DISABLING INNATE IMMUNE EVASION: NEW ATTENUATED VACCINES

RELEASE DATE:  July 2, 2004

RFA:  RFA-AI-04-023  

EXPIRATION DATE: November 24, 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: October 26, 2004
APPLICATION RECEIPT DATE: November 23, 2004  

THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism(s) 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 purpose of this RFA is to solicit research projects focused on new 
approaches for vaccine development. Research supported and conducted by the 
National Institute of Allergy and Infectious Diseases (NIAID), National 
Institutes of Health, strives to understand, treat and ultimately prevent the 
myriad infectious, immunologic, and allergic diseases that threaten millions 
of human lives. The NIAID Division of Allergy, Immunology, and 
Transplantation (DAIT) and the Division of Microbiology and Infectious 
Diseases (DMID) support extramural research to control and prevent diseases 
caused by virtually all infectious agents. This RFA program is focused on the 
NIAID Category A, B, and C pathogens, which are listed at 
http://www.niaid.nih.gov/biodefense/bandc_priority.htm. 

RESEARCH OBJECTIVES

The scientific focus of this program is the human innate immune system as a 
target for immune evasion by NIAID Category A, B, and C pathogens. The 
immediate and long-range objectives of the program are to identify and modify 
microbial and viral innate immune evasion genes for the generation of 
avirulent or attenuated strains suitable for vaccine development. The program 
will fund pre-clinical and clinical studies but will not support clinical 
trials. For NIH definitions of clinical research and clinical trials, see 
http://grants.nih.gov/grants/funding/phs398/instructions2/p3_definitions.htm.

Background

To assess the state of research on the evasion of innate immunity by 
pathogens, the NIAID recently convened two expert panels to define knowledge 
gaps and to identify scientific opportunities. In 2002, an expert panel on 
Immunity and Biodefense addressed the immunological aspects of biodefense 
preparedness research, and in 2003 a panel on Antiviral Innate Immunity 
addressed viral infection, innate immunity, and mechanisms used by viruses to 
overcome these defenses. This research solicitation is based, in part, on 
recommendations from these panels, and will support a cooperative research 
program that targets innate immune evasion mechanisms used by NIAID Category 
A-C pathogens with the goal of developing novel disease prevention 
strategies.

Innate immunity is an evolutionarily ancient form of protection against 
microbial intruders. With the introduction of an antigen-specific adaptive 
immune system in vertebrate animals, innate immune systems began to co-evolve 
with the new mechanisms of protection against infection, to create distinct 
but interrelated and complementary roles for each arm of immunity within a 
vertebrate species. Innate immune mediators activate antigen-nonspecific host 
defense mechanisms that generally inhibit, but do not totally prevent 
infection. Innate immune mediators also play immunoregulatory roles that 
affect the onset, magnitude, duration, and reactivation or memory of antigen-
specific T and B cell responses. Collectively, these properties of innate 
immune activation constitute “adjuvanticity” and they are essential for 
immediate host defenses as well as for the robust and long lasting protection 
induced by vaccines. Because innate immune responses can retard infection and 
promote long term immune memory in the adaptive immune system, virulence 
factors have evolved in many pathogens to neutralize or evade innate immune 
mediators. Examples include decoy receptors that block the activity of 
cytokines, chemokines, or Toll-like receptors and other proteins that can 
inhibit the activity of interferon-alpha, a potent host-derived anti-viral 
cytokine.

Although attenuated live pathogen vaccines are generally more effective than 
killed pathogen or subunit vaccines, a sufficient degree of attenuation must 
be attained to make live vaccines safe for human populations. This process is 
time-consuming and often unsuccessful when approached in an empirical manner. 
In contrast, an alternative strategy to achieve this goal is the rational 
design of attenuated strains via the selective deletion (or disabling) of 
innate immune evasion genes. To be effective, such a strategy must preserve 
immunodominant T and B cell epitopes and adjuvanticity of the parent strain 
such as the induction of T cell costimulatory proteins or the cytokine IL-12. 

Recent advances in immunology and microbial genetics make this novel approach 
feasible, and early results are encouraging. For example, the influenza NS1 
protein inhibits interferon-alpha, an innate immune mediator, increasing the 
severity of influenza infection. As tested in mice, selective inactivation of 
the gene encoding NS1 yields a highly attenuated strain that protects against 
wild type influenza in challenge models.

