SEX-BASED DIFFERENCES IN THE IMMUNE RESPONSE

Release Date:  February 12, 2001

RFA:  RFA-AI-01-005

National Institute of Allergy and Infectious Diseases
 (http://www.niaid.nih.gov)
National Institute of Neurological Disorders and Stroke
 (http://www.ninds.nih.gov/) 
National Institute of Arthritis and Musculoskeletal and Skin Diseases
 (http://www.nih.gov/niams/)
Office of Research on Women’s Health, National Institutes of Health
 (http://www4.od.nih.gov/orwh/)
National Multiple Sclerosis Society
 (http://www.nationalmssociety.org)

Letter of Intent Receipt Date:  June 03, 2001
Application Receipt Date:       July 10, 2001

THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS FOR R01 
AND R21 GRANTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD 
APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS 
IN RESPONSE TO THIS RFA. 

P01 GRANT APPLICATIONS IN RESPONSE TO THIS RFA MUST BE PREPARED USING A 
MULTI-PROJECT GRANT APPLICATION FORMAT; SPECIFIC INSTRUCTIONS FOR 
COMPLETING THE APPLICATION ARE IN THE NIAID BROCHURE ENTITLED 
"INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS (August 2000)”.  

PURPOSE

The National Institute of Allergy and Infectious Diseases
(NIAID), the National Institute of Neurological Disorders and Stroke 
(NINDS), the National Institute of Arthritis and Musculoskeletal and 
Skin Diseases (NIAMS), the Office of Research on Women’s Health (ORWH) 
of the National Institutes of Health (NIH) and the National Multiple 
Sclerosis Society (NMSS) invite applications to identify, characterize, 
and define differences in the immune response between males and females, 
including responses to exogenous and self-antigens, the innate and 
adaptive immune response, systemic and mucosal immune response, and 
regulation of the immune system by hormonal and non-hormonal sex 
differences. The intent of this Request for Applications (RFA) is to 
support multidisciplinary research on sex-based differences in immune 
responses that may be important in autoimmune diseases, including 
multiple sclerosis (MS), rheumatic diseases such as rheumatoid arthritis 
(RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc), 
as well as other immune mediated diseases, and the underlying mechanisms 
and clinical significance of such differences. Collaborative 
multidisciplinary research, involving investigators with expertise in 
various scientific disciplines and clinical specialties is encouraged. 
Both human studies and animal models with relevance to human disease are 
appropriate. Research that expands basic and clinical knowledge of the 
effect of sex, including hormonal and non-hormonal differences, on the 
immune response will facilitate development of improved therapeutic and 
preventive strategies for autoimmune diseases and other immune-mediated 
disorders. The focus of this RFA is the biological or physiological sex 
differences between males and females; studies of the cultural, social, 
and historical differences between males and females ("gender 
differences") are not responsive to this RFA.

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 Request for 
Applications (RFA), “Sex–Based Differences in the Immune Response”, is 
related to one or more of the focus areas. Potential applicants may 
obtain a copy of "Healthy People 2010" at 
http://www.health.gov/healthypeople.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign for-profit and 
non-profit organizations; public and private institutions, such as 
universities, colleges, hospitals, laboratories, units of State and 
local governments; and eligible agencies of the Federal government. 
Although foreign institutions are not eligible to apply for Program 
Project (P01) grants, they are permitted as subprojects.  Racial/ethnic 
minority individuals, women, and persons with disabilities are 
encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

The mechanisms of support will be the Individual Research Project Grant 
(R01), the Exploratory/Developmental Research Project Grant (R21), and 
the Program Project Grant (P01). The total requested project period for 
an application submitted in response to this RFA may not exceed four 
years for an R01, three years for an R21, and five years for a P01 
grant.

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

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

P01 grants are used to support broadly based multidisciplinary research 
programs that have a well-defined central research focus or objective.  
An important feature is that the interrelationships among the individual 
scientifically meritorious projects will result in a greater 
contribution to the overall program goals than if each project was 
pursued individually.  The program project grant consists of a minimum 
of three interrelated individual research projects that contribute to 
the program objective.  The award also can provide support for certain 
common resources termed cores.  Such resources should be utilized by two 
or more projects within the award. A P01 application should be prepared 
using the guidance and instruction provided in the NIAID Information 
Brochure for Program Projects and Grants, available at: 
http://www.niaid.nih.gov/ncn/grants/multibron.htm. 

