Subject: NIH GUIDE - Vol. 19, No. 39, November 2, 1990 - RFA AI-
From: Dot Baker <[email-masked]>
To: [email-masked]
Date: Wed, 31 Oct 90 14:56 EST

Hello Paul,
    Busy World today.   Please post this to the NIH Listserver as:
   RFAAI-91-01.110290
Thanks.
       Dottie
 ---------------------------- Text of forwarded message -----------------------
 
REQUEST FOR COOPERATIVE AGREEMENTS APPLICATIONS:
RFA:  AI-91-01
 
RE-ISSUANCE OF RFA-87-AI-14    DATED 2/87
 
P.T. 34; K.W. 0740012, 1002008, 1002045
 
MOLECULARLY TARGETED APPROACHES TO ANTIVIRAL THERAPY
 
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
 
Letter of Intent Receipt Date:  November 28, 1990
Application Receipt Date:  January 17, 1991
 
The National Institute of Allergy and Infectious Diseases (NIAID)
invites applications for research that applies an understanding of the
molecular biology of virus replication and pathogenesis to the
development of antiviral agents that are targeted to inhibit specific
viral functions.  Therapeutic and prophylactic agents (other than
vaccines) that specifically inhibit virus replicative functions without
interfering with normal cellular processes are likely to provide
clinical benefit with minimal toxicity.  Research on any virus that is a
human pathogen or that serves as a model for a human pathogen, except
for human immunodeficiency virus (HIV) and/or other retroviruses, is an
appropriate subject for a proposal.  Research on HIV antiviral agents is
the subject of a separate initiative.
 
Successful applicant(s) funded under this Request for Applications (RFA)
will be supported through Cooperative Agreements.  Cooperative
Agreements are awarded to both nonprofit and for-profit organizations
and institutions.  This type of solicitation is utilized when it is
desired to encourage investigator-initiated research projects in areas
of special importance to the NIH and where substantial programmatic
involvement by staff is anticipated.  This RFA solicitation represents a
single competition, with a specified deadline for receipt of
applications.  There are no plans to reissue this RFA at any future
time.  All applications received in response to the RFA will be reviewed
by the same NIAID Initial Review Group (IRG) and by the National
Advisory Allergy and Infectious Diseases Council.  The deadline for the
receipt of applications in response to this RFA is January 17, 1991.
Applications should be prepared and submitted in accordance with the
aims and requirements as set forth in the remainder of this document.
 
I. BACKGROUND INFORMATION
 
The Division of Microbiology and Infectious Diseases (DMID), NIAID,
invites applications for Cooperative Agreements to support research
projects to develop molecularly targeted agents as inhibitors of virus
infection.  Viral infections account for significant morbidity and
mortality, as well as economic loss, in the United States and the rest
of the world.  NIAID continues to play a central role in the development
of vaccines and therapies for viral diseases.  DMID has targeted the
control of infections caused by cytomegalovirus and other herpesviruses,
papillomaviruses, hepatitis viruses and respiratory viruses as a high
priority.  (The Division of AIDS has responsibility for the control of
HIV and other retroviral infections).  DMID sponsors programs for both
in vitro and animal model preclinical evaluation, as well as clinical
trials of promising experimental therapies.  Since there is a desperate
public health need for effective, nontoxic agents for antiviral therapy,
NIAID would like to stimulate research on the design and discovery of
novel antiviral agents.
 
The search for effective therapeutic agents to combat these serious
infections was long delayed by the widely-held belief that the
intracellular nature of virus replication made the development of
clinically useful drugs improbable.  More recently, as knowledge of the
molecular mechanisms of virus replication and pathogenesis has become
available, it is evident that there are both virus-coded and
virus-induced functions which may be specifically, or at least
selectively, inhibited.  The efficacy of acyclovir at inhibition of
herpes simplex infection is a dramatic example and has resulted in
significant industrial support for the development of derivatives of
acyclovir and some other nucleosides.  However, the detailed
understanding of the mechanisms of virus replication and the
three-dimensional structure of virions and virus proteins that is
rapidly accumulating should be exploited to investigate additional
innovative approaches to the design of molecularly targeted antivirals.
Infectious processes, which may provide vulnerable targets, include
virus adsorption and entry, the synthesis and processing of nucleic
acids and proteins, transport of macromolecules, assembly of progeny
virions, the identification of viral markers on infected cells, and the
spread of virus to uninfected cells.  It may also be possible to target
latently infected cells.
 
