Release Date:  April 3, 1998

PA NUMBER:  PA-98-051


National Institute of Allergy and Infectious Diseases


The Sexually Transmitted Diseases (STD) Branch of the Division of Microbiology
and Infectious Diseases (DMID) of the National Institute of Allergy and
Infectious Diseases (NIAID) invites applications that propose to conduct basic
research on the molecular nature of the human immune response to sexually
transmitted diseases (STDs).  The NIAID wishes to expand research in this area
to develop molecular strategies to prevent infection, transmission, disease and
disease progression by immunization.  Of particular interest is the integration
of the disciplines of immunology and microbiology leading to productive
interdisciplinary approaches that elucidate the basis of protective immunity to
sexually transmitted infections.


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 Program Announcement (PA), Research
on Molecular Immunology of STDs, is related to the priority area of sexually
transmitted diseases.  Potential applicants may obtain a copy of "Healthy People
2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report:  Stock No. 017-
001-10473-1) through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-512-1800).


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.


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



Despite control efforts to prevent spread of STDs, including human
immunodeficiency virus (HIV) infection, both bacterial and viral STDs remain
epidemic in many areas of the United States.  Current estimates predict that in
1997 there will be 14 million new cases of STDs in the U.S.  Related health care
costs are likely to exceed $7 billion.

Although curative therapy is available for some of these acute infections, many
individuals develop serious complications and chronic disease.  Furthermore,
sexually transmitted infections have been implicated in increased risk of HIV
transmission.  Recent studies indicate that the more prevalent non-ulcerative
STDs as well as ulcerative diseases increase the risk of HIV transmission at
least three to five-fold.

Three strategies are central to the prevention and control of STDs:  diagnosis
and treatment; behavioral intervention, and vaccination.  Since each of these
strategies has limitations both in efficacy and implementation, a comprehensive
control program utilizing all three components is necessary.  Vaccines are
strategically important for preventing both viral diseases for which there is no
curative treatment and bacterial diseases for which antibiotic resistance is
common or for which symptoms are so indolent that the patient neither seeks nor
receives effective therapy.  Most desirable are vaccines which prevent infection;
however, vaccines may play a critical role in reducing transmission, ameliorating
disease or interrupting disease progression.

Unfortunately, except for Hepatitis B, there are no vaccines for STDs.  STD
vaccine development is extremely difficult and complex for reasons related
primarily to 1) the nature of the host-pathogen relationship, and 2) the
consequences of co-infection with more than one sexually transmitted pathogen,
i.e., one infection may increase susceptibility to others thereby compromising
vaccine efficacy.  As obligate pathogens of humans, the etiologic agents of these
diseases have evolved to effectively avoid, subvert, or ignore the immunodominant
host response through strategies including:

o  phase variation:  the ability to turn on or off the synthesis of a surface

o  latency/immune evasion:  the ability of viruses (in particular those of the
herpes class) to evade detection and elimination by the host immune system.

o  antigenic variation:  the ability to synthesize a particular antigen from a
large repertoire of antigenic types;

o  surface microheterogeneity:  the ability to vary surface immuno-accessibility
of antigens among organisms within a population, e.g., the sporadic distribution
of the P.I. antigen on gonococci within a single bacterial colony or within
microcolonies in urethral exudate;

o  elicitation of immunodominant responses which are not protective; the ability
to present surface antigens which do not result in protective immunity.  Instead,
the immune response often results in avoidance or subversion of host defenses. 
For example, the generation of blocking antibodies during gonococcal infection,
or the generation of detrimental humoral or as changed cellular responses to heat
shock protein during chlamydial infection.

Furthermore, the presence of multiple infections in the reproductive tract is
likely to complicate vaccine development as pre-existing STDs compromise
epithelial barriers through tissue fragility, induction of inflammatory cytokines
and the recruitment of target cells, such as lymphocytes (in the case of HIV),
thereby lowering the infectious dose and compromising vaccine efficacy.

Research Objectives and Scope

A fundamental objective of the Institute's STD research program is to develop
vaccines effective in preventing and controlling STDs.  This requires focused
interdisciplinary research to create effective molecular level strategies for 
eliciting protective immunity.  "Molecular" is used here in the broadest sense
to mean the interaction between molecules of the pathogen and the host; this is
not limited to molecular genetics.

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

1.  Molecular specificity and function of immune responses

o  What is the function of the immune response to infection?  Does protective
immunity occur as the result of infection?  Since the surface of any given
pathogen is a mosaic of antigens, and any given antigen is a mosaic of epitopes,
it is essential to separate and characterize the specificity of protective and
non-protective humoral and cellular immune responses occurring in sexually
transmitted infections.

