Full Text AI-94-013

RESEARCH ON TOPICAL MICROBICIDES FOR PREVENTION OF STDS/HIV INFECTION

NIH GUIDE, Volume 23, Number 10, March 11, 1994

RFA:  AI-94-013

P.T. 34

Keywords: 
  Sexually Transmitted Diseases 
  Disease Prevention+ 
  Microbiology 
  Immunology 
  Biology, Cellular 


National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  May 13, 1994
Application Receipt Date:  July 13, 1994

PURPOSE

The Sexually Transmitted Diseases Branch of the Division of
Microbiology and Infectious Diseases (DMID), National Institute of
Allergy and Infectious Diseases (NIAID), invites research grant
applications for program projects to conduct research necessary for
the development of topical microbicides for intravaginal use to
prevent sexually transmitted diseases (STDs), including Human
Immunodeficiency Virus (HIV) infection.  The NIAID wishes to expand
research in this area through the conduct of multi-disciplinary
research in microbiology, immunology, reproductive biology,
reproductive toxicology, and cell biology.  Basic and applied
research that will lead to effective strategies for intravaginal
protection against STDs, including HIV infection, are encouraged.

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 Request
For Applications (RFA), Research on Topical Microbicides for
Prevention of STDs/HIV, is related to the priority areas of sexually
transmitted diseases and HIV infection.  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.
017-001-10473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Research grant applications may be submitted by domestic, for-profit
and non-profit organizations, public and private institutions, such
as universities, colleges, hospitals, laboratories, units of State
and local governments, and eligible agencies of the Federal
government.  Foreign organizations are not eligible to apply.
Applications from minority individuals and women are encouraged.

MECHANISM OF SUPPORT

The mechanism of support will be the Program Project grant (P01).
Multidisciplinary approaches that involve collaborative efforts among
investigators in microbiology, immunology, reproductive biology,
reproductive toxicology, and cell biology specialties are strongly
encouraged.  The total project period for applications submitted in
response to this RFA may not exceed four years.

FUNDS AVAILABLE

The estimated total funds (direct and indirect costs) available for
the first year of support for awards under this RFA will be
$1,500,000.  In Fiscal Year 1995, the NIAID plans to fund
approximately two program projects.  Applications may not request
budgets in excess of $750,000 total costs in the first year or more
than four percent annual inflationary increases for future years.  An
application with a first year requested amount in excess of $750,000
total direct cost will require written approval by senior a NIAID
official via the program officer for acceptance of the application
for processing.  The usual PHS policies governing grants
administration and management will apply.  This level of support is
dependent on the receipt of a sufficient number of applications of
high scientific merit.  Although this program is provided for in the
financial plans of the NIAID, awards pursuant to this RFA are
contingent upon the availability of funds for this purpose.  Funding
beyond the first and subsequent years of the grant will be contingent
upon satisfactory progress during the preceding years and
availability of funds.

RESEARCH OBJECTIVES

Background

The HIV pandemic has focused attention on sexually transmitted
diseases (STDs), both because HIV infection is a fatal STD and
because other STDs are implicated as risk factors for sexual
transmission of HIV.  Current global estimates indicate that 14
million people are infected with HIV, the cause of Acquired
Immunodeficiency Syndrome (AIDS).  The majority of these infections
were acquired through sexual intercourse.  Unless effective
prevention measures to stop sexual transmission of HIV are
implemented, the number of AIDS cases will continue to grow.

Separate from the HIV epidemic, STDs cause significant morbidity and
mortality and contribute greatly to increasing health care costs.  In
the United States in 1993, an estimated 12 million new cases of STDs
occurred, 64 percent of which were in people less then 24 years old,
including three million in teenagers.  In 1993, cost estimates
associated with these infections exceeded six billion dollars.

