Full Text AI-92-08


NIH GUIDE, Volume 21, Number 36, October 9, 1992

RFA:  AI-92-08

P.T. 34

  Viral Studies (Virology) 
  Cell Lines 
  Chemotherapeutic Agents 

National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  November 6, 1992
Application Receipt Date:  December 10, 1992


The Antiviral Research Branch of the Division of Microbiology and
Infectious Diseases (DMID), National Institute of Allergy and
Infectious Diseases (NIAID), invites Cooperative Agreement
applications from organizational entities willing to participate,
with the assistance of the NIAID, in furthering innovative in vitro
approaches to the study of papillomavirus infections and their
therapeutic control.  The goals of this solicitation are to stimulate
the use of in vitro papillomavirus replication systems for research
on (1) the events of papillomavirus replication and pathogenesis and
(2) the antiviral potential of experimental therapeutic agents.


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 (RFA), Papillomavirus In Vitro Cell Culture Systems,
is related to the priority area of sexually transmitted diseases.
Potential applicants may obtain a copy of "Healthy People 2000" (Full
Report:  Stock No. 017-001-00474-0) or 'Healthy People 2000" (Summary
Report:  Stock No. 017-001-00473-1) through the Superintendent of
Documents, Government Printing Office, Washington, DC 20402-9325
(telephone 202-783-3238).


Applications may be submitted by domestic and foreign for-profit or
nonprofit organizations, public and private, such as universities,
medical colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal government having
adequate resources or access to resources to support papillomavirus
in vitro cell culture research.  Applications from minority
individuals and women are encouraged.


Support for this program will be through the cooperative agreement
(U01) funding instrument.  The U01 is an assistance mechanism in
which NIAID programmatic involvement with the recipient during the
performance of the planned activity is anticipated.  The nature of
NIAID program involvement is described under SPECIAL REQUIREMENTS.
The awardee will be responsible for the planning, direction, and
execution of the proposed project and interrelated activities.
Except as otherwise stated in this RFA, the award will be
administered under PHS grants policy as stated in the Public Health
Service Grants Policy Statement, DHHS Publication No. (OASH)
90-50,000, revised October 1, 1991.  The total project period for
applications submitted in response to the present RFA may not exceed
four years.

This RFA is a one-time solicitation.  NIAID has no plans to reissue
this announcement at any future date.  Future competing continuation
applications will compete under the R01 mechanism with all
investigator-initiated applications and will be reviewed by an
appropriate DRG study section according to the customary peer review
procedures for unsolicited applications.


The NIAID anticipates making at least one award 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 availability of funds.  Although this program is
provided for in the financial plans of NIAID, awards pursuant to this
RFA are contingent upon the availability of funds for this purpose.
If appropriate, collaboration with other investigators or
institutions is permissible.  It is expected that the total direct
costs for the first year for successful applications will be around
$175,000.  However, individual awards may be higher or lower.

In general, awards will be made for a project period of up to four
years.  The earliest possible award date is July 1, 1993.  Specific
selections for awards will be made by a NIAID/DMID senior staff
committee.  Criteria will be scientific excellence, expertise,
program balance, and cost.



Papillomavirus infections are the most rapidly spreading viral
sexually transmitted disease today.  It is estimated that as many as
24 million people in the United States are infected with HPV.  This
infection not only has a serious detrimental impact on the infected
individual's quality of life, but several types of the etiologic
agent are almost certainly a cofactor in the development of cervical
carcinoma which kills 7000 American women annually.  In
immunocompromised patients, warts may grow exuberantly and cause
serious morbidity.  In addition, recurrent respiratory papillomatosis
(RRP), a fortunately rare disease believed to be acquired during
passage through the birth canal of an infected mother, can be

None of the currently available therapies, including interferon,
5-fluorouracil, cryotherapy, laser surgery and podophyllotoxin are
adequate.  Therefore, the NIAID made two awards in 1988 to
investigators to utilize rabbit, nude mouse, and primate models of
papillomavirus infections for the evaluation of experimental
therapies.  As a result of these studies, several compounds have been
identified which appear to warrant clinical evaluation.  Phase I
studies of one of these, ribavirin, as a therapy for RRP have
recently begun. Further preclinical study of the others, PMEG and
HPMPC, members of the phosphonate family of nucleotides, are targeted
for clinical studies in the near future.