Many proteins of Category A-C pathogens are thought to block interferon-alpha 
effects including:  the NS proteins of the Rift Valley Fever virus; the VP35 
protein of Ebola; the V, W, and P proteins of the Nipah virus; and the 
poxvirus E3L protein. The E3L gene, found in all poxviruses, is required for 
lethal vaccinia infection in mice and its deletion results in an attenuated 
virus. Although not yet tested, the inactivation/deletion of the genes 
encoding this, or other interferon blocking proteins, either alone or in 
combination with the inactivation/deletion of genes encoding other innate 
immune evasion proteins, might lead to novel attenuated strains suitable for 
further development as vaccines.

Research Objectives

This program will support research that focuses on rational approaches to 
selectively disable innate immune evasion genes relevant to the pathogenesis 
of Category A, B, or C organisms, while maintaining the adjuvanticity and 
immunogenicity of attenuated strains. The ultimate goal is to develop and 
validate novel approaches to vaccine design that are applicable to multiple 
pathogens. HIV/AIDS research is excluded from this RFA. Clinical trials will 
not be supported under this program, although work with human samples is 
encouraged. For the NIH definition of clinical trials, see 
http://grants.nih.gov/grants/funding/phs398/instructions2/p3_definitions.htm. 

In order to be considered responsive to the RFA, each application MUST 
include BOTH Research Areas outlined below:

Research Area 1 includes a research plan for the selective modification of 
one or more specific NIAID Category A, B, or C pathogen genes that encode 
molecules functioning in innate immune evasion. If the applicant has 
previously modified a specific NIAID Category A, B, or C pathogen gene, 
materials documenting this work may be provided in lieu of the experimental 
plan, provided the applicant proposes to test the same modified strain as a 
vaccine candidate as outlined in Research Area 2. In this case, the approach 
and results should be fully described.

AND

Research Area 2 must include an experimental plan to demonstrate both the 
attenuation (i.e. reduced growth and virulence) and retention of 
immunogenicity and adjuvanticity of the gene-modified strain(s). The use of 
human cell lines, fresh cellular isolates, or tissues is highly encouraged 
whenever possible for in vitro studies. Suitable small or large animals may 
be used as in vivo models of human infection and immune protection. In all 
cases, the usefulness and human relevance of the in vitro or in vivo models 
should be addressed, and the possible extrapolation of results to human in 
vivo infection and vaccination should be discussed. 

IF THESE REQUIREMENTS ARE NOT MET, THE APPLICATION WILL BE CONSIDERED NON-
RESPONSIVE AND WILL BE RETURNED TO THE APPLICANT WITHOUT REVIEW.

NIAID will accept applications focused on one or more Category A-C pathogens, 
as long as the proposed budget matches the scope of the project. The same 
review criteria will be used for all pathogens and application parts and the 
final score will reflect the overall evaluation of the proposal. 

MECHANISM OF SUPPORT

This RFA will use the NIH cooperative agreement (U01), an "assistance" 
mechanism, 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. The applicant will be solely 
responsible for planning, directing, and executing the proposed project. This 
RFA is a one-time solicitation and any future unsolicited, competing-
continuation application 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 July, 2005. 
Applications submitted in response to this RFA that do not receive an award 
may be revised and submitted in the future as  NEW R01 investigator-initiated 
applications using the standard receipt dates for NEW applications described 
in the instructions to the PHS 398 application. 

The NIH U01 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 
Award".

The total project period for applications submitted in response to this RFA 
may not exceed five years. At this time, the NIAID has not determined whether 
and how this solicitation will be continued beyond the present RFA.

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

FUNDS AVAILABLE 

The NIAID intends to commit a total of approximately $6M in FY 2005 to fund 5 
to 10 new 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 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. 