Furthermore, STDs disproportionately affect the female, the fetus,
and the newborn.  Gonococcal and chlamydial infections cause pelvic
inflammatory disease, infertility, and ectopic pregnancy.  Several
common STDs adversely affect pregnancy and result in spontaneous
abortion, stillbirth, chorioamnionitis, premature rupture of
membranes, preterm delivery, and postpartum endometritis.  Neonatal
infections include gonococcal conjunctivitis, which may lead to
blindness; chlamydial pneumonia, which may lead to chronic
respiratory disease; congenital syphilis and herpes encephalitis.
Moreover, genital infections due to human papillomavirus are causally
associated with cervical cancer, one of the most common cancers in
women throughout the world.

It is now clear that the risk of becoming infected or infecting
others with HIV is substantially increased if one has an STD such as
chancroid, genital herpes, syphilis, trichomoniasis, gonorrhea, or
chlamydial infection.  Over 75 studies on the role of STDs in HIV
transmission have been conducted.  In 15, STD effects could be
assessed independently of sexual behavior effects; both ulcerative
and non-ulcerative STDs increased risk of HIV transmission.  Although
the individual risk of HIV transmission associated with genital ulcer
diseases appears to be higher than the discharge diseases (up to
ten-fold compared to three to five fold), the high prevalence of
discharge diseases results in a much higher population attributable
risk.

Furthermore, data from over 80 reports on the natural history of STDs
in HIV infected people suggest that, at a community level, HIV
infection may increase the prevalence of some STDs (e.g. genital
ulcers).  If co-infection with HIV prolongs or augments the
infectiousness of individuals with STDs, and if the same STDs
increase risk of HIV acquisition, these infections may greatly
amplify one another.  This "epidemiological synergy" may be fueling
the explosive growth of the HIV pandemic in some populations
(reviewed by Wasserheit, 1991).

Based on the recommendations from four international conferences, a
consensus has emerged that safe, effective, female-controlled
chemical barriers that will block transmission are needed to prevent
sexually transmitted HIV infection as well as other STDs.  Currently
available mechanical and chemical barriers have many limitations.
Although the male condom, if used consistently and correctly, is a
very effective barrier against transmission of HIV and the discharge
diseases, it requires the active cooperation of the male partner and,
therefore, cannot be independently implemented at the discretion of
the female partner.  Although the female condom only requires partner
consent, virtually nothing is known about its efficacy in preventing
bacterial and viral STDs.  Spermicides have in vitro activity against
most sexually transmitted pathogens including HIV; however, well
designed clinical studies demonstrating, unequivocally, that
spermicides prevent STDs/HIV infection have not been done.
Furthermore, several studies have revealed that spermicides can cause
mucosal erosions and ulcers; whether these lesions might increase
risk of transmission of HIV infection is presently unknown.

In addition to the inherent limitations of these existing methods,
there are many situations in which personal, social, or cultural
barriers interfere with a woman's ability to successfully negotiate
and implement the use of barriers that could decrease risk of
infection.  Specifically, the need for a method that can be
implemented by women is grounded in the high prevalence of:  (1)
non-consensual sex, (2) sex without condom use, and (3) risky
behaviors that occur without partner knowledge.  Just as oral
contraceptives dramatically enhanced the ability of women to avoid
unwanted pregnancy, effective female-controlled topical microbicides
are urgently needed to enhance the ability of women to avoid sexually
transmitted infections.  Furthermore, chemical barriers that
inactivate pathogens in vaginal/cervical secretions, as well as in
the ejaculate could reduce female-to-male as well as male-to-female
transmission.

Topical microbicides are defined herein as preparations for
intravaginal use that are microbicidal (virucidal and/or
bactericidal); these products will prevent sexually transmitted
infections.  The ideal microbicide should have the following
characteristics:  colorless, odorless, tasteless (physically
"invisible"), stable, easy to store, fast acting for appropriate
duration, effective pre- and post-coitus, inexpensive, available
without a prescription, and safe for use at least one to two times
daily.  Candidate classes of microbicidal compounds include, but are
not limited to, detergents, chemicals such as iodophores,
carbohydrates, antibodies, defensins, and pyocins.

