THERAPEUTICS RESEARCH ON AIDS-ASSOCIATED OPPORTUNISTIC INFECTIONS

Release Date:  July 8, 1999

PA NUMBER:  PA-99-124

National Institute of Allergy and Infectious Diseases

Application Receipt Dates:  January 2, May 1, September 1

THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  IT INCLUDES
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA.

The purpose of this Program Announcement (PA) is to encourage research grant
applications aimed at novel approaches to discovery and preclinical
development of therapeutic agents against opportunistic infections (OIs) in
people with AIDS.  The intent of this PA is to seek investigator-initiated
grant applications that involve creative and original preclinical research
utilizing state-of-the-art technologies necessary to propel advances in new or
improved therapies.  No clinical trials will be supported under this PA.

Although this PA is being issued by NIAID, the National Heart, Lung, and Blood
Institute (NHLBI) and the National Institute of Dental and Craniofacial
Research (NIDCR) and also have an interest in and support research on
opportunistic infections associated with AIDS.  Applicants may wish to contact
these NIH components listed under INQUIRIES to find out about other funding
opportunities.  Institutes and Centers at NIH use different grant mechanisms
to support their portfolios of research; the components listed here may not
use all of the mechanisms specified for this Program Announcement.

Applicants for Small Business Innovation Research (SBIR) projects on
investigational areas included in this PA should consider applying through
NIAID PAR 98-073, published in the NIH Guide for Grants and Contracts on May
22, 1998, which is available on the World Wide Web at:
https://grants.nih.gov/grants/guide/pa-files/PAR-98-073.html

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 PA, Therapeutics Research on AIDS-
Associated Opportunistic Infections, is related to the priority area of human
HIV infection.  Potential applicants may obtain a copy of "Healthy People
2000" at http://www.crisny.org/health/us/health7.html.

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.  Racial/ethnic minority individuals,
women, and persons with disabilities are encouraged to apply as Principal
Investigators.

MECHANISM OF SUPPORT

This PA will use the National Institutes of Health (NIH) individual research
project grant (R01) and small research grant (R03) mechanisms of support. 
Responsibility for the planning, direction, and execution of the proposed
research for all applicable mechanisms of support will be solely that of the
applicant.  However, specific application instructions have been modified to
reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined
by the NIH.  Complete and detailed instructions and information on Modular
Grants can be found at https://grants.nih.gov/grants/funding/modular/modular.htm.

SBIR applicants should refer to NIAID PAR-98-073 cited above.

Applicants for R01 grants will request direct costs in $25,000 modules, up to
a total direct cost request of $250,000 per year. A typical modular grant
application will request the same number of modules in each year. Applications
for R01 grants may request a maximum five years of support.  Before preparing
an R01 application, the prospective applicant should consult the program
official listed under INQUIRIES to determine the responsiveness of the
proposed project to this PA.

Applicants for R03 grants may request up to $50,000 (direct costs) per year
for a period not to exceed three years.  Funds and time requested should be
appropriate for the research proposed.  Before preparing an R03 application,
the prospective applicant should consult the program official listed under
INQUIRIES to determine the responsiveness of the proposed project to this PA.

RESEARCH OBJECTIVES

The most notable advance in AIDS-associated opportunistic infections (OIs) has
been the decline in their incidence, which is a result of the effect of potent
antiretroviral therapy.  Recent findings also suggest that although the
natural history of OIs in patients with HIV infection is changing, OIs are
still an important clinical and pathophysiologic manifestation of HIV disease. 
For example, HIV-infected patients have an elevated risk of primary or
reactivated tuberculosis, and such active infectious processes may enhance HIV
replication and increase risk of death.

The long-term effectiveness of antiretroviral therapy in developed countries
remains unknown, and it is unclear whether the reduced rates of OIs are
temporary or permanent.  HIV/AIDS continues at an epidemic rate in developing
countries where antiretroviral therapy remains unavailable.

Significant pathological consequences associated with OIs in AIDS include
retinitis (human cytomegalovirus), progressive multifocal leukoencephalopathy
(JC virus), tuberculosis (Mycobacterium tuberculosis), and protracted diarrhea
(Cryptosporidium parvum, Enterocytozoon bieneusi).

Limitations of currently available drugs for treatment and prevention of OIs
include the static nature of most agents, toxicity, and emergence of
resistance.  The discovery of more potent and less toxic compounds would
provide improved medical management of these AIDS-associated complications. 
Furthermore, no standard treatments exist for opportunistic pathogens such as
JC virus, C. parvum, and E. bieneusi.

