ANTIRETROVIRAL/IMMUNE PROPHYLAXIS AGAINST HIV-1 TRANSMISSION

Release Date:  March 6, 1998

PA NUMBER:  PA-98-038

P.T.

National Institute of Allergy and Infectious Diseases

PURPOSE

The Division of AIDS (DAIDS), National Institute of Allergy and Infectious
Diseases (NIAID), invites applications to carry out basic laboratory research
addressing the use of antiretroviral and immunotherapeutic agents for prevention
of HIV-1 transmission related to high risk sexual, perinatal or parenteral
exposures.

This Program Announcement (PA) is designed to stimulate investigator-initiated
laboratory research related to pre- and post-prophylaxis regimens used to reduce
HIV-1 transmission.  The types of applications encouraged under this PA would
include laboratory studies using samples from animal model research; and from
ongoing human clinical trials or observational cohort studies in which
antiretroviral or immunotherapeutic agents are used for prophylaxis of high risk
HIV-1 exposures.

The research areas to be addressed under the PA include laboratory investigations
which elucidate: (1) the mode(s) of action of prophylactic agents in reducing the
risk of infection following exposure to retroviruses, (2) evidence for or against
abortive or transient infection, (3) early host immunologic responses following
exposure to HIV-1 or related retroviruses, and (4) clinical laboratory studies
which address the safety, tolerance and pharmacokinetics of combination
antiretroviral agents when given to uninfected individuals as prophylaxis for
high risk HIV-1 exposures.

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, Basic Research on Antiretroviral
and Immune Prophylaxis for Reduction of HIV-1 Transmission, is related to the
priority areas of HIV infection, prevention, immunization and infectious
diseases, and maternal and infant health.  Potential applicants may obtain a copy
of "Healthy People 2000" (Full Report:  Stock No. 017-001-00474-0 or Summary
Report:  Stock No. 017-001-00473-1) through the Superintendent of Documents,
Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800).

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

Traditional research project grant (R01), and small research grant (R03)
applications may be submitted in response to this program announcement. 
Applications for R01 grants may request up to five years of support.

The NIAID uses R03 grants to support small, highly innovative or pilot projects. 
Applicants for R03 grants may request up to $50,000 annual direct costs for a
period not to exceed three years.  Funds and time requested should be appropriate
for the research proposed.  Applicants for R03 grants must follow the special
application guidelines and Terms and Conditions of Award in the NIAID SMALL
RESEARCH GRANTS brochure (September 1996); this brochure is available via the WWW
at:  http://www.niaid.nih.gov/ncn/tools/broch.htm.

Responsibility for the planning, direction, and execution of the proposed
research will be solely that of the applicant.

RESEARCH OBJECTIVES

Background

A mounting body of preclinical and clinical data suggest that antiretrovirals or
immunotherapeutic agents may be protective in reducing the risk of
retroviral/HIV-1 transmission if given immediately prior to, during or post
exposure.  These data include animal studies with PMPA ((R-9-2-
Phosphonylmethoxypropyl)adenine) using feline and simian models; other simian
models in which perinatal and juvenile macaques given hyperimmune serum were
protected against viral challenge; and data from chimpanzees which demonstrated
that nevirapine given pre and post HIV challenge was protective.

Relevant human data includes perinatal HIV prevention trials and observational
data on zidovudine (ZDV) prophylaxis among health care workers following HIV
exposure.  ACTG 076 was a highly successful perinatal HIV prevention trial which
used an intensive regimen of ZDV given prenatally and intra partum to pregnant
HIV-infected women, and then post partum to their neonates.  Findings from this
study were that there was a two thirds reduction in risk of HIV infection for the
group receiving ZDV but  only 9-16% of the effect was estimated to be related to
viral load reduction.  Most importantly, at any given level of maternal viral
load, ZDV provided added protection against infant HIV infection compared to
placebo.  These data supported the possibility that ZDV was also acting as a
chemoprophylactic agent, protecting the fetus/neonate during a period of HIV
exposure.