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 or foreign institutions/organizations
o Faith-based or community-based organizations

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’ Knowledge and Expertise

Each application must propose a research and development project whose 
ultimate goal is to develop a vaccine specific for an NIAID Category A, B or 
C pathogen. Because the success of the research solicited by this RFA will 
rely on a strong synergism between the fields of innate immunity and 
microbial pathogenesis, applications are required to include individuals who 
will contribute BOTH in-depth knowledge in immunology AND expertise in the 
biology of the pathogen under study. Each application will include ONE 
Principal Investigator who is an expert in at least one of these two 
scientific fields; co-investigators and/or postdoctoral fellows with in-depth 
understanding of the other research area should be included as key personnel. 
APPLICATIONS THAT DO NOT MEET THIS REQUIREMENT WILL BE CONSIDERED NON-
RESPONSIVE AND WILL BE RETURNED TO THE APPLICANT WITHOUT REVIEW.

Milestones

Applications must define the proposed project goal, yearly milestones for 
each project, and a schedule or timeline for achieving milestones and goals. 
The outline for the milestones should be provided in a chart format (e.g. 
GANNT chart) in PHS 398 Form at the end of the experimental plan. It is 
recognized that milestones may require revision and re-negotiation during the 
course of the project period. Release of each yearly funding increment by 
NIAID will be based on a NIAID review of progress towards achieving the 
previously agreed upon milestones.
Annual Workshop

Principal investigators will be expected to participate in an annual workshop 
organized by NIAID Program Staff in order to: assess progress; discuss 
positive and negative results; arrange for the sharing of materials including 
reagents and techniques; identify new research opportunities; and establish 
research collaborations so that the program will have a maximum impact on the 
development of improved human vaccines for NIAID Category A-C pathogens. 
Travel funds for the principal investigators and other key personnel should 
be budgeted for this purpose.

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 
cooperative agreement (U01), an "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 NIAID Scientific Coordinator.

1. Monitoring Clinical Studies

Although clinical trials are excluded from this program, clinical studies 
using human samples are encouraged. When clinical studies are a component of 
the research proposed, NIAID policy requires that studies be monitored 
commensurate with the degree of potential risk to the study subjects and the 
complexity of the study. An updated NIAID policy was published in the NIH 
Guide on July 8, 2002 and is available at: 
http://grants.nih.gov/grants/guide/notice-files/NOT-AI-02-032.html. The full 
policy, including terms and conditions of award, is available at: 
http://www.niaid.nih.gov/ncn/pdf/clinterm.pdf.

2. 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 in the SPECIAL REQUIREMENTS SECTION 
of this RFA which specifies the applicants’ knowledge and expertise, the 
submission of project milestones, the participation to an annual workshop, 
and the adherence to 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) safeguarding 
Institutions' rights in inventions made under this funding mechanism and the 
reporting requirements for such inventions.

3. NIAID Staff Responsibilities

NIAID staff assistance will be provided by a NIAID Program Officer from the 
Division of Allergy, Immunology, and Transplantation (DAIT), who will serve 
as NIAID's 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.

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 (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 NIAID Scientific Coordinator will serve as a 
liaison/facilitator between the awardee, pharmaceutical and biotech 
industries, and other government agencies (e.g. 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 NIAID will be to facilitate and not 
to direct the activities. The Chief of Regulatory Affairs, DAIT, NIAID, will 
be responsible for providing guidance and assistance in the development, 
assembly, and submission of all required regulatory documents, e.g., those 
regarding the use of investigational vaccines or drugs, to the Food and Drug 
Administration. It anticipated that decisions in all activities will be 
reached by consensus and the NIAID 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.

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. 

4. Collaborative Responsibilities

NIAID Staff will provide expertise in technology and resource development, 
availability, and application; development, design, and implementation of 
studies with human samples; policies and procedures for the protection of 
human subjects; and will serve as liaison to other NIH-sponsored programs to 
facilitate collaboration and coordination.  

5. 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 IC, 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:

Francesca Macchiarini, Ph.D.
Division of Allergy, Immunology, and Transplantation
National Institute of Allergy and Infectious Diseases
Room 3070, MSC-6601
6610-B Rockledge Drive
Bethesda, MD 20892-6601
Telephone: 301-496-7551
FAX: 301-480-2381
Email: fm46w@nih.gov

o Direct questions about peer review issues to:

Thomas Hiltke
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 3254, MSC-7616
6700-B Rockledge Drive
Bethesda, MD 20892-7616
Telephone: 301-402-6891
FAX: 301-402-2638
Email: th247q@nih.gov 

o Direct questions about financial or grants management matters to:

Kim Coats
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 2243, MSC-7614
6700-B Rockledge Drive
Bethesda, MD 20892-7614
Telephone: 301-451-4576
FAX: 301-480-3780
Email: kc127b@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 NIAID 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:

Thomas Hiltke
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 3254, MSC-7616
6700-B Rockledge Drive
Bethesda, MD 20892-7616
Telephone: 301-402-6891
FAX: 301-402-2638
Email: th247q@nih.gov 

SUBMITTING AN APPLICATION

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 http://www.dunandbradstreet.com/. 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 
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.

