RESEARCH ON TOPICAL MICROBICIDES FOR PREVENTION OF STDS/HIV

Release Date:  April 13, 1998

RFA AVAILABLE:  AI-98-011

P.T.

National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  June 1, 1998
Application Receipt Date:  October 15, 1998

APPLICATIONS IN RESPONSE TO THIS REQUEST FOR APPLICATIONS (RFA) MUST BE PREPARED
USING SPECIFIC INSTRUCTIONS IN AN NIAID BROCHURE ENTITLED "INSTRUCTIONS FOR
APPLICATIONS FOR MULTI-PROJECT AWARDS" (September 1997).

PURPOSE

The Sexually Transmitted Diseases Branch of the Division of Microbiology and
Infectious Diseases (DMID), National Institute of Allergy and Infectious Diseases
(NIAID), invites grant applications for program projects to conduct research
necessary for the development of topical microbicides for intravaginal and
intrarectal use to prevent sexually transmitted diseases (STDs), including Human
Immunodeficiency Virus (HIV) infection.  The NIAID wishes to continue and 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/intrarectal 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, 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 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

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 for P01 grants; however, applications may include an international
component.  Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

The mechanism of support will be the Program Project (P01) grant. 
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
five years.

FUNDS AVAILABLE

The estimated total funds (direct and indirect costs) available for the first
year of support for this RFA will be $2.4 million.  In fiscal year 1999, the
NIAID plans to fund three program projects related to this RFA.

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 over 20 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
1997, 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
1997, cost estimates associated with these infections exceeded seven 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, to
date well designed clinical studies have not demonstrated, unequivocally, that
spermicides prevent STDs/HIV infection.  Furthermore, numerous 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 or
intrarectal use that are microbicidal (virucidal and/or bactericidal) that 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, lipids, 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

The objective of the NIAID's STD/HIV topical microbicide research program is to
develop products that are safe and effective in preventing and controlling
sexually transmitted infections.  Of interest are all products that prevent
infection whether or not they also have the capacity to prevent pregnancy.  The
development of vaginal products, i.e. spermicides, which are not microbicidal is
not an objective of this program.

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 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
which are high scientific priorities of the NIAID:

o  HIV infection
o  Bacterial Vaginosis
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 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 at least two sexually
transmitted pathogens is highly recommended.

Areas of high priority for study include but are not limited to:

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 e.g. vaginal and cervical epithelium or sperm), animal
models  to characterize bactericidal and virucidal activity of currently
available spermicidal products, new topical microbicides and inactive ingredients
(carrier formulation without active ingredient) 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, below.

SPECIAL INSTRUCTIONS FOR INCLUSION OF WOMEN AND MINORITIES IN CLINICAL  RESEARCH
STUDY POPULATIONS

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 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.

NIH POLICY AND GUIDELINES ON THE 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:

http://grants.nih.gov/grants/guide/notice-files/not98-024.html

Investigators may obtain copies from these sources or from Dr. Hitchcock (listed
in INQUIRIES below) who may also provide additional relevant information
concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by June 1, 1998, a letter of intent
that includes a descriptive title of the overall proposed research program and
the name, address and telephone number of the Principal Investigator, the names
of other participating individuals and institutions, and the number and title of
this RFA.  The letter of intent 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. Madonna at the address listed under
INQUIRIES.

APPLICATION PROCEDURES

Applications are to be submitted on the standard research grant application form
PHS 398 (rev. 5/95).  Application kits are available at most institutional
offices of sponsored research and may be obtained from the Division of Extramural
Outreach and Information, National Institutes of Health, 6701 Rockledge Drive,
MSC 7910, Bethesda, MD 20892-7910, telephone (301) 435-0714, email:
asknih@od.nih.gov.

For purposes of identification and processing, item 2 on the face page of the
application must be marked "YES" and the RFA number AI-98-011 and the words
"RESEARCH ON TOPICAL MICROBICIDES FOR PREVENTION OF STDS/HIV" must be typed in.

