Full Text AI-94-029

PEDIATRIC AIDS:  FACTORS IN TRANSMISSION AND PATHOGENESIS

NIH GUIDE, Volume 23, Number 32, August 26, 1994

RFA:  AI-94-029

P.T. 34, AA

Keywords: 
  AIDS 
  Pathogenesis 


National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  November 15, 1994
Application Receipt Date:  February 16, 1995

PURPOSE

The Division of AIDS (DAIDS) of the National Institute of Allergy and
Infectious Diseases (NIAID) invites applications for research designed
to study transmission and pathogenesis of HIV-1 in infants and
children.  Applications are sought for laboratory studies that
elucidate:  (1) the timing and mechanism of transmission of HIV from
mother to infant or (2) factors that determine whether infected
children become long-term asymptomatic survivors or suffer from rapidly
progressive disease.  The NIAID seeks applications for research studies
that utilize advances in virology, immunology, and genetics to address
these questions.  Of special interest are those basic research studies
that hold promise for development of clinical strategies to prevent
mother-to-infant transmission of HIV-1 or to treat perinatally infected
children to prolong and improve the quality of their lives.  For
applications proposing use of clinical specimens, documented access to
an adequate number of samples to address the study hypotheses will be
required.

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), Pediatric AIDS:  Factors in Transmission and
Pathogenesis is related to the priority areas of: HIV infection,
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 "Healthy People 2000" (Summary
Report:  Stock No. 017-001-00473-1) through the  Superintendent of
Documents, Government Printing Office, Washington, DC 20402-9325
(telephone 202-782-3238).

ELIGIBILITY REQUIREMENTS

Research grant applications may be submitted by domestic and foreign,
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 institutions are not eligible to apply for
First Independent Research Support and Transition (FIRST) (R29) Awards.
Applications from minority individuals and women are encouraged.

MECHANISM OF SUPPORT

The mechanisms of support will be the individual research project grant
(R01) and the FIRST (R29) award.  Multidisciplinary approaches that
involve collaborative efforts among investigators in the fields of
basic immunology, molecular biology, genetics, virology, and infectious
disease are strongly encouraged.  The total project period for an
application submitted in response to this RFA may not exceed five
years.

This RFA is a one-time solicitation for applications for new and
competing renewal awards.  Future competing renewal applications will
compete with all investigator-initiated applications and will be
reviewed according to customary referral and review procedures.

FUNDS AVAILABLE

The estimated total funds (direct and indirect costs) available for the
first year of support for all awards made under this RFA will be
$2,000,000.  In Fiscal Year 1995, the NIAID plans to fund approximately
12 R01s/R29s.  This level of support is dependent on the receipt of a
sufficient number of applications of high scientific merit.
Applications may not request more than four percent annual inflationary
increases for future years.  The usual PHS policies governing grants
administration and management will apply.  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

Mother to infant transmission of HIV continues to be one of the fastest
growing aspects in the worldwide pandemic of AIDS.  The World Health
Organization has estimated that over 10 million children worldwide will
be infected by the year 2000.  In the United States, the Centers for
Disease Control and Prevention estimate that 10,000 children are
currently infected with HIV, and approximately 6000 infants are born
annually to HIV-infected women in the U.S.  The recent success in the
AIDS Clinical Trials Group (ACTG) protocol 076 suggests that prevention
strategies in the perinatal period may be highly efficient at
decreasing mother to infant HIV-1 transmission.  The ACTG 076 study
indicated that women with greater than 200 CD4 cells x 106 /cc3 who
initiate treatment with zidovudine (ZDV) during pregnancy can prevent
transmission of HIV to their infants in about two-thirds of the cases.
However, this study did not address the effectiveness of ZDV in women
with less than 200 CD4 counts or who may be infected with ZDV-resistant
variants.  Unfortunately, other studies have indicated that women with
lower CD4 counts may have an even higher likelihood of transmitting HIV
to their infants.  The recently initiated trial (ACTG 185) comparing
HIV Immune Globulin (HIVIG) with IVIG placebo, both combined with ZDV,
will include women with a wider range of CD4 counts and prior
anti-retroviral therapy, but results of that trial will not be
available for four to five years.

In 1991, the NIAID funded a series of grants focused on two areas of
basic research in Pediatric AIDS -- early diagnosis of HIV infection
and studies to investigate factors involved in mother to infant
transmission of HIV.  These grants focused primarily on immunological
and virological factors influencing mother to infant transmission and
have led to many of the concepts about the mode and timing of perinatal
HIV transmission.  The objectives of this RFA are:  to encourage
coordinated basic research on the immunology, host genetics, and
virology associated with perinatal HIV-1 transmission, its timing and
mode, and to identify factors that appear to delay progressive
manifestations of pediatric HIV-1 infection.

