RELEASE DATE:  March 11, 2002

RFA:  AI-02-008

National Institute of Allergy and Infectious Diseases (NIAID) 



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  Where to Send Inquiries
o  Letter of Intent
o  Submitting an Application
o  Peer Review Process
o  Review Criteria
o  Receipt and Review Schedule
o  Award Criteria
o  Required Federal Citations:


The Division of Microbiology and Infectious Diseases of the National Institute 
of Allergy and Infectious Diseases (NIAID) invites applications for research 
grants designed to develop innovative yet exploratory approaches that would 
contribute to our understanding of the mechanisms that impact on the virulence 
of infections involving two or more microorganisms or strains of 
microorganisms with the exception of HIV. Projects should include studies 
aimed at understanding the interactions of pathogens with the normal flora as 
well as the interactions among pathogens themselves, and how commensal 
organisms can be used to prevent or treat infections; however, this RFA is 
limited to those projects that involve or are based on intermicrobial 
interactions that have been well documented to occur in clinical settings. The 
development of co-infection models and the use of genomic and proteomic 
technologies to identify common virulence mechanisms and host response 
patterns is encouraged. The establishment of collaborative scientific teams 
with diverse backgrounds and approaches is strongly encouraged. Overall, a 
major focus of this RFA is an invitation to use new technology and to develop 
novel ideas for further studies.


There is increasing evidence in the literature for the importance of 
polymicrobial infections in which microorganisms provide individual 
pathologies that may act in synergistic or inhibitory fashion, impacting on 
either tissue and host cell destruction, or the maintenance of health. Among 
these, bacteria-bacteria, virus-virus, parasite-parasite or virus-bacteria 
interactions have been well documented. For example, Helicobacter pylori can 
render individuals more or less susceptible to infection by certain enteric 
pathogens. Also, co-infection of Borrelia and Ehrlichia have been reported to 
enhance the severity and complicate the diagnosis of Lyme borreliosis. 
Further, the occurrence of multiple hepatotropic viruses influence the 
progression of the disease. In mice, schistosomiasis infections have been 
shown to be associated with exacerbated pathology during concomitant 
toxoplasmosis infections.  Further, recent studies in mice support 
epidemiologic evidence of a synergistic interaction between Streptoccus 
pneumoniae and influenza virus; it has been suggested that such lethal synergy 
may account for excess mortality and meningitis during the influenza 

It is conceivable that a viral or parasitic infection, for instance, may 
facilitate bacterial colonization and enhanced adherence to host cells paving 
the way for invasive disease. For example, a virus infection may induce host 
cell membrane changes such as the expression of viral glycoproteins that may 
serve as receptors for bacteria, or up-regulate platelet activating factor 
receptor thereby promoting increased bacterial adherence. Likewise, it is 
equally conceivable that a bacterial infection may pave the way for increased 
viral disease. Also, the ability of various bacteria in the microbial complex 
of the oral cavity to express surface molecules (e.g., bacteriocins) that 
specifically interact with other bacterial species and host cells has been 
suggested to be a critical determinant in plaque formation and structure. 
Indeed, a number of recent studies have focused on these research areas 
including those using experimental animal models; however, most of these 
studies are preliminary and need to be developed further. In future studies it 
will be important to examine the mechanisms associated with the actual 
pathogen-to-pathogen interaction within the same host environment that may 
lead to increased susceptibility. 

It is anticipated that a better understanding of the mechanisms involved in 
the observed clinical phenomena may provide opportunities to more critically 
evaluate the role of suspected virulence determinants involved in these mixed 
infections and the innate or specific host immune response patterns involved; 
these projects should also provide useful information for investigators in the 
development of more effective diagnostic, prevention and treatment strategies.

Research Objectives and Scope

A major focus of this RFA is to encourage investigators to develop novel yet 
exploratory approaches for examining polymicrobial interactions and to think 
beyond the one organism-one disease concept; it is hoped that the results of 
these projects would provide opportunities for future, more focused, research. 
Projects will be considered responsive to this RFA if the studies involve 
intermicrobial interactions (with the exception of HIV) that have been well-
documented to occur in clinical settings or are based on clinically 
significant studies and are designed on the basis of sound scientific 
arguments with clearly defined endpoints such as profiles of immunological 
responses, synergizing metabolic activities or the inhibition/promotion of 
adherence to host cells. Thus, applications involving virus-virus, bacteria-
bacteria, parasite-parasite, or virus-bacteria interactions, that demonstrate 
well-established links, would be considered responsive.