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the 
NIH. Complete and detailed instructions and information on Modular Grant 
applications can be found at 
http://grants.nih.gov/grants/funding/modular/modular.htm.  A notice of 
modification and update (OD-00-046) regarding modular grants was 
released on 7/24/00 and can be found at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-046.html.

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

FUNDS AVAILABLE

The estimated total funds (direct and Facilities and Administrative 
(F&A) costs) available for the first year of support for all awards made 
under this RFA will be $4,450,000: $2,000,000 from the NIAID, $750,000 
from NINDS, $500,000 from NIAMS, $200,000 from ORWH and $1,000,000 from 
NMSS. NINDS will fund grants with relevance to the central and 
peripheral nervous system. Applications considered for co-funding with 
the NMSS must have relevance to multiple sclerosis or a relevant model 
system for MS, although collaborative projects including expertise from 
a variety of scientific and clinical disciplines are encouraged. The 
NMSS will determine fulfillment of this requirement.  Although this 
program is provided for in the financial plans of the NIH and NMSS, 
awards pursuant to this RFA are contingent upon the availability of 
funds for this purpose and the receipt of a sufficient number of 
applications of high scientific merit, and for the NMSS sufficient 
applications with relevance to multiple sclerosis. In Fiscal Year 2002, 
the NIH and NMSS plan to fund approximately 5 to 10 awards. Although the 
NIH and NMSS intend to co-fund applications, separate notices of grant 
award will be sent to successful applicants by each organization 
indicating the independent commitment by each organization.  Funding 
rules and policies, including the determination of allowable indirect 
costs, of each funding organization will be applicable. Information on 
current policies for NMSS and NIH can be found at 
(http://www.nationalmssociety.org/\pdf\research\PoliciesAndProcedures.pdf) 
and http://grants.nih.gov/grants/policy/nihgps/ respectively.  Funding 
beyond the first and subsequent years of the grant will be contingent 
upon satisfactory progress during the preceding years and availability 
of funds.  Post-award administration will conform to current policies 
that govern the research grants programs of the NIH and the NMSS as 
appropriate.

RESEARCH OBJECTIVES 

Background

Sexual dimorphism in various aspects of the immune response has long 
been appreciated. In general, women mount a more vigorous immune 
response than men to infections, which may partially explain why women 
tend to live longer. However, women are also more likely than men to 
suffer from autoimmune diseases.  In multiple sclerosis, rheumatoid 
arthritis, and systemic sclerosis, for example, the female to male ratio 
is between 2:1 and 3:1 and in systemic lupus erythematosus approximately 
nine times as many women as men are affected. As a result, of the 14 
million people with autoimmune diseases in the United States, the 
majority are women. Although autoimmune diseases are more common in 
women, disease severity may be worse in men. Recent analyses of multiple 
sclerosis patients suggest men experience acceleration of disease and 
increased mortality compared to women.

The precise reasons for the sex-based differences seen in immune 
responses are unclear. The increased incidence of many autoimmune 
diseases after puberty, as well as the effect of pregnancy on the course 
of disease, suggest a role for sex hormones in these illnesses. Clinical 
remissions often occur during pregnancy in patients with multiple 
sclerosis and rheumatoid arthritis, whereas postpartum disease activity 
is increased. In contrast, pregnancy may either precipitate or 
ameliorate symptoms in patients with systemic lupus erythematosus. 
Estrogen administration induces a systemic lupus erythematosus-like 
phenotype in non-autoimmune mice transgenic for the heavy chain of a 
pathogenic DNA-specific antibody. In addition, estrogen enhances the 
efficacy of a T cell receptor-based immunotherapy for experimental 
autoimmune encephalomyelitis, an animal model of multiple sclerosis. 
Therefore evidence from a variety of sources implicates a role for sex 
hormones in modulating the incidence, course and severity of autoimmune 
disease.
 
Sex hormones also appear to influence infectious diseases. Malaria is 
one of the most serious complications of pregnancy for women living in 
endemic areas. Both estrogen and testosterone have been shown to 
suppress immunity to this disease, although pre-existing protective 
immunity is not affected by testosterone. Recent evidence also suggests 
that estrogens and progesterone regulate antigen presentation in the 
female reproductive tract and may affect susceptibility to sexually 
transmitted diseases. Unique defensins, components of the innate immune 
response produced in the male and female reproductive tract, may play a 
role in preventing sexually transmitted diseases including HIV 
infection.   