Applicants for Program Project Grants must follow special application guidelines
in the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT
AWARDS (September 1997); this brochure is available via the WWW at:
http://www.niaid.nih.gov/ncn/grants/multibron.htm

Applications must be received by October 15, 1998.  Applications that are not
received as a single package on the receipt date or that do not conform to the
instructions contained in PHS 398 (rev. 5/95) Application Kit (as modified in,
and superseded by, the NIAID BROCHURE ENTITLED "INSTRUCTIONS FOR APPLICATIONS FOR
MULTI-PROJECT AWARDS"), will be judged non-responsive and will be returned to the
applicant.  The RFA label available in the application form PHS 398 must be
affixed to the bottom of the face page.  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.

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 application.

It is highly recommended that the appropriate NIAID program contact be consulted
before submitting the letter of intent and during the early stages of preparation
of the application.  (See program contact under INQUIRIES).

Submit a signed, typewritten original of the application, including the
checklist, and three signed, exact, single-sided 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)

At the time of submission, two additional exact copies of the grant application
and all five sets of any appendix material must be sent to Dr. Madonna at the
address listed under INQUIRIES.

Concurrent submission of an R01 and a Component Project of a Multi-project
Application:  Current NIH policy permits a component research project of a multi-
project grant application to be concurrently submitted as a traditional
individual research project (R01) application.  If, following review, both the
multi-project application and the R01 application are found to be in the fundable
range, the investigator must relinquish the R01 and will not have the option to
withdraw from the multi-project grant.  This is an NIH policy intended to
preserve the scientific integrity of a multi-project grant, which may be
seriously compromised if a strong component project(s) is removed from the
program.

Investigators wishing to participate in a multi-project grant must be aware of
this policy before making a commitment to the Principal Investigator and awarding
institution.

REVIEW CONSIDERATIONS

Review Procedures

Upon receipt, applications will be reviewed for completeness by the NIH Center
for Scientific Review and for responsiveness by NIAID staff.  Incomplete and/or
non-responsive applications will be returned to the applicant without further
consideration.

Applications that are complete and responsive to the RFA will be evaluated for
scientific and technical merit by an appropriate peer review group convened by
the NIAID in accordance with the review criteria stated below.  As part of the
initial merit review, a process may be used by the initial review group in which
applications will be determined to be competitive or non-competitive based on
their scientific merit relative to other applications received in response to the
RFA.  Applications judged to be competitive will be discussed and be assigned a
priority score.  Applications determined to be non-competitive will be withdrawn
from further consideration and the Principal Investigator and the official
signing for the applicant organization will be notified.  The second level of
review will be provided by the National Advisory Allergy and Infectious Diseases
Council.

Review Criteria

The general criteria for P01 grant applications are presented in the NIAID
brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS
(September 1997).

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; adequacy of
plans for including children as appropriate for the scientific goals of the
research; the provisions for the protection of human and animal subjects; and the
safety of the research environment.

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 availability of
funds.  Program balance takes into account pathogen(s) proposed for study

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 NIAID brochure "INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT
AWARDS" 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-24
Bethesda, MD  20892
Telephone:  (301) 402-0443
FAX:  (301) 402-1456
Email:  ph22k@nih.gov

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

Dr. Gary Madonna
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4C21
Bethesda, MD  20892-7610
Telephone:  (301) 496-2550
FAX:  (301) 402-2638
Email:  gm12w@nih.gov

Direct inquiries regarding fiscal matters to:

Laura C. Eisenman
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4C26
Bethesda, MD  20892-7610
Telephone:  (301) 402-5541
FAX:  (301) 480-3780
Email:  le550@nih.gov

Schedule

Letter of Intent Receipt Date:  June 1, 1998
Application Receipt Date:       October 15, 1998
Scientific Review Date:         February 1999
Advisory Council Date:          May 1999
Earliest Date of Award:         September 1999

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 Citation is (Sec. 93.856, Microbiology and Infectious Diseases
Research, or No. 93.855 - Immunology, Allergy, and Transplantation Research, or
both, as appropriate).  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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