Ideally topical microbicides would not be inherently spermicidal but
could be formulated with or without spermicidal activity.
Non-contraceptive microbicides would be extremely useful for women
who wish to become pregnant, or for those women who use one of the
many safe, effective methods for contraception that either have no
protective effect against infection or, arguably, exacerbate risk of
infection.  Indeed, a person's contraceptive choices may change over
a lifetime.  However, no matter what an individual's current
contraceptive preference, if they are sexually active, they will
desire/require protection from sexually transmitted infections.

Scope of Research

A fundamental objective of the NIAID's STD/HIV research programs is
to develop topical microbicides effective in preventing and
controlling sexually transmitted infections.  Whereas it is
recognized that safe, spermicidal-microbicides are important outcomes
in the search for female-controlled barrier methods to prevent HIV
infection and STDs, the development of spermicides which are not
microbicidal is not an objective of NIAID.

Arguably the most productive approach to identifying safe, effective
molecular strategies for blocking the early steps in the infectious
process is based on multi-disciplinary efforts including, but not
limited to,  microbiology, immunology, reproductive biology,
reproductive toxicology, and cell biology.  Applicants are strongly
encouraged to include microbiology and two additional disciplines in
the program project.

A wide range of basic and applied research questions must be answered
in order to meet this programmatic objective.  Research issues and
areas of high priority to the NIAID and to this RFA include, but are
not limited to, the following:

Diseases of interest

Applicants are encouraged to address the following sexually
transmitted diseases of high scientific priority to the NIAID:

o  HIV infection
o  Chlamydial infection
o  Gonorrhea
o  Trichomoniasis
o  Genital Ulcer Diseases, including syphilis, genital herpes (herpes
simplex virus 1 and 2) and chancroid
o  Human papillomavirus infection

The goal, as envisioned, is to develop topical microbicides with
activity against a combination of pathogens including viral,
bacterial and protozoan. With respect to HIV prevention, it is
theoretically possible that microbicides may be used to prevent HIV
infection primarily or secondarily.  For example, a microbicide might
be virucidal and prevent HIV infection through direct viral
neutralization.  Another plausible outcome is development of a safe
microbicide that was bactericidal but did not inactivate enveloped
viruses such as HIV .  Given the role of the discharge STDs in
increasing risk of HIV transmission, a microbicide with this
specificity would prevent gonorrhea and chlamydial infection directly
and HIV infection secondarily.  For these reasons, research on two
sexually transmitted diseases, preferably one viral and one
bacterial, is highly recommended.

Early steps in infectious processes

Studies delineating the chronology and biology of the early steps in
the host/pathogen interaction including, but not limited to, the role
of inflammation in altering kinetics and infectious dose and the role
of cell-free versus cell-associated pathogens in the transmission of
disease are encouraged.

Microbicide evaluation

Of interest are in vitro (using established tissue culture systems),
ex vivo (using primary human cells eg. vaginal and cervical
epithelium or sperm) and pre-clinical characterization of
bactericidal and virucidal activity of currently available
spermicidal products, new topical microbicides and inactive
ingredients (carriers) in existing or new products.

Biology of the reproductive tract

It is critical to identify and characterize the "endogenous"
anatomical, physiological, hormonal, immunological and
microbiological factors of the female reproductive tract that play a
role in resistance and susceptibility to infection including, but not
limited to, vaginal pH, mucus, estrogen and other hormones, cervical
ectopy and normal flora including lactobacilli.

Reproductive toxicology

Using materials from human subjects (i.e., cell or organ cultures) or
established model systems, studies on the effects of topical
microbicides on the normal vaginal environment, including but not
limited to, alteration of vaginal pH, mucus, surface receptors,
normal flora (e.g., lactobacilli and yeast), and induction of
inflammatory processes are encouraged.  Studies on characterization
of spermicidal, teratogenic, mutagenic, or carcinogenic properties of
topical microbicides are also of interest.  Appropriate models for
studying the reproductive toxicology of topical microbicides might
include, but are not limited to, those that measure vaginal/cervical
irritation/inflammation, or effects on sperm, or on embryogenesis.
If animal models are included, these should be well-established
models, e.g., those developed for characterizing adverse effects of
spermicidal contraceptives.