Not all sex-based differences in immune responses are necessarily 
hormonally related. Recent studies show increased incidence and numbers 
of fetus-derived cells in blood and affected tissues of postpartum women 
with scleroderma as compared to healthy women, suggesting a role for 
microchimerism in the pathogenesis of autoimmune disease. In addition, 
human and animal studies suggest sex-related factors may interact with 
susceptibility genes leading to differential expression of autoimmune 
disease in males and females. Thus, both hormonal and non-hormonal 
factors appear to contribute to sex-based differences in the immune 
response, however, the mechanisms remain unclear.

In 1995 the NIH sponsored a meeting on Gender and Autoimmunity and 
recently participated in a Task Force on Gender, MS and Autoimmunity 
organized by the National Multiple Sclerosis Society. The latter 
resulted in a major review article entitled “A Gender Gap in 
Autoimmunity” (Science 283:1277,1999, and the Science web site 
http://www.sciencemag.org/feature/data/983519.shl). Both workshops 
recommended increased support for basic and clinical research on sex-
based differences in the immune response. This RFA is in response to 
these recommendations and expands upon a 1996 NIH Program Announcement 
“Gender in the Pathogenesis of Autoimmune Diseases: Mechanisms.”

Research Objectives and Scope

While both the NIH and the NMSS are currently supporting some sex-based 
research, this new program will: (1) target basic and clinical 
investigation of sex differences in all aspects of the immune response, 
(2) encourage new and established investigators to address existing 
gaps, and (3) foster multidisciplinary research collaborations to focus 
on existing opportunities. 

Research topics of interest include, but are not limited to the 
following:

o  Mechanisms that underlie sex-based differences in susceptibility to 
and severity of autoimmunity, infectious diseases, or other immune-
mediated diseases.

o  Molecular basis for differences between males and females in the 
immune response, including the adaptive, innate, and mucosal immune 
systems.

o  Differences between males and females in adaptive immune responses 
including, but not limited to, T and B cell development, tolerance 
induction, antibody production, antigen presentation and processing, and 
immune regulation.

o Differences in the triggering or response mechanisms in innate 
immunity that may be responsible for the sexual dimorphism observed in 
response to pathogens.

o Differences in the immune response to infections of the central and 
peripheral nervous system. 
 
o  Mechanisms of sex hormone regulation of the immune response in normal 
and disease states in males and females.  

o  The effect of pregnancy on the immune response and identification of 
postpartum changes that are responsible for either protection from or 
provocation of autoimmunity.

o  Mechanisms of microchimerism in the etiopathogenesis of autoimmune 
disease. 

o  The genetic basis for sex differences in autoimmunity.

The above examples of research topics are not meant to be all-inclusive 
or restrictive. Investigators are encouraged to develop their own 
innovative hypothesis-driven approaches to achieve the goals of this 
RFA.   

SPECIAL REQUIREMENTS

The NIH and the NMSS plan to sponsor an annual meeting to encourage the 
exchange of information among investigators supported under this RFA, 
foster collaborative efforts, and identify resources that would enhance 
the productivity of this research program. Applications should include a 
statement indicating the willingness of the applicant institution to 
participate in such annual meetings. For this purpose, travel funds for 
an annual two-day meeting, to be held in the Washington DC area should 
be included in the budget request.

TERMS AND CONDITIONS OF AWARD

When clinical studies or trials are a component of the research 
proposed, NIAID policy requires that studies be monitored commensurate 
with the degree of potential risk to study subjects and the complexity 
of the study.  In such cases, specific Terms and Conditions of Award 
will apply.  NIAID policy was announced in the NIH Guide on February 24, 
2000 and is available at: 
http://grants.nih.gov/grants/guide/notice-files/NOT-AI-00-003.html.  
The full policy including terms and 
conditions of award are available at: 
http://www.niaid.nih.gov/ncn/pdf/clinterm.pdf

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups 
and their sub-populations must be included in all NIH supported 
biomedical and behavioral research projects involving human subjects, 
unless a clear, compelling rationale, and justification are provided 
that inclusion is inappropriate with respect to the health of the 
subjects or the purpose of the research. This policy results from the 
NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43).