Likewise, the CDC has reported case control observational data on health care
workers following needle stick exposure which suggests that ZDV postexposure-
prophylaxis was protective in reducing the risk of transmission by 80% when
compared to no treatment.  Given the PHS recommendations regarding
chemoprophylaxis for health care workers following needlestick injuries with
exposure to blood or secretions from HIV-infected individuals, there is a
critical need to assess the role of chemoprophylaxis in reducing risk of
infection from those exposures which currently contribute to the majority of new
cases of HIV.  These exposures include high risk sexual contact, perinatal
exposure, as well as exposure to HIV through illicit intravenous drug use.

Research Objectives and Scope

The goals of this PA are to:

o  Stimulate and support basic research into modes of action of successful
prophylactic regimens which use antiretrovirals and immune agents;

o  Foster collaborations between basic laboratory researchers and clinical
investigators engaged in animal or human studies utilizing prophylactic agents
to reduce transmission following exposures to HIV-1 or other relevant
retroviruses.

The NIAID wishes to support basic laboratory research addressing the use of
prophylactic antiretroviral and/or immune regimens for prevention of HIV-1
transmission just prior to, during or following perinatal, parenteral or high
risk sexual exposures.  This PA encourages investigators with proposals for basic
research studies to collaborate with investigators engaged in ongoing animal or
human studies testing the efficacy or effectiveness of antiretroviral and
immunotherapeutic regimens used for prophylaxis against HIV or related
retroviruses.  General research topics of interest under this PA include, but are
not limited to, studies addressing the following areas:

o  Modes of action of successful antiretroviral or immunotherapeutic agents used
for prophylaxis against HIV-1 or related retroviruses during high risk exposures

o  The importance of the timing of prophylactic interventions (e.g.
administration of such agents pre-exposure, during, or post-exposure to virus)
on the success of the intervention strategy

o  The impact of highly active antiretroviral therapy on reducing
transmissibility of HIV-1 from infected individuals

o  Evidence for or against abortive infection following HIV exposure among those
receiving prophylactic agents.  For example this might include PCR studies to
detect transient evidence of virus among ultimately uninfected individuals who
received prophylactic agents, or studies addressing possible differences in
detection of virus following varied routes of exposure (i.e. sexual versus
parenteral exposure).

o  Study of the types and breadth of host immune cellular and humoral responses
during or following episodes of high risk HIV-1 exposure.  These studies might
include assessment of CTL's, cytokine production, or host lymphoproliferative
responses in various body compartments (e.g. genital tract, blood, lymphoid
tissue).

o  Clinical laboratory-based studies addressing safety, tolerance, and
pharmocokinetics of combination antiretrovirals or immunotherapeutic agents used
prophylactically among nonHIV-infected individuals

o  Laboratory studies addressing evidence for or against immunologic responses
(e.g CTLs or cytokine production) to HIV-1 exposure among uninfected infants born
to HIV-infected women; including immunologic responses during the breast feeding
period

o  Sequelae (both negative or positive) of prophylactic antiretroviral and immune
interventions among both infected and uninfected individuals exposed to
antiretroviral or immunotherapeutic prophylactic interventions (e.g. risk of
later cancers, or organ toxicities; delay in disease progression or long term
reduction in viral load)

o  Animal studies addressing the above topics using relevant retroviral models

Over the next decade, there will be increasing numbers of exposed but uninfected
individuals receiving prophylactic agents -- including adults engaged in high
risk sexual behaviors, intravenous drug users, and infants born to HIV-infected
women.  Better understanding of mechanisms of action of successful prophylactic
regimens, their safety and tolerance when used in combination among uninfected
individuals, as well as host responses to HIV exposure will further scientific
knowledge regarding the safety and effectiveness of approaches as well as
correlates of immunity among uninfected individuals following HIV-1 exposure.

Proposed laboratory investigations that address the research issues described
above or related research areas will be considered responsive to this PA. 
Collaborations between basic laboratory researchers and clinical investigators
who follow perinatal or adult cohorts receiving prophylactic regimens for
prevention of HIV-1 infection are strongly encouraged under this PA; as are
investigations using relevant animal research models which address the role of
prophylactic antiretroviral or immune agents.

