Release Date:  October 20, 1999

RFA: AI-00-002

National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date: December 15, 1999
Application Receipt Date: January 19, 2000


As part of DHHS-wide efforts for civilian defense from 
possible bioterrorism, the Division of Microbiology and 
Infectious Diseases (DMID), National Institute of Allergy 
and Infectious Diseases (NIAID), National Institutes of 
Health (NIH), invites research applications to (1) discover 
and design drugs against orthopoxvirus and (2) provide 
sufficient quantities of promising compounds for evaluation 
in animals.


The Public Health Service (PHS) is committed to achieving 
the health promotion and disease prevention objectives of 
"Healthy People 2000," a PHS-led national activity for 
setting priority areas.  This Request for Applications 
related to one or more of the priority areas.  Potential 
applicants may obtain a copy of "Healthy People 2000" at


Applications may be submitted by domestic 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.  Foreign institutions are not 
eligible to apply however foreign investigators may 
participate as collaborators, consultants or subcontractors.  
Racial/ethnic minority individuals, women, and persons with 
disabilities are encouraged to apply as Principal 


The administrative and funding mechanism to be used to 
undertake this program will be the 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.  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.  Details 
of the responsibilities, relationships, and governance of a 
study funded under cooperative agreement(s) are discussed 
later in this document under the section Terms and 
Conditions of Award.

The total project period for applications submitted in 
response to this RFA may not exceed five years.  At present, 
the NIAID is administratively limiting the duration of U01 
cooperative agreements to four years; this administrative 
limitation may change in the future.  At this time, the 
NIAID has not determined whether or how this solicitation 
will be continued beyond the present RFA.


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 $1.5 
million. However, depending on Fiscal Year 2000 budget 
appropriations, this amount may increase. In Fiscal Year
2000 the NIAID plans to fund 1 to 4 awards. In Fiscal Year
2001, with the addition of the scale-up synthesis, the 
estimated total funds will be $1.75 million. The usual NIH 
policies governing grants administration and management will 
apply.  Although this program is provided for in the financial
plans of the NIAID, 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. 
Funding beyond the first and subsequent years of the grant 
will be contingent upon satisfactory progress during the 
preceding years and availability of funds.



In recent years, there has been a significant change in both 
the nature and degree of the threat posed by the use of 
weapons of biological warfare.  The risk of using such 
weapons once appeared to be restricted to international 
conflicts involving small numbers of industrialized nations. 
However, an increasing number of developing countries, as 
well as terrorist groups, and rogue individuals now view the 
use of biological weapons as agents of terror, rather than 
as instruments of warfare.  Recent events, such as 
disclosures of international biological weapons programs, 
the bacterial contamination of restaurant food by cultists, 
and the delivery of a putative anthrax bacterial culture to 
a DC office, have dramatized both the possibility of 
bioterrorist attack and the vulnerability of the U.S. 
population to such an event.  Although the DoD has developed 
some defenses for biological warfare to protect military 
personnel, comparable and additional defenses need to be 
developed to protect the civilian population.  One is that 
the populations to be protected are different as civilians 
include people of all ages and physical conditions.  Thus, 
the important research goals for biological agents with the 
potential terrorist use include; 1) rapid, accurate 
diagnosis; 2) effective therapy for those infected; 3) 
protective vaccination for those at risk of exposure; and 4) 
basic research, which provides the essential underpinning of 
the other areas. 

Of the organisms that might be used in bioterrorism, 
smallpox would likely have the most horrific impact on the 
health of the U.S. population.  As the result of a 
successful immunization program, smallpox disease was 
eliminated in the U.S. by the 1960s. Routine immunization 
against smallpox was terminated. Americans today either have 
never been immunized or were vaccinated more that 30 years 
ago – and those have little, if any, remaining protection.  
Smallpox is highly contagious and mortality is in the range 
of 30%.  There is no available antiviral therapy.  As a 
result of the eradication of the disease, antiviral research 
on smallpox and related orthopoxviruses has largely been 
abandoned. This Request for Applications (RFA) will support 
broad, innovative, multidisciplinary approaches to the 
design and discovery of drugs for prophylactic and/or 
therapeutic use in the event of an outbreak of smallpox.

The NIAID has already initiated some activities in this 
area. Current contractors engaging in antiviral screening 
and animal models of viral infections have been supplemented 
to establish cell-based in vitro anti-vaccinia virus screens 
and murine animal models of vaccinia and cowpox. Any 
investigators who have novel compounds can request services 
of our contractors to evaluate their compounds with the 
approval of NIAID’s project officer. 