All investigators proposing research involving human subjects should 
read the UPDATED "NIH Guidelines For Inclusion of Women and Minorities 
as Subjects in Clinical Research," published in the NIH Guide for Grants 
and Contracts on August 2, 2000 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); a 
complete copy of the updated Guidelines are available at: 
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm.  
The revisions relate to NIH-defined Phase III clinical trials and 
require:  a) all applications or proposals and/or protocols to provide a 
description of plans to conduct analyses, as appropriate, to address 
differences by sex/gender and/or racial/ethnic groups, including 
subgroups if applicable; and b) all investigators to report accrual, and 
to conduct and report analyses, as appropriate, by sex/gender and/or 
racial/ethnic group differences.

NIH POLICY AND GUIDELINES ON THE INCLUSION OF CHILDREN AS PARTICIPANTS 
IN RESEARCH:

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

All investigators proposing research involving human subjects should 
read the "NIH Policy and Guidelines on the Inclusion of Children as 
Participants in Research Involving Human Subjects" that was published in 
the NIH Guide for Grants and Contracts, March 6, 1998, and which is 
available at the following URL address: 
http://grants.nih.gov/grants/guide/notice-files/not98-024.html.    

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

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.  Reviewers are cautioned that 
their anonymity may be compromised when they directly access an Internet 
site.

LETTER OF INTENT

Prospective applicants are asked to submit, by June 03, 2001, a letter 
of intent that includes a descriptive title of the overall proposed 
research; the name, address and telephone number of the Principal 
Investigator; and the number and title of this RFA.  Although the letter 
of intent is not required, is not binding, does not commit the sender to 
submit an application, 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 to plan the review.  
The letter of intent is to be sent to Dr. Nasrin Nabavi at the address 
listed under INQUIRIES.

LETTER OF AUTHORIZATION

This RFA is co-sponsored by the NMSS. In order for an application to be 
considered for funding by the NMSS, applicants must submit a brief 
letter of authorization co-signed by the Principal Investigator and the 
Business Official of the applicant institution authorizing release of 
any letter of intent, the application, priority score, and summary 
statement to the NMSS. This letter of authorization should be submitted 
directly to Dr. Denise Wiesch at the address listed under INQUIRIES.  

APPLICATION PROCEDURES

Applicants are strongly encouraged to call NIAID, NINDS, or NIAMS 
program staff with any questions regarding the responsiveness of their 
proposed project to the goals of this RFA.  

The research grant application form PHS 398 (rev. 4/98) is to be used in 
applying for these grants. Application kits are available at most 
institutional offices of sponsored research and from the Division of 
Extramural Outreach and Information Resources, National Institutes of 
Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, 
telephone (301) 435-0714, email: GrantsInfo@nih.gov. Applications are 
also available on the World Wide Web at 
http://grants.nih.gov/grants/forms.htm.

For purposes of identification and processing, item 2a on the face page 
of the application must be marked "YES" and the RFA number "AI-01-005" 
and the words "SEX-BASED DIFFERENCES IN THE IMMUNE RESPONSE" must be 
typed in.

The RFA label and line 2 of the application should both indicate the RFA 
number.  The RFA label must be affixed to the bottom of the face page.  
Failure to use this label could result in delayed processing of the 
application such that it may not reach the review committee in time for 
review.

The sample RFA label available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been 
modified to allow for this change.  Please note this is in pdf format.

Applications must be received by July 10, 2001.  Applications that are 
not received as a single package on the receipt date or that do not 
conform to the instructions contained in PHS 398 (rev. 4/98) Application 
Kit (as modified in, and superseded by, the NIAID BROCHURE ENTITLED 
"INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS") will be judged 
non-responsive and will be returned to the applicant.  

If the application submitted in response to this RFA is substantially 
similar to a grant application already submitted to the NIH for review, 
but that has not yet been reviewed, the applicant will be asked to 
withdraw either the pending application or the new one.  Simultaneous 
submission of identical applications will not be allowed, nor will 
essentially identical applications be reviewed by different review 
committees.  Therefore, an application that is essentially identical to 
one that has already been reviewed cannot be submitted in response to 
this RFA.  This does not preclude the submission of substantial 
revisions of applications already reviewed, but such applications must 
include an introduction addressing the previous critique.

