Subject: RFA AI-91-06 2/l/9l NIH Guide
From: Dot Baker <[email-masked]>
To: [email-masked]
Date: Thu, 31 Jan 91 09:14 EST

Hi Paul,
   Another one.  Please post to the listserver as:
      RFAAI-91-06.910101
  Thanks.  Dottie
 ---------------------------- Text of forwarded message -----------------------
 
REQUEST FOR APPLICATIONS
 
HIV IN MOTHERS AND INFANTS:  IMMUNITY AND EARLY DIAGNOSIS
 
RFA:  AI-91-06
 
P.T. 34; K.W. 0715008, 0775020, 0403020, 0710070
 
National Institute of Allergy and Infectious Diseases
 
Letter of Intent Receipt Date:  March 15, 1991
Application Receipt Date:  May 7, 1991
 
PURPOSE:  The National Institute of Allergy and Infectious
Diseases (NIAID) invites applications for individual
research project (RO1) grants to investigate the role of the
immune system in preventing perinatal transmission of the
Human Immunodeficiency Virus (HIV) and to develop novel
methods of diagnosis of HIV infection in infants prior to
eight weeks of age.  HIV-1 is recognized as the causative
agent of the Acquired Immunodeficiency Syndrome (AIDS).  HIV-
infected women and children born to HIV-infected mothers are
now the fastest growing populations of AIDS patients.
Approximately 20-35% of children born to mothers infected
with HIV-1 become infected either in utero or at birth.
Immune mechanisms may prevent transmission of HIV-1 from
mother to infant; therefore, immunotherapy could potentially
benefit the mother clinically and protect her child.  More
definitive information about the potential role of specific
immune responses in preventing or altering the rate of
perinatal transmission of HIV is needed to design effective
intervention strategies.  There is also an urgent need for
research focused on improved methods for detection of
perinatally acquired HIV infection during gestation and
during the newborn period.  In addition, methods that can be
used to establish the timing and frequency of perinatal
infection are needed.
 
Research efforts considered responsive to this RFA are to:
(i) determine if there are immune responses in mothers that
are protective for their infants, including assessment of
humoral and cell-mediated immunity and viral parameters;
and (ii) define humoral and cell-mediated immunity to HIV-1
in infected and uninfected infants.  These studies should be
aimed at one or more of the following long-term goals:  (a)
the design of a vaccine to interrupt transmission by
inducing protective immunity in mother and/or infants; (b)
design of a strategy to interrupt perinatal transmission of
HIV using passively transferred antisera or monoclonal
antibodies; (c) the identification of sensitive methods to
detect HIV infection during gestation and/or in newborns up
to eight weeks of age; (d) determination of the timing,
frequency, and mechanism of perinatally acquired HIV
infection.
 
Applications that involve collaborating scientists or
institutions are encouraged, but not required, for response to
this announcement.  However, access to a relevant patient
sample collection that is sufficient to allow evaluation of
hypotheses must be demonstrated.  These samples must include
the relevant clinical and laboratory data regarding HIV
infection and immune status in the mother and infant.
Hence, collaboration with prospective epidemiologic studies
of pregnant women and infants is especially desirable.
Research plans that would use funds from these grants to
support the actual conduct of clinical trials will be judged
nonresponsive, but plans for immunologic and virologic
assessment of samples from women and infants enrolled in
epidemiology or therapy trials that are supported by other
funds are encouraged.
 
I.    BACKGROUND
 
The NIAID plays a central role in organizing and funding
immunologic investigations of AIDS.  The Vaccine Research
and Development Branch, Division of AIDS (DAIDS), has undertaken a
leading role in organizing scientists into National
Cooperative Vaccine Development Groups (NCVDG-AIDS) for the
development of new vaccine candidates and AIDS Vaccine
Evaluation Units (AVEU) for clinical trials of vaccine
candidates.  The Epidemiology Branch, DAIDS, supports
research directed on the natural history of perinatally
acquired HIV infection and pediatric AIDS.  Studies on the
development and use of drug therapy for HIV are supported
through the Developmental Therapeutics Branch and the
Treatment Program, DAIDS.  The NIAID also supports
individual research investigations in vaccine development as
well as the epidemiology and immunopathology of AIDS.
 
