coordinator. The NIH Scientific Coordinators 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.

During performance of the award, the NIH Scientific Coordinators, 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 (e.g., 
determining where a particular reagent can be found); coordinating or 
participating in the collection and/or analysis of data; advising in 
management and technical performance; or participating in the preparation of 
publications. The NIH Scientific Coordinators or his/her designee will serve 
as a liaison/facilitator between the awardee, pharmaceutical and biotech 
industries, and other government agencies (e.g., FDA, USDA, CDC) 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 Principal 
Investigator and the Steering Committee.

In addition, the NIH Program Directors will be responsible for normal 
programmatic monitoring and stewardship for the award.  The NIH Program 
Directors will approve changes in proposed research objectives and redirection 
of research projects.  The NIH reserves the right to terminate or curtail a 
study (or any individual award) in the event of (a) substantial shortfall in 
progress, data reporting, quality control, or other major breach of the 
protocol; (b) substantive changes in the consensus protocol to which the NIH 
does not agree; (c) reaching a major study endpoint substantially before 
schedule with persuasive statistical significance; or (d) animal welfare 
issues that may dictate a premature termination.

3. Collaborative Responsibilities

The Steering Committee

A Steering Committee will serve as the governing board of the cooperative 
group of researchers.  At a minimum, voting membership of the Steering 
Committee will include the NIAID Scientific Coordinator, the NIDDK Scientific 
Coordinator, 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. Each 
member of the Steering Committee will have one vote.  A Chairperson will be 
selected by the Steering Committee from among the non-federal Committee 
members. The Steering Committee may appoint additional members by majority 
vote.  Subcommittees of the Steering Committee may be established as 
necessary.  In addition, the NIH may appoint up to two members of an NIH 
scientific advisory panel to the Steering Committee as non-voting members.  
Federal votes cannot exceed 25%.  Program Directors from other sponsoring 
Institutions will serve on the Steering Committee as either voting or non-
voting members, dependent upon federal votes not exceeding 25%.  Awardee 
members of the Steering Committee will be required to accept and implement 
common guidelines and procedures approved by the Steering Committee.

The NIAID Scientific Coordinator will schedule the meetings of the Steering 
Committee and actively assist the Chair in developing the meeting agendas.  
The Committee will meet at least twice the first year and annually thereafter.  
At least one of the meetings in the first year and the annual meetings will be 
in Bethesda, MD.  The NIAID Scientific Coordinator will ensure coordination of 
the Steering Committee’s activities and implementation of the group’s 

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; and future plans.  The first such report will be 
submitted to the NIH Scientific Coordinators no later than 13 months after the 
initial notice of award and yearly thereafter.

The Steering Committee will:

o  Evaluate progress of the xenotransplantation projects and provide guidance 
to investigators regarding study implementation and conduct;
o  Establish protocols and subcommittees for evaluation, recommendation, and 
modification of ongoing xenotransplantation studies from cooperative group 
o  Establish protocols and subcommittees, as needed, for the solicitation, 
receipt, review, development, and evaluation of potential new, pilot, or 
collaborative projects or potential resource sharing opportunities, if 
additional funds are available for such projects; 
o  Advise NIH on scientific opportunities, emerging needs, and impediments;
o  Prepare Annual Reports; and
o  Develop guidelines for publication of collaborative project results.

Cooperation with Other NIH-Sponsored Programs

In order to most efficiently utilize research resources and rapidly exchange 
scientific information to promote xenotransplantation objectives, it is 
anticipated that cooperation or opportunities to collaborate with other NIH 
funded programs will be initiated in future years and will be coordinated and 
facilitated by the NIH Program Directors.

4. Arbitration

Any disagreement that may arise on scientific/programmatic matters (within the 
scope of the award) between award recipients and I/C may be brought to 
arbitration. An arbitration panel will be composed of three members – one 
chosen by the awardee, a second member selected by the NIH, 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.


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 

o Direct questions about scientific/research issues to:

Crystal Y. Koh, Ph.D
Division of Allergy, Immunology, and Transplantation
National Institute of Allergy and Infectious Diseases
Room 3026, MSC-6601
6610 Rockledge Drive
Bethesda, MD 20892-7640
Telephone: 301-496-5598
FAX: 301-480-0693

Thomas L. Eggerman, M.D., Ph.D.
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Room 697, MSC-5460
6707 Democracy Boulevard 
Bethesda, MD  20892-5460
Telephone:  (301) 594-8813
FAX:  (301) 480-3503

o Direct questions about peer review issues to:

Mercy Prabhudas, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 3256, MSC-7616
6700-B Rockledge Drive
Bethesda, MD 20892-7616
Telephone: (301) 451-2615
FAX: (301) 402-2638

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 


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:

Mercy Prabhudas, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 3256, MSC-7616
6700-B Rockledge Drive
Bethesda, MD 20892-7616
Telephone: (301) 451-2615
FAX: (301) 402-2638


Applicants for U19 grants must follow special application guidelines in the 
AWARDS; this brochure is available via the WWW at 

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 DUNS number can be obtained by calling (866) 705-5711 or 
through the web site at The DUNS number 
should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 
document is available at in an interactive 
format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, 

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

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:

Mercy Prabhudas, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 3256, 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 
November 22, 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 
will be judged non-responsive and will be returned to the applicant.


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

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 

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.

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.


Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NIAID and the NIDDK. Incomplete and/or non-responsive 
applications will be returned to the applicant without further consideration 
or review.

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 NIH 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 an appropriate national advisory council or 


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 

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 

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:

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.


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.


Letter of Intent Receipt Date:      October 22, 2004
Application Receipt Date:           November 22, 2004
Peer Review Date:                   March 15, 2005
Council Review:                     May 25, 2005
Earliest Anticipated Start Date:    June 30, 2005


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.


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 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.

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on 
hESCs can be found at and at Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see 
It is the responsibility of the applicant to provide, in the project 
description and elsewhere in the application as appropriate, the official NIH 
identifier(s) for the hESC line(s) to be used in the proposed research. 
Applications that do not provide this information will be returned without 

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

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


This program is described in the Catalogue of Federal Domestic Assistance at in the following citations: No. 93.855, Immunology, 
Allergy, and Transplantation Research; No. 93.847, Diabetes, Endocrinology, 
and Metabolism 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 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 

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices

H H S Department of Health
and Human Services

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