Preliminary studies in this area have already been reported although the
majority of novel approaches have been directed at HIV.  Advances in
crystallographic molecular modelling have led to the ability to predict
the tertiary structure of the active sites of viral particles and
enzymes and illustrate the interaction of these entities with known
inhibitors.  This ability has already led to the design of novel
inhibitors for the HIV protease and rhinovirus adsorption and uncoating.
"Anti-sense" oligonucleotides complementary to important viral
regulatory or coding sequences inhibit virus replication in tissue
culture and may also be effective in vivo.  Selective inhibition of
enzymes encoded by the viral genome, as well as cellular enzymes whose
synthesis is enhanced as a result of infection, has been achieved in
several instances.  Molecular identification of the cellular receptors
for virus adsorption should permit the design of agents that block the
first stage of virus infection.  Immunoliposomes have been developed on
the assumption that they may reduce drug toxicity by enabling specific
and selective delivery.  These and other imaginative approaches to the
development of targeted antiviral therapies are made possible by the
recent explosion in our knowledge of the molecular details of virus
replication and pathogenesis.
 
II.  RESEARCH GOALS AND SCOPE
 
The purpose of this RFA is to stimulate research in the development of
novel molecularly targeted approaches to antiviral therapy.  This
includes strategies for both the design of novel specific agents and
development of methods for selective drug delivery.  The strategies
proposed should involve a molecular rationale for anticipated antiviral
activity without significant concomitant cellular and/or organism
toxicity.  The preparation and testing of derivatives of previously
identified nucleoside analogue antiviral agents does not constitute a
novel approach.  However, investigators may propose to extend a
preliminary approach, such as those listed above in Section I, or apply
such an approach to a different system.  Investigators will choose the
virus and system they prefer for these studies, but the selected virus
should either be a clinically important human pathogen or serve as a
model for a human viral pathogen.  Possible choices include, but are not
limited to:  hepatitis B, C, and D virus, papillomavirus,
cytomegalovirus, herpes simplex virus, varicella zoster virus, influenza
viruses, respiratory syncytial virus, parainfluenza, rotavirus,
coxsackievirus, and rhinovirus.  The development of agents inhibitory to
HIV and other retroviruses is the focus of a separate RFA and,
therefore, proposals to target HIV will not be accepted in response to
this initiative.
 
III.  MECHANISM OF SUPPORT
 
A. Award(s) will be made as Cooperative Agreements.  These are
assistance relationships with substantial involvement of NIAID staff, as
outlined under Part IV, "Terms of Award".  Universities, medical
colleges, hospitals, and laboratories or other public, private, or
for-profit institutions are eligible.
 
B. NIAID anticipates making ten to fifteen awards as a result of this
request.  However, the number of awards to be made is dependent upon
receipt of a sufficient number of applications of high scientific merit
and upon the availability of funds.  If appropriate, collaboration with
other investigators or institutions is encouraged.  It is expected that
the initial year's awards for successful applications will average
$150,000 in direct costs, however, individual awards may be higher or
lower.  Awards will be made for a project period of up to five years.
(When the applicant institution is outside the United States, awards
will be limited to three years.) The earliest possible award date is
July 1, 1991.  It is the intent of DMID to fund a group of proposals
that will ensure that a variety of approaches and virus systems will be
investigated.  The specific recommendations for proposals to receive
awards will be made by a staff committee.  Committee members will be the
Director, DMID and the chiefs of the Antiviral Research Branch, the
Enteric Diseases Branch, the Respiratory Diseases Branch, and the
Sexually Transmitted Diseases Branch.  Criteria will be technical
excellence and program balance.  NIAID has no plans to reissue this
announcement.
 
IV.  TERMS OF AWARD:  AWARDEE RIGHTS AND RESPONSIBILITIES; NATURE OF
PARTICIPATION OF NIAID STAFF
 
Under the Cooperative Agreement, a partner relationship between the
recipient of the award and NIAID exists in which the applicant is
responsive to the requirements and conditions set forth in the RFA.
Specifically, 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 all aspects of scientific and
technical management of the project in accordance with the terms
mutually agreed upon prior to the award.  The applicant must define the
research objectives and approaches in accord with his/her own interests
and perceptions of novel and exploitable molecular approaches to the
development of specific novel antiviral agents and must develop the
details of the research design following the guidance given in this RFA.
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.  The data obtained will be the property of
the awardee.
 
