Full Text CA-93-11

HTLV-INDUCED HUMAN DISEASES:  PROTECTIVE IMMUNE RESPONSES AND
POTENTIAL FOR VACCINE DEVELOPMENT

NIH GUIDE, Volume 22, Number 4, January 29, 1993

RFA:  CA-93-11

P.T. 34

Keywords: 
  Cancer/Carcinogenesis 
  Neurological Disorders 
  Immunology 
  Viral Studies (Virology) 
  Pathogenesis 


National Cancer Institute

Letter of Intent Receipt Date:  March 16, 1993
Application Receipt Date:  May 14, 1993

PURPOSE

The human T-cell lymphotropic virus type I (HTLV-I) is recognized as
the etiological agent of a subset of human leukemias, the adult
T-cell leukemia/lymphoma (ATL) and a chronic degenerative neurologic
disease in humans known as tropical spastic paraparesis (TSP), also
called HTLV-associated myelopathy (HAM).  This virus and especially
the antigenically related HTLV-II virus are widespread in certain
U.S. populations, such as intravenous drug abusers, many or most of
whom are simultaneously infected with human immunodeficiency virus
(HIV).  In addition to the ability of HTLV-I to cause cancers or
other diseases on its own, the HTLV viruses potentiate and activate
the expression of HIV in vitro and in human populations, may
accelerate progression to clinical AIDS, including a contribution to
the development of AIDS-associated cancers in such people.  Thus,
HTLV-I and related human retroviruses are important pathogens with
multiple pathogenic and oncogenic potentials and pose a potential
threat to humans.  Knowledge is needed to facilitate the eventual
development of vaccines to prevent HTLV infections and cancer
development in high risk populations.  Additionally, studies to be
initiated through this Request for Applications (RFA), such as the
determination of protective immune responses against the HTLVs and
specific mechanisms of protective immunity, may provide valuable
clues on how protective immune responses in humans control persistent
viral infections caused by pathogenic viruses such as HIV and others
associated with subsequent malignant disease. Thus, studies of HTLVs
can provide valuable information on how to develop vaccines against
other pathogenic and potentially oncogenic human viruses.

HEALTHY PEOPLE 2000

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 RFA,
HTLV-Induced Human Diseases:  Protective Immune Responses and
Potential for Vaccine Development, is related to the priority area of
vaccine development against human 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).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal government.
Applications from minority and women investigators are encouraged.

MECHANISM OF SUPPORT

Support of this program will be through the National Institutes of
Health (NIH) research project grant (R01).  Applicants will be
responsible for the planning, direction, and execution of the
proposed project.  The total project period for applications
submitted in response to this RFA should not exceed four years.
Awards 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, 1990, and 45 CFR Part 74, 42 CFR
Part 52, or 45 CRF Part 92, as applicable.

Because the nature and scope of the research proposed in response to
this RFA may vary, it is anticipated that the range of amounts of the
direct cost awards will vary from $75,000 to $125,000.

This RFA is a one-time solicitation.  Future unsolicited competitive
continuation applications will compete with all other
investigator-initiated research grant applications and be peer
reviewed by a chartered study section in the Division of Research
Grants (DRG), NIH.  However, if the Natinoal Cancer Institute (NCI)
determines that there is a sufficient continuing program need, a
request for competitive continuation applications will be announced.
Only recipients of awards under this RFA will be eligible to apply.

FUNDS AVAILABLE

Approximately $500,000 in total costs per year for four years will be
committed to fund applications that are submitted in response to this
RFA.  It is anticipated that three to four awards will be made.  The
level of funding is dependent on the receipt of a sufficient number
of applications of high scientific merit.  The total project period
for applications submitted in response to the present RFA should not
exceed four years.  The earliest feasible start date for the initial
awards will be December 1, 1993. Although this program is provided
for in the financial plans of the NCI, the award of grants pursuant
to this RFA is also contingent upon the availability of funds for
this purpose.