Submit a signed, typewritten original of the application, including the 
Checklist, and three signed, exact, single-sided photocopies, in one 
package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express mail or courier service)

At the time of submission, two additional exact copies of the grant 
application and all five sets of any appendix material must be sent to:

Dr. Nasrin Nabavi
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 2212
6700-B Rockledge Drive
Bethesda, MD  20892

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

Applicants from institutions that have a General Clinical Research 
Center (GCRC) funded by the NIH National Center for Research Resources 
may wish to identify the GCRC as a resource for conducting the proposed 
research.  If so, a letter of agreement from either the GCRC Program 
Director or Principal Investigator should be included with the 
application.

SPECIAL INSTRUCTIONS FOR COMPLETION OF P01 GRANT APPLICATIONS IN 
RESPONSE TO THIS RFA 

Applicants for P01 grants must follow special application guidelines in 
the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-
PROJECT AWARDS (August 2000); this brochure is available via the WWW at: 
http://www.niaid.nih.gov/ncn/grants/multibron.htm.

The brochure presents specific instructions for sections of the PHS 398 
(rev. 4/98) application form that should be completed differently than 
usual.  For all other items in the application, follow the usual 
instructions in the PHS 398.

Concurrent submissions of a component research project of a multi-
project (P01) grant application as a traditional individual research 
project (R01) to this RFA is prohibited. However, investigators may 
submit a component research project to NIH as an unsolicited R01 
recognizing that if both are found competitive and approved for award 
the P01 will be awarded and the unsolicited R01 must be withdrawn by the 
applicant.
  
SPECIFIC INSTRUCTIONS FOR R01 and R21 GRANT APPLICATIONS

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

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

o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form 
Page 4 of the PHS 398. It is not required and will not be accepted with 
the application.

o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the 
categorical budget table on Form Page 5 of the PHS 398. It is not 
required and will not be accepted with the application.

o BUDGET NARRATIVE JUSTIFICATION - Prepare a Modular Grant Budget 
Narrative page. (See 
http://grants.nih.gov/grants/funding/modular/modular.htm for sample 
pages.) At the top of the page, enter the total direct costs requested 
for each year.  This is not a Form page.

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

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

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

o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information 
used by reviewers in the assessment of each individual's qualifications 
for a specific role in the proposed project, as well as to evaluate the 
overall qualifications of the research team. A biographical sketch is 
required for all KEY personnel, including consultants, following the 
instructions below. No more than three pages may be used for each 
person. A sample biographical sketch may be viewed at: 
http://grants.nih.gov/grants/funding/modular/modular.htm.

- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on 
research projects ongoing or completed during the last three years;
- List selected peer-reviewed publications, with full citations.

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

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

Effective for the receipt dates beginning September 1, 2000, R01 and R21 
applications not in compliance with the modular application instructions 
will be returned to the applicant institution.   

An R01 and R21 application will be considered NON-COMPLIANT if:

1.  The requested direct cost budget is not in modules of $25,000 for 
all years of support for requests up to $250,000 per year.  

2.  A detailed itemized categorical budget is provided.

3.  The Budget Narrative Justification page includes an itemized 
justification for one or more of the following: equipment, supplies, 
travel, other expenses, etc. but the number of modules requested in each 
year is the same, or the information is not intended to explain the 
request for a different number of modules in one or more years.

4.  OTHER SUPPORT pages are supplied, in addition to or in the absence 
of the section in the Biographical Sketch identifying “Research Projects 
Ongoing or Completed During the Last Three Years.”

5.  The Biographical Sketch lists “Current and Pending Support” instead 
of or in addition to the required information.

REVIEW INFORMATION  

Review Procedures

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

Review Considerations

Applications that are complete and responsive to the RFA will be 
evaluated for scientific and technical merit by an appropriate peer 
review group convened by the Division of Extramural Activities, NIAID in 
accordance with the review criteria stated below. As part of the initial 
merit review, all applications will be discussed, be assigned a priority 
score, receive a written critique and a second level of review provided 
by the appropriate NIH advisory council.  The NMSS’s Research Programs 
Advisory Committee will review all projects considered for NMSS co-
funding.

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

Review Criteria for P01 grant applications

The general criteria for P01 grant applications are presented in the 
NIAID brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT 
AWARDS (August 2000).  