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.  The staff assistance mandated by the
cooperative agreement mechanism will permit NIAID staff to participate
in, but not direct, the research to ensure that important disease
targets are addressed.  A member of the NIAID staff will serve as
Scientific Coordinator and will participate as a member of the research
team.  The Scientific Coordinator will be the Chief, Antiviral Research
Branch, DMID.  The Scientific Coordinator will interact closely 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, replacement of staff;
coordinating or participating in collection and/or analysis of data; and
advising in management and technical performance.  The Scientific
Coordinator may organize 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 coordination of all components including assisting the
awardees in:
 
1.  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.
 
2.  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.
 
3.  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.  DMID has facilities to evaluate compounds in vitro for
activity against panels of herpesviruses (HSV-1, HSV-2, CMV, VZV, and
EBV), respiratory viruses (influenza A, influenza B, parainfluenza,
respiratory syncytial virus, adenovirus, and measles), and hepatitis B.
Compounds are also evaluated for toxicity for stationary and
exponentially growing primary human fibroblasts and for activity against
multiple strains of each virus which include recent clinical isolates
and drug-resistant strains.  DMID also supports animal models for most
of the above-listed viruses as well as human and rabbit
papillomaviruses.  For example, the awardee may devise an agent that
inhibits the expression of cloned respiratory syncytial virus or
hepatitis B virus genes in vitro.  The NIAID Scientific Coordinator can
arrange for the agent to receive more extensive in vitro testing as well
as evaluation in a cotton rat animal model for RSV infections or a
woodchuck model for hepatitis B infection.  In addition, the awardee may
want NIAID to assist in the eventual clinical testing of the agent.
Alternatively, the awardee may pursue testing of his/her agent
independently.
 
4.  Prior approval of changes of key personnel including the Principal
Investigator and co-investigators.
 
5.  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 agents.
Funds for travel to this meeting should be included in the budget.
 
6.  In addition to the annual symposium, the NIAID Scientific
Coordinator will interact informally with the principal investigators
through additional meetings, averaging once a year, at the Principal
Investigator's institution as well as by regular telephone and written
communication.
 
It is anticipated that decisions in all activities outlined above, as
well as changes in research direction, will be reached by consensus of
the Principal Investigator and the NIAID Scientific Coordinator.  Such
changes may be occasioned by the emerging clinical importance of
different infections or the suitability of developed approaches for the
design of antiviral therapies for other infections.  The manner of
reaching this consensus and the decision-making authority will rest with
the Principal Investigator.  However, if a dispute should arise, the
decision of a three-member arbitration team will be binding.  One member
of this team will be chosen by the Principal Investigator and the second
will be chosen by the NIAID Scientific Coordinator.  These two members
of the arbitration team will select the third member.
 
Although the NIAID Scientific Coordinator may participate in discussions
on planning and evaluation, the recipients of these awards will be
responsible entirely for the design, conduct, and evaluation of their
proposed research.  The NIAID Scientific Coordinator will not direct,
nor be liable for, the awardee's research activities.  The awardee will
be responsible for publishing and disseminating the results of his/her
studies.  In the event that collaborative studies with NIAID grantees,
awardees, or contractors, are undertaken (as described above), the NIAID
Scientific Coordinator may assist in the design of study protocols and
evaluation of data.
 
These special Terms of Award are in addition to, and not in lieu of,
otherwise applicable OMB administrative guidelines, HHS Grant
Administration Regulations at 45 CFR Part 74, and other HHS, PHS, and
NIH grant administration policy statements.
 
V. METHOD OF APPLICATION
 
A. LETTER OF INTENT
 
Prospective applicants are asked to submit, by November 28, 1990, a
short letter of intent that includes a descriptive title of the proposed
research, and the names and affiliation(s) of proposed key
investigators.  The letter of intent is requested in order to provide an
indication of the number and scope of applications to be reviewed.  The
letter of intent does not commit the sender to submit an application,
nor is it a requirement for submission of an application.
 
The letter of intent should be sent to:
 
Dr. Olivia Preble
Chief,  Microbiology and Immunology Review Section
Program and Project Review Branch
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Westwood Building, Room 3A10
Bethesda, MD  20892
Telephone:  (301) 496-8208
 
B.  Format of Applications
 
1.  Applications must be submitted on form PHS 398 (Rev.  10/88, 9/89),
the application form for research grants.  Application kits are
available at most institutional business offices or may be obtained from
the Office of Grants Inquiries, Room 449, Westwood Building, Division of
Research Grants, NIH.  The format and detail applicable to regular
research grant applications should be followed, and the requirements
specified under Review Criteria (VII.C.) must be fulfilled.
 