Research studies to be investigated under this RFA are expected to develop new 
technologies and novel, mechanistic ideas for polymicrobial interactions. 
Projects to be examined include, but are not limited to the following:

1) Determination of whether an active viral or parasitic infection precedes a 
more severe bacterial infection or vice versa.
2) Definition of the environmental/physiological conditions that might 
contribute to the microbial synergy or inhibition. 
3) Identification of microbial virulence genes and/or proteins that may be 
uniquely expressed during co-infection.
4) Evaluation of host response patterns, in response to single vs. multiple 
infections, required to elicit synergy or inhibition.
5) Characterization of the polymicrobial interactions associated with 
carriage of pathogens and those interactions that lead to invasion.
6) Examination of the use of commensal organisms in the prevention and 
treatment of infections (e.g. probiosis).


The mechanism of support will be the Exploratory/Developmental Research 
Project Grant, R21. The total requested project period for an application 
submitted in response to this RFA may not exceed two years. As an applicant 
you 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.

NIAID uses R21 grants to provide short-duration support for preliminary 
studies of a highly speculative nature, which are expected to yield, within 
this time frame, sufficient information upon which to base a well-planned and 
rigorous series of further investigations. Applications will request direct 
costs in $25,000 modules.  A typical modular grant application requests the 
same number of modules in each year. Funds and time requested should be 
appropriate for the research proposed.  Applicants may not include travel or 
large equipment in the requested budget. 

It is hoped that successful grantees funded through this program will seek 
continuing support for research further through the R01 grant mechanism. 
Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts that have been adopted by the 
NIH. Complete and detailed instructions and information on Modular Grant 
applications have been incorporated into the PHS 398 (rev. 5/01). Additional 
information on Modular Grants can be found at

The anticipated award date is April 1, 2003.

NIAID intends to commit approximately $3,000,000 in FY 2003 to fund 10 to 12 
new and/or competitive continuation grants in response to this RFA. An 
applicant may request a project period of up to 2 years and a budget for 
direct costs of up to $150,000 per year. 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. 


You may submit (an) application(s) if your 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


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.


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 your questions about scientific/research issues to:

Dr. Christopher E. Taylor  
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases  
Room 3128, MSC-7630
6700-B Rockledge Drive
Bethesda, MD  20892-7630
Telephone:  (301) 496-5305
FAX:        (301) 496-8030

o  Direct your questions about peer review issues; address the letter of 
intent; mail two copies of the application and all five sets of appendices to:
Gregory Jarosik, Ph.D.  
Division of Extramural Activities  
National Institute of Allergy and Infectious Diseases  
Room 2224, MSC-7616
6700-B Rockledge Drive  
Bethesda, MD  20892-7616
Telephone:  (301) 496-0695
FAX:        (301) 402-2698

o  Direct your questions about financial or grants management matters to:

Lesia Norwood  
Division of Extramural Activities  
National Institute of Allergy and Infectious Diseases  
Room 3221, MSC-7614
6700-B Rockledge Drive  
Bethesda, MD  20892-7614  
Telephone:  (301) 402-6581
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:

Gregory Jarosik, Ph.D.  
Division of Extramural Activities  
National Institute of Allergy and Infectious Diseases  
Room 2224, MSC-7616
6700-B Rockledge Drive  
Bethesda, MD  20892-7616
Telephone:  (301) 496-0695
FAX:        (301) 402-2698


Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001). The PHS 398 is available at in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 710-0267, 


To apply, please follow NIH guidelines for submission of an R21 application as 
listed below:

1.  The description (abstract) must include a brief explanation of the 
proposed activity, and how it is consistent with the exploratory/development 
nature of the R21 mechanism as described in this notice. 