2.  Immunity of the reproductive tract

o  How can protective immunity be induced in the reproductive tract?  Given that
protection against infection is absolutely dependent upon functional (i.e.,
protective), neutralizing antibodies at mucosal surfaces, the phenotype
(including isotype), source, and specificity of these antibodies must be
described.  The role of CD4, CD8 and CD16 cells as well as other effector cells
in protective immunity must be elucidated.

o  Can humoral and/or cellular immunity be induced which offers partial
protection i.e., reduces transmission, ameliorates disease or prevents disease

o  What are the kinetic parameters of protective immune responses and how can
protective immunity be enhanced both in terms of efficacy and longevity?  It is
necessary to characterize and compare protective immunity stimulated by direct
inoculation of regional mucosal surfaces, other mucosal surfaces (e.g., oral) and
parenteral routes.  The role of cellular immunity in this process must be

o  What are the differences between the immune responses of the male and female
reproductive tract?  How do reproductive hormones influence infectivity and the
host response to infection?  What is the role of regional immunity in prevention
or manifestation of sexually transmitted infections?  Currently, little is known
about the immunology of the female reproductive tract, and even less is known
about the male reproductive tract.  Does partial immunity play a role in
asymptomatic disease, and if so, can this be correlated with the higher
prevalence of silent infections in women compared to men?

3.  Diseases of interest

Applicants are strongly encouraged to submit research projects which address the
following diseases of high scientific priority to the Institute and to this PA:

o  Chlamydial infection and gonorrhea:  As etiologic agents of PID, development
of vaccines for chlamydial infection and gonorrhea are of the highest priority. 
This urgency is in recognition of the high rates of morbidity and the significant
socio-economic costs associated with pelvic inflammatory disease (PID).  Special
emphasis is placed on chlamydial infections because they are often silent in
women and chlamydial PID more often results in tubal scarring and related

o  Human papillomavirus infection:  The development of vaccines for the
relatively limited number of sexually transmitted HPV types associated with
progression to serious disease, (e.g., types 16, 18, 31, and 33), is a priority
because of the widespread prevalence and marked increase of HPV-related disease
in the last decade.

o  Syphilis:  Of all the STDs, syphilis should be one of the easiest to control
because the cases are clustered, and good diagnostic tests as well as effective
treatments are available.  However, the epidemic of the eighties underscores the
need to develop effective vaccines and behavioral interventions.  The
epidemiology of syphilis suggests that protective immunity does occur, although,
the specific mechanisms are unknown.  Furthermore, there is evidence to suggest
that the immune system also plays a significant role in the pathogenesis of
syphilis; additional research must be conducted to delineate the role of the
immune response in this disease.

o  Genital Herpes:  Human studies involving several different herpes vaccines
suggest that it may be possible to ameliorate disease frequency and severity
through vaccination.  Special emphasis should be placed on delineating the role
of the immune system in preventing primary infection, preventing the
establishment of latency, and preventing transmission to neonates.

o  Trichomoniasis:  Recent studies have implicated this pathogen as a cause of
adverse pregnancy outcomes, specifically premature rupture of membranes.  Results
of studies in the naturally occurring animal infections suggest that prevention
of infection and amelioration of disease might be achieved through vaccination.

o  HIV is not a pathogen of interest under this PA, although study of the natural
history of STDs in an HIV-positive population is responsive if the emphasis is
on the role of the altered immune system on the course of the STD(s) under


The immune response in women and in men is of interest.  Women are important both
because of the gaps in our understandings of the female reproductive tract and
because of the disproportionate burden of STD morbidity (e.g., infertility,
ectopic pregnancy, cervical cancer, fetal wastage, low birth weight, and
congenital/perinatal infection) that is borne by women and their perinatally
infected children.  For men, arguably little is known about the immunology of the
male reproductive tract or about the chronic sequelae of STDs in men (e.g.
importance in infertility, role in chronic prostatitis).

Additionally, STDs greatly impact the health of minority populations and youth
in the United States.  Both the incidence of STDs and the incidence of their
long-term and potentially fatal sequelae are consistently higher among African
and Hispanic Americans than among white Americans.  Moreover, numerous
epidemiological studies have documented high prevalence of STDs and STD sequelae
in youth -- of the projected 10 to 13 million cases of STDs occurring this year,
63 percent are expected to occur in people younger than 25 years old.  For these
reasons, applicants are strongly encouraged to study STDs in populations that are
at greatest risk; these populations include women, men, minorities living in
inner cities or rural areas, adolescents and infants.


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 program staff
listed under INQUIRIES.  Program staff may also provide additional relevant
information concerning the policy.


Applications are to be submitted on the grant application for PHS 398 (rev. 5/95)
and will be accepted on the standard application 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:

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:

BETHESDA, MD 20892-7710
BETHESDA, MD 20817-7710 (for express/courier service)

Applicants from institutions that have a General Clinical Research Centers (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


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 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.

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

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
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


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 program announcement, and availability of


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:

Dr. Jill Horowitz
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 3A23
Bethesda, MD  20892-7640
Telephone:  (301) 402-0443
FAX:  (301) 402-1456

Direct inquiries regarding fiscal matters to:

Todd Ball
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4B35
Bethesda, MD  20892-7610
Telephone:  (301) 402-5512
FAX:  (301) 480-3780


This program is supported under authorization of the Public Health Service Act,
Sec. 301, as amended.  The Catalogue of Federal Domestic Assistance Citation is
No. 93.856 - Microbiology and Infectious Disease 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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