Scope of Research Sought in this RFA

The NIAID wishes to support continued research in Pediatric AIDS in the
following targeted areas.

o  Studies attempting to define the timing of perinatal transmission
relative to HIV-1 viral load and disease progression.

o  Coordinated studies of immunological, virological and host genetic
factors that might influence perinatal HIV-1 transmission.

o  Studies that evaluate viral pathogenesis with a specific focus on
infection of cell subsets in fetuses, neonates and young infants.

o  Studies that investigate oral or mucosal surfaces either as the
exposure route for infants or as a source of perinatal infection by
AIDS viruses.

o  Studies that evaluate the immunology, physiology, genetics and
virology of children with long-term survival of HIV infection.

These are examples of appropriate studies; other studies addressing
risk for or timing of transmission of HIV-1 from mother to infant, or
disease progression in the infant may be proposed.

Advances in quantitative HIV culture techniques, polymerase chain
reaction (PCR) detection of HIV, detection of immune
complex-dissociated HIV-1 p24 antigen, and detection of HIV- specific
IgA have enabled clinical research teams to rapidly and accurately
identify HIV-infected children within the first several months of life.
It now appears that, in the absence of breastfeeding, about half of the
infants infected with HIV at or before birth can be identified at the
time of birth, whereas HIV is not detected in the remaining children
until one to twelve weeks after birth.  These and other findings have
suggested that there may be at least two modes of perinatal HIV
infection and that the timing of infection (in utero versus
intrapartum) may greatly affect viral load and disease progression in
the infant.  Stratification of data based on the time of initial
detection of HIV-1 may be useful in studies of perinatal or postnatal
(breastfeeding) infection.

Several other issues regarding perinatal HIV transmission and pediatric
AIDS have received only limited attention.  Although early detection of
HIV infection is possible, information about immunological and
virological factors that influence perinatal transmission is still
fragmentary and studies that have coordinately evaluated both
immunological factors and viral factors are limited in scope.  Although
it is widely believed that genetic factors may play a role in
susceptibility to or severity of HIV infection, only a few studies have
evaluated genetic factors related to perinatal HIV transmission along
with either virological or immunological parameters.  Thus, studies of
the host (mother and child) genetics and immune responses coordinated
with HIV virology will be considered responsive to this RFA.

Fetuses, neonates, and young infants may become infected by entry of
the virus into their blood (across the placenta) or by exposure of
mucosal surfaces to HIV-infected blood, cervical secretions, or milk.
Certain viral characteristics may facilitate infection of infants by
one or both of these routes.  Non-syncytium inducing (NSI) variants of
HIV that can replicate well in macrophages and monocytes appear to be
the predominant type of HIV that has been obtained from infants in
several small studies.  Macrophage-tropic and/or cytopathic HIV
variants might have a selective advantage in transmission, pathogenesis
or evasion of immune defenses.  Studies that address these topics with
respect to perinatal infection will be considered responsive to this
RFA.

Some recent data suggest that intrapartum transmission of HIV may occur
by the oral/mucosal route.  Studies that coordinate virological and
immunological studies of mucosal surfaces in HIV-infected infants
and/or women during different stages of pregnancy are of utmost
importance to resolve issues of intrapartum transmission.  Studies to
evaluate the specificity, function and timing of pediatric IgA
responses to HIV might shed light on the route and mode of exposure in
infants that become infected with HIV.  Highly focused animal studies
to address oral transmission and potential intervention strategies will
be considered responsive to this RFA.

Finally, a number of children that have become infected with HIV have
led disease-free lives for more that seven years with relatively little
impact upon their CD4 cell number, immune system or health.
Intensified studies on immunology, physiology, genetics and virology in
these children might shed light on the factors that allow successful
control of HIV infection and progression to AIDS.

Clinical samples, if required, may be drawn from clinical trials or
ongoing natural history studies.  This solicitation is not intended for
direct conduct of clinical trials, patient care, or maintenance of
natural history cohorts.  Availability of adequate numbers of clinical
samples or animal resources to address the study hypotheses MUST BE
documented in the application.

STUDY POPULATIONS

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results from
the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43)
and supersedes and strengthens the previous policies (Concerning the
Inclusion of Women in Study Populations, and Concerning the Inclusion
of Minorities in Study Populations) which have been in effect since
1990.  The new policy contains some new provisions that are
substantially different from the 1990 policies.  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 as a separate Part VIII
in the Federal Register of March 28, 1994 (59 FR 14508-14513).  This
was also reprinted in the NIH GUIDE FOR GRANTS AND CONTRACTS of March
18, 1994, Vol. 23, No. 11.