2.  Although preliminary data are neither expected nor required for an R21 
application, they may be included.

3.  Sections a-d of the Research Plan may not exceed 10 pages, including 
tables and figures.
4.  Appendix materials should be limited, as is consistent with the 
exploratory nature of the R21 mechanism, and should not be used to circumvent 
the page limit for the research plan.  Copies of appendix material will only 
be provided to the primary reviewers of the application and will not be 
reproduced for wider distribution. The following materials may be included in 
the appendix:
o  Up to five publications, including manuscripts (submitted or accepted for 
publication), abstracts, patents, or other printed materials directly relevant 
to the project.  These may be stapled as sets.
o  Surveys, questionnaires, data collection instruments, and clinical 
protocols.  These may be stapled as sets.
o  Original glossy photographs or color images of gels, micrographs, etc., 
provided that a photocopy (may be reduced in size) is also included within the 
10-page limit of items a-d of the research plan.  

Include five collated sets of all appendix material, in the same package with 
the application, following all copies of the application. Identify each item 
with the name of the principal investigator. 
up to $250,000 per year in direct costs must be submitted in a modular grant 
format.  The modular grant format simplifies the preparation of the budget in 
these applications by limiting the level of budgetary detail.  Applicants 
request direct costs in $25,000 modules.  Section C of the research grant 
application instructions for the PHS 398 (rev. 5/2001) at includes step-by-step 
guidance for preparing modular grants.  Additional information on modular 
grants is available at

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:

Gregory Jarosik, Ph.D.  
Division of Extramural Activities  
National Institute of Allergy and Infectious Diseases  
Room 2224, MSC-7616
6700-B Rockledge Drive  
Bethesda, MD  20892-7616

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 Center for Scientific Review (CSR) 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.  The 
CSR will not accept any application that is essentially the same as one 
already reviewed. This does not preclude the submission of substantial 
revisions of applications already reviewed, but such applications must include 
an Introduction addressing the previous critique.

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

Incomplete applications will be returned to the applicant without further 
consideration.  And, if the application is not responsive to the RFA, CSR 
staff may contact the applicant to determine whether to return the application 
to the applicant or submit it for review in competition with unsolicited 
applications at the next appropriate NIH review cycle.

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  Receive a written critique
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 second level review by the National Institute of Allergy and 
Infectious Diseases Council


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 discuss the following aspects 
of your application in order to judge the likelihood that the proposed 
research will have a substantial impact on the pursuit of these goals: 

o  Significance 
o  Approach 
o  Innovation
o  Investigator
o  Environment
The scientific review group will address and consider each of these criteria 
in assigning your application's overall score, weighting them as appropriate 
for each application.  Your 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. 

(1) SIGNIFICANCE:  Does your study address an important problem? If the aims 
of your application are achieved, how do they advance scientific knowledge?  
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?  Do you acknowledge potential problem areas and consider alternative 

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

(4) INVESTIGATOR: Are you appropriately trained and well suited to carry out 
this work?  Is the work proposed appropriate to your experience level as the 
principal investigator and to that of other researchers (if any)?

(5) ENVIRONMENT: Does the scientific environment in which your 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 

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your 
application will also be reviewed with respect to the following:

o PROTECTIONS: The adequacy of the proposed protection for humans, animals, or 
the environment, to the extent they may be adversely affected by the project 
proposed in the application.

o INCLUSION: 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 included in the 
section on Federal Citations, below)

o DATA SHARING: The adequacy of the proposed plan to share data.

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

Letter of Intent Receipt Date:	  May 21, 2002  
Application Receipt Date:      	  June 21, 2002
Scientific Peer Review Date:   	  October, 2002
Advisory Council Date:         	  January, 2003
Earliest Anticipated Award date:  April, 2003


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

o  Scientific merit (as determined by peer review)
o  Availability of funds
o  Programmatic priorities.


involving Phase I and II clinical trials must include provisions for 
assessment of patient eligibility and status, rigorous data management, 
quality assurance, and auditing procedures.  In addition, it is NIH policy 
that all clinical trials require data and safety monitoring, with the method 
and degree of monitoring being commensurate with the risks (NIH Policy for 
Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998:  

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 (
files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are 
available at 
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 

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. 
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 is available at 

policy requires education on the protection of human subject participants for 
all investigators submitting NIH proposals for research involving human 
subjects.  You will find this policy announcement in the NIH Guide for Grants 
and Contracts Announcement, dated June 5, 2000, at

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 
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. 

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, 
"Impact of Microbial Interactions on Infectious Diseases", 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 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  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.

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.

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