Research Objectives and Experimental Approaches

The goal of this PA is the discovery of agents for treatment of AIDS-
associated OIs.  Given present advances in molecular biology, the principal
objectives of the PA are to stimulate original and innovative preclinical
research to (1) identify and characterize new, pathogen-specific molecular
targets and (2) develop promising therapeutic approaches based on new targets.

Opportunistic pathogens emphasized by this PA are: human cytomegalovirus
(HCMV), JC virus, Mycobacterium tuberculosis, Cryptosporidium parvum, and the
microsporidia.

Areas of study include but are not restricted to the following:

o  discovery of efficacious new therapeutic agents (chemo- or immuno-based
therapeutics) for treatment of AIDS-associated OIs;

o  identification of molecular targets for therapeutic agents utilizing state-
of-the-art molecular genetic technology;

o  discovery and evaluation of novel, selective chemical entities generated by
combinatorial chemistry or combinatorial genomics methodologies;

o  development of improved delivery systems for therapeutic agents (improved
bioavailability, pharmacokinetics); and

o  development of improved in vitro (cell culture) and in vivo (animal model)
systems for drug evaluations.

Before preparing an R01 or R03 application, the prospective applicant should
consult the program official listed under INQUIRIES to determine the
responsiveness of the proposed project to this PA.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and
their subpopulations must be included in all NIH supported biomedical and
behavioral research projects involving human subjects, unless a clear and
compelling rationale and justification is provided that inclusion is
inappropriate with respect to the health of the subjects or the purpose of the
research.

This policy results from the NIH Revitalization Act of 1993 (Section 492B of
Public Law 103-43.  All investigators proposing research involving human
subjects should read the "NIH Guidelines for Inclusion of Women and Minorities
as Subjects in Clinical Research," which was published in the Federal Register
of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and
Contracts, Vol. 23, No. 11, March 18, 1994, available on the web at: 
https://grants.nih.gov/grants/guide/1994/94.03.18/notice-nih-guideline008.html.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them. 
This policy applies to all initial (Type 1) applications submitted for receipt
dates after October 1, 1998.  All investigators proposing research involving 
human subjects should read the "NIH Policy and Guidelines" on the Inclusion of
Children as Participants in Research Involving Human Subjects that was
published in the NIH Guide for Grants and Contracts, March 6, 1998, and is
available at the following URL address:
https://grants.nih.gov/grants/guide/notice-files/not98-024.html

Investigators also may obtain copies of these policies from the program staff
listed under INQUIRIES.  Program staff may also provide additional relevant
information concerning the policy.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used in
applying for these grants, with the modifications noted below.  These forms
are available at most institutional offices of sponsored research; 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: grantsinfo@nih.gov; and on the internet at
https://grants.nih.gov/grants/forms.htm

Applications must be identified by checking "YES" on line 2 of the face page
of the application form, and the number and title of this program announcement
must be typed in.

BUDGET INSTRUCTIONS

The total direct costs must be requested in accordance with the program
guidelines and the modifications made to the standard PHS 398 application
instructions described below:

PHS 398

o  FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in
$25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total
Direct plus Facilities and Administrative (F&A) costs] for the initial budget
period. Items 8a and 8b should be completed indicating the Direct and Total
Costs for the entire proposed period of support.

o  DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4
of the PHS 398.  It is not required and will not be accepted with the
application.

o  BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the
categorical budget table on Form Page 5 of the PHS 398.  It is not required
and will not be accepted with the application.

o  NARRATIVE BUDGET JUSTIFICATION - Use a Modular Grant Budget Narrative page. 
(See https://grants.nih.gov/grants/funding/modular/modular.htm for sample pages). 
At the top of the page, enter the total direct costs requested for each year.

o  Under Personnel, List key project personnel, including their names, percent
of effort, and roles on the project.  No individual salary information should
be provided.

For Consortium/Contractual costs, provide an estimate of total costs (direct
plus facilities and administrative) for each year, each rounded to the nearest
$1,000.  List the individuals/organizations with whom consortium or
contractual arrangements have been made, the percent effort of key personnel,
and the role on the project.  Indicate whether the collaborating institution
is foreign or domestic.  The total cost for a consortium/contractual
arrangement is included in the overall requested modular direct cost amount.

Provide an additional narrative budget justification for any variation in the
number of modules requested.

o  BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by
reviewers in the assessment of each individual's qualifications for a specific
role in the proposed project, as well as to evaluate the overall
qualifications of the research team.  A biographical sketch is required for
all key personnel, following the instructions below.  No more than three pages
may be used for each person.  A sample biographical sketch may be viewed at:
https://grants.nih.gov/grants/funding/modular/modular.htm

- Complete the educational block at the top of the form page;
- List current position(s) and any honors;
- Provide information, including overall goals and responsibilities, on
research projects ongoing or completed during the last three years.
- List selected peer-reviewed publications, with full citations;

o  CHECKLIST - This page should be completed and submitted with the
application.  If the F&A rate agreement has been established, indicate the
type of agreement and the date.  All appropriate exclusions must be applied in
the calculation of the F&A costs for the initial budget period and all future
budget years.

o  The applicant should provide the name and phone number of the individual to
contact concerning fiscal and administrative issues if additional information
is necessary following the initial review.