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

Note:  Studies of mother-to-infant transmission may, by their nature,
include women but not men as study subjects.  The gender of their
infants will be unknown to the investigator in studies beginning during
pregnancy.  If the population of HIV-infected women available for study
is limited to, or primarily composed of, one racial or ethnic group,
investigators should explain the circumstances in the application and
address potential ways to overcome this limitation.

LETTER OF INTENT

Prospective applicants are asked to submit, by November 15, 1994, a
letter of intent that includes a descriptive title of the overall
proposed research, the name, address and telephone number of the
Principal Investigator, and the number and title of this RFA.  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. Dianne Tingley at the address listed under INQUIRIES.

APPLICATION PROCEDURES

Applications are to be submitted on the standard research grant
application form PHS 398 (rev. 9/91).  For purposes of identification
and processing, item 2a on the face page of the application must be
marked "YES" and the RFA number and the words "PEDIATRIC AIDS: FACTORS
IN TRANSMISSION & PATHOGENESIS" must be typed in.

Application forms may be obtained from the institution's office for
sponsored research or its equivalent and from the Office of Grants
Information, Division of Research Grants, National Institutes of
Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892, telephone
(301) 710-0267.

It is highly recommended that the Program Officers in the Vaccine
Research and Development Branch be contacted in the early stages of
preparation of the application.  (See program contact in INQUIRIES
below.)

Applications must be received by February 16, 1995.  Applications that
are not received by the receipt date or that do not conform to the
instructions contained in PHS 398 (rev. 09/91) application kit, 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.  FIRST (R29) applications must
include at least three sealed letters of reference attached to the face
page of the original application.  FIRST (R29) applications submitted
without the required number of reference letters will be considered
incomplete and will be returned 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 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.

Submit a signed, typewritten original of the application including the
checklist, three signed, exact, single-sided photocopies, and one copy
of any appendix material, in one package to:

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

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

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 should be included with the
application.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by DRG and
for responsiveness to the RFA by NIAID staff.  Incomplete applications
will be returned to the applicant without further consideration.  If
NIAID staff find that the application is not responsive to the RFA, it
will be returned without further consideration.

Applications that are complete and responsive to this RFA will be
evaluated for scientific and technical merit by an appropriate peer
review group convened by the NIAID.  As part of the initial merit
review, a process (triage) may be used by the initial review group in
which the applications will be determined to be competitive or
non-competitive based on their scientific merit relative to other
applications received in response to this 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/program director
and the official signing for the applicant organization will be
promptly notified.

The factors to be considered in the evaluation of scientific merit of
each application will be those used in the review of traditional
research project grant applications, including:  the novelty,
originality, and feasibility of the approach; the training, experience,
and research competence of the investigator(s); the adequacy of the
experimental design; and the adequacy and suitability of the
facilities. The initial review group will also be instructed to provide
an assessment of the extent to which the proposed research that might
advance the fields of research specifically targeted by this RFA.

While the following review factors do not usually influence the
priority score, they are nonetheless carefully considered by the
initial review group:  the appropriateness of the requested budget to
the work proposed; the adequacy of protection of human subjects and/or
animals in research; and the adherence, whenever appropriate, to NIH
guidelines concerning adequate representation of women and minorities
in clinical research.  Any documented concerns expressed by the initial
review group about any of these factors on a given application may
influence the recommendation of the Advisory Council concerning funding
of that application.

AWARD CRITERIA

Funding decisions will be made on the basis of scientific and technical
merit as determined by peer review, program priorities, and the
availability of funds.

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.
Potential applicants are welcome to seek clarification of any issues or
questions.

Direct inquiries regarding programmatic issues to:

Bonnie J. Mathieson, Ph.D. or Patricia E. Fast, M.D., Ph.D.
Division of AIDS
National Institute of Allergy and Infectious Diseases
Solar Building, Room 2B06
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-8200
FAX:  (301) 402-1506 or (301) 480-5703

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

Dianne Tingley, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C16
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-0818
FAX:  (301) 402-2638

Direct inquiries regarding fiscal matters to:

Ms. Carol Alderson
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B27
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-7075
FAX:  (301) 480-3780

Schedule

Letter of Intent Receipt Date:   November 15, 1994
Application Receipt Date:        February 16, 1995
Scientific Review Date:          June/July 1995
Advisory Council Date:           September 1995
Earliest Award Date:             September 1995

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance, No. 93.856 Microbiology and Infectious Diseases Research
and 93.855 Immunology, Allergy and Transplantation 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.

The Public Health Service strongly encourages all grant recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products.  This is consistent with the PHS mission to protect and
advance the physical and mental health of the American people.

.

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