Projects may involve collaboration among investigators at several
institutions.  Consortium arrangements should follow "Guidelines for
Establishing and Operating Consortium Grants, January 1989",
available from the individuals listed under INQUIRIES.

Project Leaders and Program Directors should budget for an annual
one-day progress review meeting at a site to be designated (either in
Bethesda or in association with a relevant national meeting).

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements are required to include minorities and women
in study populations so that research findings can be of benefit to
all persons at risk of the disease, disorder or condition under
study; special emphasis must be placed on the need for inclusion of
minorities and women in studies of diseases, disorders and conditions
which disproportionately affect them.  This policy is intended to
apply to males and females of all ages.  If women or minorities are
excluded or inadequately represented in clinical research,
particularly in proposed population-based studies, a clear compelling
rationale must be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues must be addressed in developing a research
design and sample size appropriate for the scientific objectives of
the study.  This information must be included in the form PHS 398
(rev. 9/91) in Sections 1-4 of the Research Plan AND summarized in
Section 5, Human Subjects.  Applicants are urged to assess carefully
the feasibility of including the broadest possible representation of
minority groups.  However, NIH recognizes that it may not be feasible
or appropriate in all research projects to include representation of
the full array of United States racial/ethnic minority populations
(i.e., Native Americans [including American Indians or Alaskan
Natives], Asian/Pacific Islanders, Blacks, Hispanics).

The rationale for studies on single minority population groups should
be provided.

For the purpose of this policy, clinical research is defined as human
biomedical and behavioral studies of etiology, epidemiology,
prevention (and preventive strategies), diagnosis, or treatment of
diseases, disorders or conditions, including but not limited to
clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

If the required information is not contained within the application,
the application will be returned.  Peer reviewers will address
specifically whether the research plan in the application conforms to
these policies.  If the representation of women or minorities in a
study design is inadequate to answer the scientific question(s)
addressed AND the justification for the selected study population is
inadequate, it will be considered a scientific weakness or deficiency
in the study design and will be reflected in assigning the priority
score to the application.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not support
applications that do not comply.

LETTER OF INTENT

Prospective applicants are asked to submit, by May 13, 1994, a letter
of intent that includes a descriptive title of the overall proposed
research, the name, address and telephone number of the Program
Director, and the number and title of this RFA.  Prospective
applicants are also asked to submit a list of the project leaders and
other key investigators and their institution(s).  Although the
letter of intent is not required, is not binding, does not commit the
sender to submit an application, and does not enter into the review
of subsequent applications, the information that it contains 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 at the address listed under INQUIRIES.

APPLICATION PROCEDURES

In preparing the application, the applicant should bear in mind the
research objectives of this RFA.  P01 applications should be prepared
using the guidance and instructions provided in "NIAID Program
Project Grants and Multiproject Cooperative Agreements (rev. 02/94),"
which may be requested from Dr. Olivia Preble at the address listed
under INQUIRIES.  Failure to follow these instructions may result in
delays in the review or in an incomplete application.

Applications are to be submitted on form PHS 398 (rev. 9/91), the
standard application form for research grants.  Application kits are
available at most institutional offices of sponsored research and may
be obtained from the Office of Grants Information, Division of
Research Grants, National Institutes of Health, Westwood Building,
Room 449, Bethesda, MD 20892, telephone 301/710-0267.  Applicants
must adhere to the format and requirements specified in the PHS 398
application kit.

For purposes of identification and processing, mark "YES" in item 2a
on the face page of the application and type in the RFA number
AI-94-013 and the title "RESEARCH ON TOPICAL MICROBICIDES FOR
PREVENTION OF STDS/HIV."  The RFA label available in the form PHS 398
must be affixed to the bottom of the face page of the original
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.

The signed, typewritten original of the application, including the
Checklist, and three exact single-sided copies must be sent to:

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

At the time of submission, two additional copies and all five sets of
appendices must also be sent to Dr. Olivia Preble at the address
listed under INQUIRIES.