Although preliminary evaluations of experimental agents are performed
in vitro prior to in vivo evaluation for all other DMID-supported
animal models, until recently there has not been a suitable in vitro
system for evaluation of anti- HPV agents.  In the past few years,
several research groups have developed in vitro systems in which many
of the events of papillomavirus replication have been reported to
occur.  The availability of these systems provides an unparalleled
opportunity to investigate the mechanisms of papillomavirus
replication and pathogenesis at a molecular level.  This basic
research may also result in the identification of viral genes which
are promising targets for therapeutic intervention.  In addition,
these systems should provide a means to evaluate the potential
anti-papillomavirus activity of experimental agents and provide a
rational basis for selecting agents whose activity warrants further
study in the animal models.


The research to be supported by this RFA will be focussed on the use
of in vitro culture systems for studies of the multiple events of
virus replication including viral DNA replication and preferably
expression of late genes.  The culture systems will also be used to
study the effect of experimental therapeutic agents on these events.
Research applications should propose an in vitro system of studying
multiple replication events of papillomaviruses such as early gene
expression, viral DNA replication and preferably also the expression
of late genes.  Applicants should also provide a description of
research plans for study of compounds with therapeutic potential.


Terms and Conditions of Award

The Cooperative Agreement mechanism involves a partnership between
the recipient of the award and the NIAID.  The role of the NIAID is
to provide technical assistance and guidance to the Principal
Investigator.  The following terms and conditions pertaining to the
scope and nature of the interaction will be incorporated in the
Notice of Award.  These agreements will be in addition to the
customary programmatic and financial negotiations which occur in the
administration of grants.  The Terms of Award described in this
section are in addition to, and not in lieu of, otherwise applicable
OMB administrative guidelines; DHHS Grant Administration Regulations
at 45 CFR 74; other DHHS, PHS Grant Administration Policy Statement
and other NIAID administrative terms of award.

Decisions regarding a change of scope of the originally funded
application must be reviewed and approved by the NIAID Scientific
Coordinator in accord with the PHS Grants Policy Statement.  Such
changes may occur due to emerging research findings of other
investigators.  In the event of a dispute, the decision of a three
member arbitration team, described under Arbitration Procedures, will
be binding.

Although the NIAID Scientific Coordinator may participate in
discussions on research planning and data analysis, the recipient(s)
of these award(s) will be responsible entirely for the design,
conduct, and analysis of their research findings.  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 research results.

Responsibilities of the Awardee

Under Cooperative Agreement assistance mechanisms, the NIH identifies
general or specific program areas for support, and the performers
define and implement the specific aims, objectives and approaches for
their awarded project activities. 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 the
aspects of scientific and technical management of the project as
specified in the Terms and Conditions of Award.

The data obtained will be the property of the awardee who will retain
custody of and primary rights to the data.

The awardee will be responsible for:

a.  Project Implementation and Management

The Principal Investigator is to define and implement the specific
aims, objectives, and approaches for in vitro research on
papillomaviruses.  Specifically, the awardee will be responsible for:

Defining research objectives and approaches in accord with his/her
own interests and perceptions of novel and feasible approaches to
conducting in vitro research on papillomavirus replication and the
effects of experimental antiviral agents on the events of

Designing, planning, and conducting the necessary research protocols
stipulated in the application;

Ensuring that the results obtained are analyzed, interpreted, and
published in a timely manner;

Modifying research protocols as appropriate; and Providing
information to the NIAID Scientific Coordinator concerning progress.

b.  Budget

The Principal Investigator should adequately justify the requested
budget for each twelve month segment.  Budget planning must include
such line items as personnel, major equipment, travel, etc.  Trips to
the NIAID must be projected once a year for the Principal
Investigator and possibly one or two other key personnel, if
appropriate.  Meetings will be for the purpose of maintaining project
cohesiveness, program and product standards, providing technical
assistance and other expertise.  The NIAID Scientific Coordinator
will attend each meeting.  Additional communications will be made by
telephone or telephone conference call.

c.  Reporting Requirements

An annual progress report is required.  In addition, the awardee will
keep the Scientific Coordinator apprised of experimental results on a
more frequent basis when the research involves the evaluation of an
experimental compound's anti-papillomavirus activity.

d.  Publications

The Government, via the Scientific Coordinator, will have access to
data generated under this cooperative agreement and may periodically
review the data and progress reports.  Information obtained from the
data may be used by the Scientific Coordinator for the preparation of
internal reports on the awardee(s)' activities.  However, the awardee
will retain rights to the data and timely publication is encouraged.
Publication or oral presentation of work done under this agreement is
the responsibility of the Principal Investigator and will require
appropriate acknowledgement of NIAID support.

Responsibilities of the NIAID

Assistance via U01s differs from the traditional research grant.  In
addition to the normal programmatic and administrative stewardship
responsibilities, the awarding component anticipates substantial
programmatic involvement during performance of the project.  Under
the U01 mechanism, NIAID staff will facilitate and participate in,
but not direct, the research in order to ensure that research
priorities for papillomaviruses 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
Investigator to assist with and facilitate the overall research
planning and data analysis.  During performance of the project the
NIAID Scientific Coordinator may provide assistance by participating
in the design of specific 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.