RESEARCH OBJECTIVES

Background

HTLV-I, first isolated in 1980, is recognized chiefly as the
etiologic agent of ATL, a disease that is endemic in southern Japan,
central Africa and the Caribbean basin.  Worldwide, approximately one
to two million people are infected with the virus.  In the endemic
areas of HTLV infection, up to 10 percent of the population have been
found to be infected.  The virus establishes a chronic, latent
infection in susceptible humans.  The incubation period prior to
disease induction generally runs into several decades, after which
approximately three to six percent of those infected develop ATL or a
chronic degenerative neurologic disease known as TSP, otherwise known
as HAM.  Other diseases in which HTLV-I is suspected to play a role
include mild immune impairment, polymyositis, rheumatoid
arthritis-like disease, B-cell lymphoma, Guillain-Barre syndrome,
Mycosis Fungoides, and Infective Dermatitis.  HTLV-II has only in
rare instances been isolated, or found in proviral form in humans
with or without evidence of malignancy.  However, recently HTLV-II
has been found to be widely prevalent in U.S. populations who abuse
intravenous drugs.  Thus, this potentially oncogenic virus may pose a
real threat to humans.  Prevention of HTLV-induced human diseases may
conceivably be achieved through the development and use of
appropriate and effective vaccines.  To examine this question and to
assess the current status of research in this area, the Biological
Carcinogenesis Branch of the Division of Cancer Etiology (DCE), a
part of the NCI, sponsored a workshop entitled "Human T-cell
Lymphotropic Virus-Induced Diseases:  Protective Immune Responses and
Potential for Vaccine Development" on January 31, 1992.  An
additional important purpose of the workshop was to determine the
future directions for research in this important area relating to
vaccine development efforts that could be enhanced through grant or
contract funds from the NCI.  This RFA is issued in accordance with
the workshop recommendation that extramural research be stimulated in
this area with set-aside funds.

Research Goals and Scope

The overall goal of this RFA is to stimulate HTLV research related to
vaccine development efforts that will eventually lead to the vaccine
prevention and control of HTLV-induced malignancies and other
diseases.  Broad areas of research emphasized by this RFA are:  the
development and use of HTLV animal models suitable for vaccine
related studies; definition of protective immune responses and the
identification of viral epitopes responsible for inducing such
protective immune responses; the delineation of specific mechanisms
of protective immunity against virus infection and cancer
development; and the development and evaluation of candidate vaccines
in animal models.  Specific examples of such studies include, but are
not limited to:  (1) the development and use of HTLV animal models,
including those associated with neoplastic sequelae, suitable for
vaccine related studies; (2) elucidation of specific mechanisms of
protective immunity against primary infection with HTLV, such as the
immunity elicited in rabbits against HTLV-infected cells through the
intravenous administration of hyperimmune globulins directed against
HTLV (passive immunity); (3) the development of vaccination
strategies to elicit mucosal immunity in the naturally-occurring STLV
primate animal models; (4) characterization of host protective immune
responses to define the relevance of regional immunity (e.g. mucosal,
central nervous system immune responses); (5) definition of
protective immune responses to synthetic peptides and conformation
dependent epitopes; (6) characterization of specific B- and T-cell
immune responses to natural or experimental infections with HTLV-I
and HTLV-II; (7) identification of viral epitopes responsible for
inducing protective immunity against virus infection/cancer
development; (8) development and evaluation in animal models of
immunoprevention approaches to elicit active or passive immunity with
the aims of preventing primary infection and cancer development; the
approaches suggested include the use of vaccines directed against
specific viral structural components and/or products of regulatory
genes, tax and rex, and the administration of hyperimmune gamma
globulin to elicit passive immunity; (9) investigation of the
emergence of viral variants/defective virus capable of evading the
immune system in humans chronically infected with HTLV-I; (10)
analysis of cross-protection between HTLV-I and HTLV-II and other
variants (group-specific vs. type-specific immunity); (11)
development of standardized assay procedures for accurately
quantitating infectious virus and virus-neutralizing antibodies.

LETTER OF INTENT

Prospective applicants are asked to submit, by February 21, 1993, a
letter of intent that includes a descriptive title of the proposed
research, the name and address of the Principal Investigator, the
names of other key personnel, the participating institutions, and the
number and title of the RFA in response to which the application may
be submitted.