To ensure their review, applications must be received by both the
Division of Research Grants and Dr. Olivia Preble by July 13, 1994.
Applications not received by the receipt date will be returned to the
applicant without review.

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 essentially 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.

REVIEW CONSIDERATIONS

Review Procedures

Applications will be reviewed by Division of Research Grants (DRG)
staff for completeness and by NIAID staff to determine administrative
and programmatic responsiveness to this RFA.  Those judged to be
incomplete or non-responsive will be returned to the applicant
without review.  Those considered complete and responsive may be
subjected to a triage review by an NIAID peer review group, to
determine their scientific merit relative to the other applications
submitted in response to this RFA.  The NIAID will withdraw from
competition those applications judged by the triage peer review group
to be noncompetitive for award and will so notify the applicant
investigator and the institutional business official.  Those
applications judged to be competitive for award will be further
reviewed for scientific and technical merit by a Review Committee
convened by the Division of Extramural Activities, NIAID.  The second
level of review will be provided by the National Advisory Allergy and
Infectious Diseases Council.

Review Criteria

The review criteria for P01 grant applications are the review
criteria for large, multi-component, interdisciplinary program
projects as outlined in the document entitled NIAID PROGRAM PROJECT
GRANTS AND MULTIPROJECT COOPERATIVE AGREEMENTS (rev. February 1994).
The application must include a justification for the appropriateness
of the proposed studies for the P01 grant mechanism.  The
distinguishing features of a program project grant include:

o  A unifying well-defined goal or problem area of research to which
each project relates and contributes, thereby producing a research
environment that allows each research effort to share the creative
strengths of others.

o  A program director who possesses recognized scientific and
administrative competence; she/he should show a substantial
commitment of time and effort to the program and exercise leadership
in its quality control.

o  Each research project should, as assessed by peer review, stand on
its own independent scientific merit, as well as complement other
projects whenever feasible.

o  These multiple projects require the participation of established
investigators in several disciplines, or investigators with special
expertise in several areas of one discipline.  All investigators
should contribute to and share in the responsibilities of fulfilling
the program objective.

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 GCRC as a resource for conducting
the proposed research.  If so, a letter of agreement from either the
GCRC Program Director or Principal Investigator could be included
with the applications.

AWARD CRITERIA

Funding decisions will be made on the basis of scientific and
technical merit as determined by peer review, program priorities and
balance, and the availability of funds.  The totality of the awarded
projects will reflect the programmatic objectives described above.

INQUIRIES

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

Requests for the document entitled "NIAID PROGRAM PROJECT GRANTS AND
MULTIPROJECT COOPERATIVE AGREEMENTS" (rev. 2/94) as well as inquiries
regarding programmatic issues may be directed to:

Dr. Penelope J. Hitchcock
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
Solar Building, Room 3A-21
Bethesda, MD  20892
Telephone:  (301) 402-0443
FAX:  (301) 402-1456
Email:  penny@exec.niaid.pc.niaid.nih.gov

Direct inquiries regarding review issues, address the letter of
intent, and mail two copies of the application and all five sets of
appendices to:

Dr. Olivia Preble
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C20
Bethesda, MD  20892
Telephone:  (301) 496-8208
FAX:  (301) 402-2638

Direct inquiries regarding fiscal matters to:

Ms. Sharie Bernard
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B32
Bethesda, MD  20892
Telephone:  (301) 496-7075

Schedule

Letter of Intent Receipt Date:  May 13, 1994
Application Receipt Date:       July 13, 1994
Scientific Review Date:         October 1994
Advisory Council Date:          February 1995
Earliest Date of Award:         April 1995

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance, No. 93.856 - Microbiology and Infectious Diseases
Research.  Awards will be made under the authority of the Public
Health Service Act, Title III, Section 301 (Public Law 78-410, as
amended; 42 USC 241) and administered under PHS grants policies and
Federal Regulations 42 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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