Involvement of the Scientific Coordinator comprises:

a.  Coordination between NIAID and Awardee.

The establishment of channels of collaboration and communication is
expected. Shortly after any award is made, key project personnel and
NIAID staff will meet to discuss provision of NIAID technical
assistance in accordance with the RFA guidelines.

b.  Collaborative Participation:

Providing assistance in avoiding unwarranted duplication of effort;

Retaining the option to suggest possible changes of direction in the
research endeavors based on the acquisition, and provision to the
awardee, of new information;

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; and may
participate in the design of experiments, and

Providing assistance, when appropriate, in designing protocols and in
analysis and interpretation of research data.

c.  Provision of Important Information and Collaborations:

Principal Investigators may not have immediate access to needed
information. Therefore, NIAID will facilitate meeting these needs and
ensure that the awardee(s) become active participants in the
Antiviral Research Branch Preclinical Research Program.  This Program
consists of:  (a) twelve U01 awards for research on potential
molecular targets for novel antivirals and strategies for the design
of new agents; (b) two N01 awards for the application of standard,
well-characterized assay methodologies for the evaluation of the
anti- herpesvirus and anti-respiratory virus potential of large
numbers of compounds; (c) seven N01 awards for animal models of human
viral infections (including papillomaviruses) that are used for
evaluation of experimental therapies and research on pathogenesis;
and (d) five U01 awards for studies of viral replication and
pathogenesis that are targeted towards the eventual development of
improved diagnostic methodologies.  The interaction of the awardee(s)
with other investigators in this program, as well as the consequent
early receipt of data from those laboratories pursuing related
research goals, will facilitate and expedite research progress.

d.  Provision of Needed Resources

The NIAID may provide assistance by suggesting potential sources of
agents for antiviral evaluation and/or facilitating the obtaining of
these agents by the Principal Investigator.  The specific agents to
be tested will be decided upon by the Principal Investigator with
assistance from the Scientific Coordinator. The application should
include an estimate of how many compounds with therapeutic potential
will be studied annually.

e.  Monitoring

There shall be periodic on-site or reverse-site monitoring of the
status of the Principal Investigator's research.  Such visits may
include discussions regarding scientific technique and methodology,
review of data, review of data analysis, suggestions to improve the
quality of the research, staff recruitment and training, and overall
evaluation efforts.  In addition, the NIAID Scientific Coordinator,
as a part of the annual review process, will review the status of the
research, using information obtained from site visits and the annual
progress reports to justify continued funding.

f.  Annual Meeting

The NIAID Scientific Coordinator will organize an annual symposium in
Bethesda, Maryland at which the Principal Investigator(s) will
discuss their progress.  This symposium will include other NIAID
Antiviral Research Branch-supported investigators engaged in
preclinical antiviral research.  This symposium will facilitate
evaluation of the feasibility of the attempted antiviral approaches,
and will promote productive interactions among Principal
Investigators.  Applicants should include funds for travel to this
meeting for the Principal Investigator, and other key personnel if
warranted, in their proposed budget.

g.  Ongoing Communication

In addition to the annual symposium, the NIAID Scientific Coordinator
will interact informally with each principal investigator through
additional meetings, averaging once a year, at the Principal
Investigator's institution or at professional scientific meetings as
well as by teleconferences, regular telephone calls, and written

Arbitration Procedures

The Terms and Conditions of Award, listed in this RFA, require that
the NIAID Scientific Coordinator participate in the decision-making
process concerning the continuation of an award based on successful
performance of the Awardee during the planning, developmental, and
implementation period of the U01.  Disagreements (e.g., programmatic,
technical, and evaluation) arising pursuant to these approvals will
be arbitrated by an Arbitration Panel composed of one award recipient
designee, one NIAID designee, and a third designee, with expertise in
the relevant area, chosen by the other two.  These special
arbitration procedures 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 DHHS regulations at 45 CFR, Part 16.


Prospective applicants are asked to submit, by November 6, 1992, a
letter of intent that includes a descriptive title of the proposed
research, and the names and affiliation(s) of proposed key
investigators.  The NIAID requests a letter of intent in order to
provide an indication of the number and scope of applications to be
received.  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 will not enter into the review of
any application subsequently submitted.  It 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. Olivia Preble
Chief, Microbiology and Immunology Review Section
Scientific Review Branch
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C20
6003 Executive Boulevard
Rockville, MD  20892


Applications are to be submitted on form PHS 398 (rev. 09/91).
Application kits are available at most institutional business
offices, and may be obtained from: Office of Grants Inquiries,
Division of Research Grants, National Institutes of Health, 5333
Westbard Avenue, Westwood Building, Room 449 Bethesda, MD 20892,
telephone (301) 496-7441.