Further, an orthopoxvirus genomics facility will be 
established under a separate RFA to assist with the 
identification of gene targets for intervention. Some 
genomic information will be available through this research 

In addition, the NIAID has entered into an agreement with 
the U.S. Army Medical Research Institute of Infectious 
Diseases (USAMRIID) to perform in-depth preclinical 
evaluation of candidate drugs in animal models, primarily 
the infection of non-human primates with monkeypoxvirus. 

Although compounds with activity against vaccinia virus in 
cultured cells have repeatedly been reported in the 
literature, a drug that meets the requirements of efficacy, 
safety and ease of delivery, qualities essential for 
response to a potential terrorist event, has not been 
identified.  This RFA will support the design and discovery 
of such new agents.  Through studies of antivirals developed 
for other infections, scientists at USAMRIID have recently 
identified a potential anti-orthopoxvirus drug: cidofovir, 
an FDA-approved drug for retinitis caused by human 
cytomegalovirus (HCMV) in AIDS patients.  Cidofovir 
demonstrated significant efficacy for the treatments of 
cowpox infection in mice and monkeypox in cynomolgus 
monkeys.  However, this drug has several disadvantages - 
including the need to be given intravenously and serious 
potential toxicity — problems that make it impractical for 
emergency use.

Viruses are intracellular pathogens sharing many of the 
nutritional requirements and synthetic pathways with the 
host cells they infect.  Therefore, an ideal antiviral agent 
will be one that effectively interdicts viral infection as a 
consequence of interaction with a target that is unique to 
the virus, and hence has little or no impact on uninfected 
host tissues.  In principle, such selective antiviral 
activity is best achieved by directing drugs toward virus-
specific genes, enzymes, or cellular receptors, or other 
cellular gene that contributes to pathogenesis.  Recent 
developments in chemistry and biology suggest that one can 
logically apply such information for rational design and 
discover selective antiviral drugs.  A recent dramatic 
example is the design of clinically effective inhibitors 
based on the crystal structures of the HIV protease and 
influenza neuraminidase.  Recent preliminary clinical trials 
have also shown encouraging results with inhibitors of the 
picornavirus receptor-binding interaction.  Antisense 
oligonucleotides targeting specific viral mRNA sequences of 
HIV, HCMV, or human papillomavirus (HPV) are also now in 
clinical trials. 

Advances in the science of molecular diversity generated 
from combinatorial libraries, natural products, and chemical 
databases present a series of rich sources of novel 
diversified chemical entities ready for drug discovery. 
Knowledge-based searches of such sources could lead to the 
discovery of active compounds with unanticipated structures. 

These advanced knowledge and technologies have provided 
unprecedented opportunities for identifying novel 
therapeutics, and for hastening the drug discovery process.

Research Objectives and Scope

This Request for Applications (RFA) will support research to 
design and discover pharmaceuticals suitable for the mass 
treatment of smallpox virus infection.  The objective is to 
stimulate preclinical research in the design, synthesis, 
discovery, and in vitro evaluation of novel compounds aimed 
at the effective prophylaxis and/or therapy of smallpox 
virus infection for the purpose of civilian defense against 

Viral-specific or virus-induced events in viral replication, 
pathogenesis, and host interaction pathways might provide 
appropriate targets for selective antiviral agents. 
Important or new targets would then be utilized for new lead 
generation and optimization. 

Possible strategies may include, but are not limited to:
o Structural determination of viral gene targets, molecular 
modeling and de novo design, quantitative structure-activity 
relationships, computer-assisted structural searching, 
mechanism-based design, and/or transport and receptor-based 
o Exploitation of molecular diversity generated from 
structure-based combinatorial libraries (chemical or 
biological) and natural products coupled with 
functional/target-based high-throughput screening 

o Optimization of lead compounds by the principles of 
medicinal chemistry.

Investigators should have the capability of scale-up 
synthesis of up to five compounds per year to supply 
sufficient amounts for animal model evaluations. Funds
will be added to this initiative in the second year for this 
purpose.  It is assumed that there will not be any compounds 
ready for animal evaluation in the first year.

The areas outlined above are not intended to be all-

Collaborations between different scientific disciplines, 
such as chemistry and virology, as well as collaborations 
between industrial and academic investigators are 

The following areas of investigation, some of which are 
supported by different initiatives, will be considered not 
responsive to this RFA:

o Pharmacological agents such as therapeutic vaccines, 
cytokines, antibodies, and biological response modifiers.

o Large-scale random screening of compounds.

o Development of alternative synthetic methods for cost 
effective re-synthesis of currently existing compounds.

o Development of prodrugs for currently existing compounds.

o Development of animal models.

o  Extensive studies required for the clinical development 
of identified potential drugs, such as toxicological testing 
and formulation development.