Review Criteria for R01 and R21 grant applications

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

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  
The reviewers will comment on the following aspects of the application 
in their written critiques in order to judge the likelihood that the 
proposed research will have a substantial impact on the pursuit of these 
goals.  Each of these criteria will be addressed and considered by the 
reviewers in assigning the overall score weighting them as appropriate 
for each application.  Note that the application does not need to be 
strong in all categories to be judged likely to have a major scientific 
impact and thus deserve a high priority score.  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.

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

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

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

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

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

Schedule

Letter of Intent Receipt Date:    June 03, 2001  
Application Receipt Date:         July 10, 2001
Scientific Peer Review Date:      November 15, 2001
Advisory Council Date:            February 15, 2002
Earliest Anticipated Award date:  April 01, 2002 

AWARD CRITERIA
  
Funding decisions will be made on the basis of scientific and technical 
merit as determined by peer review, programmatic priorities, and the 
availability of funds. The earliest anticipated date of award is April 
01, 2002.

INQUIRIES  
  
Written and telephone inquiries concerning this RFA are encouraged.  The 
opportunity to clarify any issues or questions from potential applicants 
is welcome.

Direct inquiries regarding programmatic (research scope and eligibility) 
issues to:  

Denise Wiesch, Ph.D.  
Program Officer, Clinical Immunology Branch
Division of Allergy, Immunology and Transplantation
NIAID, NIH 
Room 5253, MSC-7640
6700-B Rockledge Drive
Bethesda, MD  20892-7640
Telephone:  (301) 496-7104
FAX:        (301) 402-2571
E-Mail: dwiesch@niaid.nih.gov 

A. P. Kerza-Kwiatecki, Ph.D.
Program Director, NINDS, NIH 
Rockville, MD 20852          
NSC, Rm. 2115
6001 Executive Blvd., 
Bethesda, MD 20892-9521
Telephone: 301-496-1431
FAX: 301-402-2060
E-mail: AK45W@NIH.GOV 

J. Elizabeth Gretz, Ph.D.
Extramural Program Director,
Rheumatic Diseases/NIAMS
45 Center Drive, Natcher Building, 45, Rm 5As19j
Bethesda, MD 20892
Phone : 301-594-5032
FAX : 301-480-4543
E-mail: gretze@mail.nih.gov
             
Lisa Begg, Dr.P.H.
Director of Research Programs, ORWH, OD, NIH
1 Center Dr., Bethesda, MD, 20892
Telephone: 301/402-1770 
FAX: 301.402.1798  
E-mail: beggl@od.nih.gov 
  
Direct inquiries regarding review issues; address the letter of intent 
to; and mail two copies of the application and all five sets of 
appendices to:
  
Nasrin Nabavi, Ph.D.  
Division of Extramural Activities  
National Institute of Allergy and Infectious Diseases  
Room 2212
6700-B Rockledge Drive  
Bethesda, MD  20892
Telephone:  (301) 496-2550
FAX:        (301) 402-2638
E-Mail:     nnabavi@niaid.nih.gov

Direct inquiries regarding fiscal matters to:  

Karen McVay  
Division of Extramural Activities  
National Institute of Allergy and Infectious Diseases  
Room 2252
6700-B Rockledge Drive  
Bethesda, MD  20892  
Telephone:  (301) 402-6578
Fax:        (301) 480-3780
E-mail:     km18f@nih.gov 

Dianna Jessee
Grants Management Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Room 3261, MSC 9619
Bethesda, MD 20892-9619
Telephone: (301) 496-9231
Fax: (301) 402-0219
Email: dj35j@nih.gov

Melinda Nelson
Grants Management Officer
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, Natcher Building Rm 5As49f
Bethesda, MD 20892-6500
Telephone: (301) 594-3535
FAX (301) 480-5450
E-mail: nelsonm@mail.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalogue of Federal Domestic 
Assistance No. 93.855 - Immunology, Allergy, and Transplantation 
research, No. 93.853 - Extramural Programs in the Neurosciences and 
Neurological Disorders, and No. 93.846 - Arthritis, Musculoskeletal and 
Skin 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 Public Health Service strongly encourages all grant and contract 
recipients to provide a smoke-free workplace and promote the non-use of 
all tobacco products. In addition, Public Law 103-227, the Pro-Children 
Act of 1994, prohibits smoking in certain facilities (or, in some cases, 
any portion of a facility) in which regular or routine education, 
library, day care, health care or early childhood development services 
are provided to children.  This is consistent with the PHS mission to 
protect and advance the physical and mental health of the American 
people.

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