The format and detail applicable to regular research grant
applications must be followed.

For purposes of identification and processing, mark "yes" in item 2a
on the face page of the application.  Also in item 2, under "number"
list the RFA number, which is RFA AI-92-08, and under title type in
grant program", type in "COOPERATIVE AGREEMENT".  In addition, the
RFA label available in the application form PHS 398 must be affixed
to the bottom of the face page and placed on top of the entire
package.  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 research proposed should describe plans to accommodate the RFA
research program requirements and NIAID staff involvement.

The original and three copies are to be mailed or delivered to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

Two copies are to be mailed or delivered to:

Dr. Olivia Preble
Chief, Microbiology and Immunology Review Section
Scientific Review Branch
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C20
6003 Executive Boulevard
Rockville, MD  20892

Applicants using express mail or a courier service should change the
zip code to 20852 for the Solar Building.

Applications must be received by both DRG and Dr. Olivia Preble by
December 10, 1992.  Applications received after December 10, 1992
will be returned without review or will be sent to a DRG study
section as an unsolicited R01 for that study section's next review
cycle.  If the application submitted in response to this RFA is
substantially similar to a 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.


Applications will be received by the NIH Division of Research Grants
(DRG) and will usually be assigned to NIAID.  Should an application
contain research plans that significantly overlap with programs of
another institute, PHS Referral Guidelines will prevail in the
assignment of that application.

Review Procedures

Applications will be reviewed by DRG for completeness and by NIAID
staff to determine administrative and programmatic responsiveness to
this RFA.  Any application that is incomplete or does not meet the
minimum requirements of this RFA will be returned to the applicant
without scientific peer review.

Applications considered complete and 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 NIAID 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 official.

Those applications judged to be competitive for award will be
reviewed by the standard NIH dual peer review system.  The initial,
or first level,  review for scientific and technical merit will be
conducted by the Scientific Review Branch of the Division of
Extramural Activities, NIAID during February/March, 1993.  The second
level of review will be provided by the National Advisory Allergy and
Infectious Diseases Council in June, 1993.


o  Factors to be considered in scientific evaluation of the
competitive applications include:

o  Originality and scientific merit of research approach, design, and
methodology as well as the potential scientific, technical, or
medical significance of the proposed research.  There will be special
interest in the advantages and limitations of proposed in vitro
culture systems.

o  Research experience and competence of the Principal Investigator
and staff to conduct the proposed studies.  The experience of the
Investigators with in vitro culture systems for papillomaviruses and
expertise in papillomavirus molecular biology are important.

o  Adequacy of time/effort which the Principal Investigator and staff
would devote to the proposed studies.

o  Adequacy of facilities and resources.

o  Reasonableness of proposed costs.


While scientific merit is a prime consideration for selecting
applications for award, programmatic relevance, reasonableness of
proposed budget, and availability of funds also will be considered.


Direct inquiries relevant to the programmatic aspects of this RFA to:

Dr. Catherine Laughlin
Chief, Antiviral Research Branch
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
Solar Building, Room 3A-22
6003 Executive Boulevard
Rockville, MD  20852
Telephone:  (301) 496-8285
FAX:  (301) 402-1456

Direct inquiries regarding review procedures and requirements to:

Dr. Olivia Preble
Chief, Microbiology and Immunology Review Section
Scientific Review Branch
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C-20
6003 Executive Boulevard
Rockville, MD  20852
Telephone:  (301) 496-8208
FAX:  (301) 402-2638

Direct inquiries regarding fiscal matters to:

Mr. Todd Ball
Grants Management Branch
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B-22
6003 Executive Boulevard
Rockville, MD  20852
Telephone:  (301) 496-7075
FAX:  (301) 480-3780


Letter of Intent Receipt Date:     November 6, 1992
Application Receipt Date:          December 10, 1992
Review by Initial Review Group:    February/March 1993
Review by NIAID Advisory Council:  June 1993
Earliest Award Date:               July 1, 1993


This program is described in the Catalog of Federal Domestic
Assistance No. 93.856, Microbiology and Infectious Diseases Research.
Awards are made under authorization of the Public Health Service Act,
Title IV, Part A (Public Law 78-410; as amended.  Awards will be
administered under PHS grants policies and Federal Regulations 42 CFR
Part 52 and 45 CFR Part 74.  This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency review.


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