NIAID-supported contractors who engage in preclinical 
evaluation of potential antiviral compounds can be available 
to further evaluate the antiviral agents designed and 
discovered by investigators supported by this RFA.  The 
contractors provide NIAID-supported animal models, which 
examine compounds' in vivo efficacy and toxicity and limited 
pharmacokinetics.  The models currently available are murine 
models of vaccinia and cowpox.  Highly promising candidate 
drugs can be further studied in monkeypox model by the 
investigators of USAMRIID.

It is anticipated that this RFA will lead to the 
identification and optimization of lead structures.


The administrative and funding instrument used for this 
program is the 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.  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.

Cooperative agreements are subject to the administrative 
requirements outlined in OMB circulars A-102 and A-110.  All 
pertinent HHS, PHS, and NIH grant regulations, policies and 
procedures, with particular emphasis on PHS regulations at 
42 CFR part 52 and HHS regulations at CFR 45 Part74, are 
applicable. These special terms and conditions pertaining to 
the scope and nature of the interaction between the NIAID 
and the investigators will be incorporated in the Notice of 
Grant Award.  However, these terms will be in addition to,  
not in lieu of,the customary programmatic and financial 
negotiations that occur in the administration of cooperative 


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

a.  The Principal Investigator defines the details for the 
project within the guidelines of the RFA, retains primary 
responsibility for the performance of the scientific 
activity, and agrees to accept close assistance of NIAID 
staff in aspects of scientific and technical management of 
the project in accordance with the terms mutually agreed 
upon prior to the award.

b.  The awardee is to plan and conduct the research 
stipulated in the application and to ensure that the results 
obtained are analyzed and published in a timely manner.  
Awardees will retain custody of and have primary rights to 
the data developed under these awards, subject to Government 
rights of access consistent with current HHS, PHS, and NIH 

c.  The awardee is to participate in an annual meeting of 
investigators funded under this and related RFAs to discuss 
progress and strategies for future research.


Assistance via Cooperative Agreement differs from the 
traditional research grant in that, in addition to the 
normal programmatic and administrative stewardship 
responsibilities, the component awarding the Cooperative 
Agreement anticipates substantial programmatic involvement 
during performance of the project.  NIAID staff assistance 
is to participate in, but not direct, the research to ensure 
that important disease targets are addressed.  The Antiviral 
Research and Antimicrobial Chemistry Program Officer, 
Virology Branch, DMID will serve as Scientific Coordinator 
and will participate as a member of the research team.  The 
Scientific Coordinator will interact with the Principal 
Investigators and Co-investigators in the overall research 
planning and in data analysis.  During performance of the 
award, the NIAID Scientific Coordinator may provide 
appropriate assistance by participating in the design of 
research group activities; advising in the selection of 
sources or resources; coordinating or participating in 
collection and/or analysis of data; and, advising in 
management and technical performance.  The Scientific 
Coordinator may assist with arrangements for the further 
evaluation, both in vitro and in animal models, of agents 
resulting from this research.  However, the role of NIAID 
will be to facilitate and not to direct the activities. 
Specifically, it is presently envisioned that the NIAID will 
be actively engaged in the facilitation of components 
including assisting the awardees in:

a.  Collaborative participation in overall research planning 
and data analysis.  Specifically, the NIAID Scientific 
Coordinator may suggest studies within the scope of the 
award's objectives and research activities; may present to 
the investigators experimental findings from published 
sources or from contract projects in support of these 
suggestions; may participate in the design of experiments; 
and may participate in the analysis of results.

b.  Provision of needed resources and information that may 
not be otherwise available to the investigator.  This may 
include the provision of data from testing conducted in 
resource contract laboratories subject to the terms of 
confidentiality agreements with drug sponsors. NIAID staff 
will coordinate collaboration between this activity and 
other components of the orthopoxvirus research program, such 
as the genomics facility and animal model evaluation.

c.  In the event that an awardee's research results in a 
procedure or a product that requires testing of a nature 
beyond the awardee's capabilities, the NIAID Scientific 
Coordinator may provide resources available to the Institute 
for comprehensive preclinical efficacy evaluations.

d.  The NIAID Scientific Coordinator will organize an annual 
symposium in Bethesda, Maryland at which the principal 
investigators will discuss their progress.  This will 
facilitate overall program planning and development, the 
evaluation of the feasibility of the attempted approaches, 
and will promote productive interactions among the 
successful applicants.  The NIAID Scientific Coordinator 
will also ensure the participation in this symposium of 
investigators from other NIAID preclinical and clinical 
programs to provide the most relevant antiviral expertise 
possible to facilitate planning for future research and 
expedite the design and development of novel antiviral 