2.  For purposes of identification and processing, mark "yes" in item 2
on the face page of the application and type in the words COOPERATIVE
AGREEMENT FOR MOLECULARLY TARGETED APPROACHES TO ANTIVIRAL THERAPY and
the RFA number AI-91-01.
 
The RFA label (found in the 10/88 revision of application form PHS 398)
must be affixed to the bottom of the face page of the original copy of
the application.  Failure to use this label could result in delayed
processing of your application such that it will not reach the review
committee in time for review.
 
3.  The research proposed should describe plans to accommodate the RFA
research program requirements and NIAID staff involvement.  Note that
the applications will be judged by the stated review criteria (see
section VIII.C.).
 
C. Application Procedure
 
1.  The completed original application and four (4) exact copies should
be sent or delivered to:
 
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**
 
TWO (2) ADDITIONAL COPIES MUST BE SENT TO:
 
Dr. Olivia Preble
Chief, Microbiology and Immunology Review Section
Program and Project Review Branch
National Institute of Allergy and
  Infectious Diseases
National Institutes of Health
Westwood Building, Room 3A10
Bethesda, MD  20892
Telephone:  (301) 496-8208
 
VI. CONSEQUENCES OF LATE APPLICATIONS AND DUPLICATE SUBMISSIONS
 
To ensure their review, applications must be received by both the
Division of Research Grants (DRG) and Dr. Olivia Preble by January 17,
1991.  Applications received after the above date will be returned
without review.  If the application submitted in response to this RFA is
substantially similar to a research grant application already submitted
to the NIH for review, but 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 cannot be submitted in
response to this RFA that is essentially identical to one that has
already been 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.
 
VII.  REVIEW PROCEDURES AND CRITERIA
 
A. Assignment of Applications:  Applications will be received by the NIH
DRG and assigned to NIAID.
 
B. Review Procedures:  Applications will be reviewed by NIAID staff to
determine administrative and programmatic responsiveness to this RFA;
those judged to be non-responsive will be returned to the applicant
without review.  Those applications considered responsive to the RFA may
be subjected to a triage review by an NIAID peer review group to
determine their scientific merit relative to the other applications in
response to the RFA.  The NIH will withdraw from competition those
applications judged by the triage peer review group to be noncompetitive
for award and will notify the applicant principal investigator and the
institutional business official.
 
Those applications judged to be competitive for award will be reviewed
for scientific and technical merit by a Review Committee convened by the
Division of Extramural Activities, NIAID, during March 1991.  The second
level of review will be provided by the National Advisory Allergy and
Infectious Diseases Council in May 1991.
 
C. Review Criteria:
 
The factors to be considered in scientific evaluation of the
applications are:
 
1.  Originality and scientific merit of research approach, design, and
methodology as well as the potential scientific, technical, or medical
significance of the proposed research.
 
2.  Research experience and competence of the Principal Investigator and
staff to conduct the proposed studies.
 
3.  Adequacy of time (effort) that the Principal Investigator and staff
would devote to the proposed studies.
 
4.  Adequacy of facilities.
 
5.  Reasonableness of proposed costs.
 
The review criteria listed above will be those used by the initial
review group.  In selecting applications for funding, while scientific
merit is of prime consideration, applications also will be evaluated for
programmatic relevance and importance.
 
VIII.  FUTURE FUNDING
 
This is a one-time request for applications.  NIAID has no plans to
reissue this announcement at any future date.
 
IX.  INQUIRIES
 
Investigators seeking information relevant to this RFA should contact
Dr. Catherine Laughlin at the address below.  Questions regarding review
procedures should be addressed to Dr. Preble, at the address given in
Section V.A.
 
Dr. Catherine Laughlin
Chief, Antiviral Research Branch
Division of Microbiology
  and Infectious Diseases
National Institute of Allergy
  and Infectious Diseases
Westwood Building, Room 753
Bethesda, MD  20892
Telephone:  (301) 496-8285
 
This program is supported under authorization of the Public Health
Service Act, Sec. 301(c), Public Law 78-410; as amended.  The catalog of
Federal Domestic Assistance citation is Sec. 93.856, Microbiology and
Infectious Diseases Research.  Awards will be administered under PHS
grant policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part
74.  This program is not subject to the intergovernmental review