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:

Thomas Hiltke
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 3254, MSC-7616
6700-B Rockledge Drive
Bethesda, MD 20892-7616
BETHESDA, MD 20817 (for express mail/courier service)
Telephone: 301-402-6891
FAX: 301-402-2638
Email: th247q@nih.gov 

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.

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 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 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

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:

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human 
subjects and protections from research risk relating to their participation 
in the proposed research will be assessed. (See criteria included in the 
section on Federal Citations, below)

INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of 
plans to include subjects from both genders, all racial and ethnic groups 
(and subgroups), and children as appropriate for the scientific goals of the 
research. Plans for the recruitment and retention of subjects will also be 
evaluated. (See Inclusion Criteria in the sections on Federal Citations, 
below).

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:      October 26, 2004
Application Receipt Date:           November 23, 2004   
Peer Review Date:                   April, 2005                              
Council Review:                     May, 2005
Earliest Anticipated Start Date:    July, 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

HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated with 
reference to the risks to the subjects, the adequacy of protection against 
these risks, the potential benefits of the research to the subjects and 
others, and the importance of the knowledge gained or to be gained. 
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm

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.

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of 
the NIH that women and members of minority groups and their sub-populations 
must be included in all NIH-supported clinical research projects unless a 
clear and compelling justification is provided indicating that inclusion is 
inappropriate with respect to the health of the subjects or the purpose of 
the research. This policy results from the NIH Revitalization Act of 1993 
(Section 492B of Public Law 103-43).

All investigators proposing clinical research should read the AMENDMENT "NIH 
Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research - Amended, October, 2001," published in the NIH Guide for Grants and 
Contracts on October 9, 2001 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html);
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.

The amended policy incorporates: the use of an NIH definition of clinical 
research; updated racial and ethnic categories in compliance with the new OMB 
standards; clarification of language governing NIH-defined Phase III clinical 
trials consistent with the new PHS Form 398; and updated roles and 
responsibilities of NIH staff and the extramural community. The policy 
continues to require for all NIH-defined Phase III clinical trials that: a) 
all applications or proposals and/or protocols must provide a description of 
plans to conduct analyses, as appropriate, to address differences by 
sex/gender and/or racial/ethnic groups, including subgroups if applicable; 
and b) investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: 
The NIH maintains a policy that children (i.e., individuals under the age of 
21) must be included in all human subjects research, conducted or supported 
by the NIH, unless there are scientific and ethical reasons not to include 
them. 

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines" on the inclusion of children as participants in 
research involving human subjects that is available at 
http://grants.nih.gov/grants/funding/children/children.htm.

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH 
policy requires education on the protection of human subject participants for 
all investigators submitting NIH proposals for research involving human 
subjects. This policy announcement is in the NIH Guide for Grants and 
Contracts Announcement, dated June 5, 2000, at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research 
on hESCs can be found at http://stemcells.nih.gov/index.asp and at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). 
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 
review.

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.

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The 
Department of Health and Human Services (DHHS) issued final modification to 
the “Standards for Privacy of Individually Identifiable Health Information”, 
the “Privacy Rule,” on August 14, 2002. The Privacy Rule is a federal 
regulation under the Health Insurance Portability and Accountability Act 
(HIPAA) of 1996 that governs the protection of individually identifiable 
health information, and is administered and enforced by the DHHS Office for 
Civil Rights (OCR). 

Decisions about applicability and implementation of the Privacy Rule reside 
with the researcher and his/her institution. The OCR website 
(http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including 
a complete Regulation Text and a set of decision tools on “Am I a covered 
entity?” Information on the impact of the HIPAA Privacy Rule on NIH processes 
involving the review, funding, and progress monitoring of grants, cooperative 
agreements, and research contracts can be found at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

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


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