Clinical specimens required for the proposed laboratory studies could be drawn
from a variety of sources, including ongoing animal studies investigating
transmission of retroviruses; perinatal or adult HIV cohorts offered
chemoprophylactic regimens at specific clinical sites; ongoing multi-site
clinical trial, quasi-experimental studies,  registries or epidemiologic studies. 
Program Staff at DAIDS can offer assistance to laboratory-based investigators
wishing to contact clinical investigators with relevant specimens from perinatal
or pediatric HIV cohorts.  Contact the DAIDS Program Officer listed under
INQUIRIES for further assistance.

Note:  This program announcement is not intended for direct conduct of clinical
trials, patient care, or maintenance of natural history cohorts.  Capability to
access adequate numbers of clinical samples or animal resources to address the
study hypotheses must be documented in the application.

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
sub populations must be included in all NIH supported biomedical and behavioral
research projects involving human subjects, unless a clear and compelling
rationale and justification are provided that inclusion is inappropriate with
respect to the health of the subjects of 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 have been published in the Federal Register of March 28, 1994
(FR 59 14508-14513) and the NIH Guide for Grants and Contracts, Vol. 23, No. 11,
March 18, 1994.

Investigators may obtain copies from these sources or from the DAIDS Program
Officer (listed under INQUIRIES).  Program staff may also provide additional
relevant information concerning the policy.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application for PHS 398 (rev. 5/95)
and will be accepted on the standard application AIDS deadlines as indicated in
the application kit.  Application kits are available at most institutional
offices of sponsored research and may be obtained 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:
asknih@od.nih.gov.

For purposes of identification and processing, item 2 on the face page of the
application must be marked "YES".  The PA number and the PA title must also be
typed in section 2.

The completed, signed original and five legible, single-sided copies of the
application and five copies of appendices must be sent or delivered 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)

R03 Applicants.  Applicants for small research (R03) grants are to follow the
application guidelines in the NIAID SMALL RESEARCH GRANTS brochure (September
1996) which is available from the program staff listed under INQUIRIES and via
the WWW at:  http://www.niaid.nih.gov/ncn/tools/broch.htm

R03 applications that do not conform to the instructions in the brochure will be
judged non-responsive and returned to the applicant.

ALL APPLICANTS REQUESTING $500,000 OR MORE IN ANNUAL DIRECT COSTS.  The NIH
Policy Update on Acceptance for Review of Unsolicited Applications that Request
More Than $500,000 Direct Cost for Any One Year applies to applications in
response to this PA.  The Policy Update was published in the NIH Guide for Grants
and Contracts, Volume 25, No. 14, May 3, 1996, and became effective June 1, 1996. 
Potential applicants must contact the appropriate program staff listed in
INQUIRIES below to initiate clearance processes for acceptance of their
applications if ANNUAL DIRECT COSTS EXCEED $500,000 FOR ANY ONE YEAR.

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
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.  When the subject of an application is of interest to more than one
component of NIH, dual assignments are made.  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.

R01 applications will be reviewed for scientific and technical merit by study
sections of the Center for Scientific Review, NIH, 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.

R03 applications that are complete and responsive to this PA will be evaluated
for scientific and technical merit by an appropriate peer review group convened
by the NIAID.

Review Criteria

The five 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 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 methods? 
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
project budget and duration; the adequacy of plans to include 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.

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 issues may be directed to:

Mary Glenn Fowler, MD, MPH
Division of AIDS
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 2A09
Bethesda, MD  20892
Telephone:  (301) 496-6177
FAX:  (301) 402-3684
Email:  mf25c@nih.gov

Direct inquiries regarding fiscal matters to:

Jane Unsworth
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4B25
Bethesda, MD  20892-7610
Telephone:  (301) 402-6824
FAX:  (301) 480-3780
Email:  ju3a@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance Nos.
93.855 and 93.856.  This program is supported under authorization of the Public
Health Service Act, Sec. 301(c), 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 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.

Return to Volume Index

Return to NIH Guide Main Index

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)