Although a letter of intent is not required, is not binding, and does
not enter into the review of subsequent applications, it is requested
in order to provide an indication of the number and scope of
applications to be reviewed.  It also allows NCI 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. Padman S. Sarmaat the
address listed under INQUIRIES.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research; from the Office of
Grants Inquiries, Division of Research Grants, National Institutes of
Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone
301/496- 7441; and from the NCI Program Director named below.

The RFA label available in the 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 number and title must be typed on line 2a of the
face page of the application form, "Response to Specific Program
Announcement" and the YES box must be marked.

Submit a signed, typewritten original of the application, including
the Checklist, and three signed, exact photocopies, in one package to
the address below.  The photocopies must be clear and single sided.

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

At time of submission, send two additional copies of the application
to:

Ms. Toby Friedberg
Referral Officer, Division of Extramural Activities
National Cancer Institute
Executive Plaza North, Room 650
6130 Executive Boulevard
Rockville, MD  20852-9903

Applications must be received by May 14, 1993. An application
received after that date will be returned to the applicant.  The
Division of Research Grants (DRG) will not accept any application in
response to this announcement that is essentially the same as one
currently pending initial review, unless the applicant withdraws the
pending application.  The DRG 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.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed by NIH staff for
completeness.  Incomplete applications will be returned to the
applicant without further consideration.  Evaluation for
responsiveness to the RFA is an NCI program staff function.
Applications will be judged to determine responsiveness to the goals
and objectives of the RFA.  Applications judged non-responsive will
be returned to the applicant but may be submitted as
investigator-initiated research grants at the next receipt date.
Questions concerning the relevance of proposed research to the RFA
may be directed to program staff listed in INQUIRIES.

If the number of applications is large compared to the number of
awards to be made, the NCI may conduct a preliminary scientific peer
review to eliminate those applications which are clearly not
competitive. The NCI will withdraw from further competition those
applications judged to be noncompetitive and notify the applicant and
institutional business official.

Those applications judged to be both competitive and responsive will
be further evaluated according to the review criteria stated below
for scientific and technical merit by an appropriate peer review
group convened by the Division of Extramural Activities, NCI.

1.  The scientific merit, technical and medical significance of the
proposed research, including the appropriateness and adequacy of the
experimental approach and methodology proposed to carry out the
research.  Familiarity with the proposed techniques should be
demonstrated, e.g., by the presentation of preliminary data.

2.  The research experience, expertise and qualifications of the
principal investigator and proposed staff and/or collaborators to
perform the proposed experiments.

3.  Documentation of the adequacy of the facilities and resources
necessary to perform the research.

4.  Appropriateness of the proposed budget and duration in relation
to the proposed research.

The second level of review by the National Cancer Advisory Board
considers the special needs of the Institute and the priorities of
the National Cancer Program.

The review group will critically examine the submitted budget and
will recommend an appropriate budget and period of support for each
scored application.  The Principal Investigator must spend a minimum
of 20 percent time and effort on this project.

AWARD CRITERIA

The earliest anticipated date of award is April 1994.

Factors, including the scientific and technical merit reflected in
the priority score, availability of funds and relevance to selected
areas of programmatic emphasis, will be used to make award decisions.

INQUIRIES

The opportunity to clarify any issues or questions from potential
applicants is welcome.  Written and telephone inquiries concerning
the objectives and scope of this RFA and inquiries about whether or
not specific proposed research would be responsive are encouraged and
may be directed to:

Dr. Padman Sarma, D.V.M., Ph.D.
Program Director, RNA Virus Studies I
Division of Cancer Etiology
National Cancer Institute
Executive Plaza North, Room 540
Bethesda, MD  20892
Telephone:  (301) 496-9734

Direct inquiries regarding fiscal matters to:

Mr. Joseph H. FitzGerald
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Room 243
Bethesda, MD  20892
Telephone:  (301) 496-7800, Ext. 15

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance Number 93.393, Cancer Cause and Prevention Research.
Awards are made under the authorization of the Public Health Service
(PHS) Act, Title IV, Part A (Public Law 78-410, as amended by Public
Law 99-158, 42 U.S.C. 241 and 285) and 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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