Submit a signed, typewritten original of the application and five signed,
photocopies, in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)

The Center for Scientific Review (CSR) will not accept any application in
response to this PA 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 from institutions that have a General Clinical Research Center
(GCRC) funded by the NIH National Center for Research Resources (NCRR) may
wish to identify the Center as a resource for conducting the proposed
research.  If so, a letter of agreement from the GCRC Program Director must be
included in the application material.

REVIEW CONSIDERATIONS

Review Procedures

Applications will be assigned on the basis of established PHS referral
guidelines.  Upon receipt, applications will be reviewed for completeness by
the NIH Center for Scientific Review.  Incomplete applications will be
returned to the applicant without further consideration.

Applications will be reviewed for scientific and technical merit in accordance
with the standard NIH peer review procedures.  As part of the initial merit
review, all applications will receive a written critique and undergo a process
in which only those applications deemed to have the highest scientific merit,
generally the top half of the applications under review, will be discussed,
assigned a priority score, and receive a second level review by the
appropriate national advisory council.

Review Criteria

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 an important problem? 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
field?

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?

The initial review group will also examine: the appropriateness of proposed
budget and duration; the adequacy of plans to include children and both
genders and minorities and their subgroups as appropriate for the scientific
goals of the research and plans for the recruitment and retention of subjects;
the provisions for the protection of human and animal subjects; and the safety
of the research environment.

The personnel category will be reviewed for appropriate staffing based on the
requested percent effort.  The direct costs budget request will be reviewed
for consistency with the proposed methods and specific aims.  Any budgetary
adjustments recommended by the reviewers will be in $25,000 modules.  The
duration of support will be reviewed to determine if it is appropriate to
ensure successful completion of the requested scope of the project.

AWARD CRITERIA

Applications will compete for available funds with all other favorably
recommended applications.  The following will be considered when making
funding decisions: quality of the proposed project as determined by peer
review, program balance among research areas of the announcement, and
availability of funds.

INQUIRIES

Written and telephone inquiries are encouraged.  The opportunity to clarify
any issues or questions from potential applicants is welcome.

Inquiries regarding programmatic (research scope and eligibility) issues may
be directed to:

Chris Lambros, Ph.D.
Division of AIDS
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 2C40, MSC 7620
Bethesda, MD  20892-7620
Telephone:  301-435-3769
FAX:  301-402-3171
Email:  clambros@niaid.nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Linda Shaw
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4B33, MSC 7610
Bethesda, MD  20892-7610
Telephone:  301-402-6611
FAX:  301-480-3780
Email:  lshaw@niaid.nih.gov

The National Heart, Lung, and Blood Institute (NHLBI) has an interest in
supporting research on the pulmonary, cardiovascular and hematologic aspects
of opportunistic infections associated with HIV infection.  Therefore,
applications of mutual interest are likely to be given a secondary assignment
to NHLBI in accordance with the NIH referral guidelines.  Inquiries regarding
NHLBI programmatic issues may be directed to:

Hannah H. Peavy, M.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 10018, MSC 7952
Bethesda, MD  20892-7952
Telephone:  301-435-0222
FAX:  301-480-3557
Email:  hannah_peavy@nih.gov

The National Institute of Dental and Craniofacial Research (NIDCR) has an
interest in opportunistic infections in the oral cavity.  Therefore,
applications of mutual interest are likely to be given a secondary assignment
to NIDCR in accordance with the NIH referral guidelines.  Inquiries regarding
NIDCR programmatic issues may be directed to:

Dennis F. Mangan, Ph.D.
Division of Extramural Research
National Institute of Dental and Craniofacial Research
Building 45, Room 4AN-32F, MSC 6402
Bethesda, MD  20892-6402
Telephone:  301-594-2421
FAX:  301-480-8318
Email:  dennis.mangan@nih.gov

AUTHORITY AND REGULATIONS

This program is supported under authorization of the Public Health Service
Act, Sec. 301 (c), Public Law 78-410, as amended.  The Catalogue of Federal
Domestic Assistance Citations are Sec. 93.856, Microbiology and Infectious
Diseases Research, and No. 93.855 - Immunology, Allergy, and Transplantation
Research.  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 review.

The PHS strongly encourages all grant and contract 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.

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