3.  Arbitration

Any disagreement that may arise on scientific or 
programmatic matters (within the scope of the award) between 
award recipients and the NIAID may be brought to 
arbitration.  An arbitration panel will be composed of three 
members -- one selected by the individual awardee in the 
event of an individual disagreement, a second member 
selected by the NIAID, and the third member with expertise 
in the relevant area and selected by the two prior members 
will be formed to review any scientific or programmatic 
issue that is significantly restricting progress.  While the 
decisions of the Arbitration Panel are binding, these 
special arbitration procedures will in no way affect the 
awardee's right to appeal an adverse action in accordance 
with PHS regulations at 42 CFR Part 50, subpart D, and HHS 
regulations at 45 CFR Part 16.


Prospective applicants are asked to submit, by December 15, 
1999, 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 subsequent applications, the information that it contains 
allows NIAID staff to estimate the potential review workload 
and to avoid conflict of interest in the review.  The letter 
of intent is to be sent to Dr. Madelon Halula at the address 
listed under INQUIRIES.


The research grant application form PHS 398 (rev. 4/98) is 
to be used in applying for these grants.  These forms are 
available: (1) at most institutional offices of sponsored 
research; (2) from the Division of Extramural Outreach and 
Information Resources, National Institutes of Health, 6701 
Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, 
telephone 301/710-0267, email:; and (3) 
on the internet at

The RFA label available in the PHS 398 (rev. 4/98) 
application form must be affixed to the bottom of the face 
page of the application.  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 on the RFA 
label and the YES box must be marked.  The sample RFA label 
at: has 
been modified to allow for this change.  Please note this 
is in pdf format.

Applications must be received by the application receipt 
date of January 19, 2000.  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.

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

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. Halula at the address listed 

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 


Review Considerations

Upon receipt, applications will be reviewed for completeness
and adherence to the Special Instructions above by the NIH
Center for Scientific Review and for responsiveness by NIAID 
staff; those judged to be incomplete will be returned to the 
applicant without review.  Those considered to be non-
responsive will be returned without 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.  As 
part of the initial merit review, a process will be used by 
the initial review group in which all applications receive a 
written critique and undergo a process in which only those 
applications deemed to have the highest scientific merit 
will be discussed, assigned a priority score, and receive a 
second level review by the National Advisory Allergy and 
Infectious Diseases Advisory Council.

Review Criteria

The criteria to be used in the evaluation of 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 the goal of the 
RFA? 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 

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?

In addition to the above criteria, in accordance with NIH 
policy, all applications will also be reviewed with respect 
to the following:

o  The adequacy of plans to include both genders, minorities 
and their subgroups, and children as appropriate for the 
scientific goals of the research.  Plans for the recruitment 
and retention of subjects will also be evaluated.

o  The reasonableness of the proposed budget and duration in 
relation to the proposed research

o  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 

Funding decisions will be made on the basis of scientific 
and technical merit as determined by peer review, program 
balance, and the availability of funds.  The earliest 
anticipated date of award is September 2000.

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:  

Dr. Christopher Tseng  
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases  
Room 3134
6700-B Rockledge Dr. MSC 7630
Bethesda, MD  20892-7630
Telephone:  (301) 496-7453
FAX:  (301) 496-8030
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:
Madelon Halula, Ph.D.  
Division of Extramural Activities  
National Institute of Allergy and Infectious Diseases  
6700-B Rockledge Dr. MSC 7616, Room 2150
Bethesda, MD  20892-7616  
Telephone:  (301) 496-2550
FAX:  (301) 496-2638

Direct inquiries regarding fiscal matters to:  

Annette Hanopole  
Division of Extramural Activities  
National Institute of Allergy and Infectious Diseases  
6700-B Rockledge Drive MSC 7614, Room 2122
Bethesda, MD  20892-7614
(zip for express mail is 20817)
Telephone:  (301) 496-7075
Fax: (301) 480-3780

Letter of intent receipt date: December 15, 1999
Application receipt date: January 19, 2000 
Scientific review date: June 2000 
Advisory Council date: September 2000
Earliest award date: September 2000 


This program is described in the Catalog of Federal Domestic 
Assistance No. 93.856, Microbiology and Infectious Diseases 
Research, and No. 93.855 - Immunology, Allergy, and 
Transplantation Research. Awards are made under 
authorization of the Public Health Service Act, Title IV, 
Part A (Public Law 78-410, as amended by Public Law 99-158, 
42 USC 241 and 285) 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 PHS strongly encourages all grant 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.

Return to Volume Index

Return to NIH Guide Main Index

Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS) - Government Made Easy

Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.