The AIDS epidemic is rapidly expanding to include women and
children.  Women now represent 12% of AIDS cases in the
U.S., and it is presently estimated that 14% of HIV-infected
individuals are women, of whom the majority (about 80%) are
of child-bearing age.  Of these, approximately 6000 bear
children each year, and about 1200-2100 of these infants
will be infected with HIV.  In many other countries the
prevalence of AIDS in women and children is much higher than
in the United States.  Among children born to HIV-infected
women, however, a fraction estimated between 65 and 80% have
no evidence of infection.  It is not known what factors
either protect a fetus or newborn infant or predispose it to
infection.
 
The time and method of viral infection of the fetus/newborn
have not been established.  Preliminary studies of abortuses
suggest that a significant number of fetuses may be infected
as early as the end of the first trimester.  On the other
hand, most newborn infants, who eventually are found to be
infected, seem clinically and immunologically normal at
birth and HIV cannot be isolated from them.  This suggests
intrapartum exposure or postnatal activation of an infection
acquired during gestation.  Cases of infection by HIV after
Caesarean section have been reported (although exposure of
mucous membranes to blood during delivery may have
occurred).  Cases of transmission via breast milk have also
been reported; in these cases, the mother was infected post-
partum by transfusion.  Exchange of blood prior to birth or
at birth between mother and infant has been documented and
maternal lymphocytes can be found before or after birth in
many children.
 
Although diagnosis of HIV infection can now be made in most
infants within six months, the lack of reliable methods to
diagnose infection at birth and during the first few months
of life has hampered efforts to apply existing treatments
and to design new and more effective strategies to prevent
and treat perinatally acquired HIV infection.  Thus there is
an urgent need for improved immunologic, virologic, and/or
molecular biologic methods to diagnose congenitally acquired
HIV infection.  There is also a need for new methods that
to establish the timing and frequency of
perinatal transmission from an infected mother to her
offspring.
 
In summary, there is evidence that some fetuses are infected
in the first or second trimester.  However, the majority of
infected infants appear to be healthy at birth, and 65-80%
of all infants seem to escape infection altogether.  It is
unknown if free virus can cross the placenta, but infected
maternal blood cells can be found postpartum in the
circulation of some infants.  Infection may also occur by
mucosal exposure to maternal secretions and blood during
birth.  Transmission of HIV by breast feeding has been
documented after mothers have become infected peripartum.
 
To date, trials of immune-based therapy have been designed to
treat HIV-infected adults.  Preclinical studies to
investigate the unique aspects of treating pregnant women
who are HIV-positive, with the dual goals of benefiting the
mother and preventing transmission of HIV to her child, are
also being considered.  Treatment of infants is complicated
by the fact that approximately 20-35% of children born to
HIV-positive mothers are infected with HIV, whereas about
65-80% remain uninfected (or protected).  The rational
design of clinical trials of AIDS therapies in HIV-positive
pregnant women and their infants requires a basic
understanding of the correlates of immunity and the
potential benefit or harm that may be caused by immune
responses directed against HIV or its gene products.
Therefore, the NIAID plans to expand the current scope of
research into the immune correlates of protection of infants
from perinatal transmission of HIV infection.
 
Little is known about the immune responses that might affect
perinatal transmission.  Four studies have suggested a
correlation between the presence of certain maternal
antibodies and a reduced risk of infection in the infants
(Broliden et al., AIDS, 3:577, 1989; Rossi et al, Proc.
Natl. Acad. Sci. USA, 86:8055, 1989; Goedert et al., Lancet,
ii, 1352, 1989; Devash et al. Proc. Natl. Acad. Sci.
87:3445, 1990).  In each study, the antibody measured was
directed against gp120 envelope protein:  high titer anti-
gp120 antibodies against conserved portions of the V3
hypervariable loop of gp120, and high-affinity/avidity
antibodies against the principle neutralizing domain (PND)
of the V3 hypervariable loop have been identified as
potential correlates of protection.  Reports of correlation
of transmission with the stage of the mother's illness or
viral burden of the mother have been inconclusive.  Maternal
antibody may protect the fetus by reducing the quantity of
infectious virus in the maternal circulation and/or by
passive transfer of protective antibody to the fetus during
the last three to four months of pregnancy.  One of the
reports suggested an increased incidence of HIV infection in
premature infants (who may have lower levels of passively-
acquired maternal antibody).  So far, no information is
available to assess the ability of antibodies from an
individual mother to neutralize or react with the virus
variant transmitted to her own infant.
 
A preliminary report has described cytotoxic cells in the
blood of newborn infants of seropositive women that kill
HIV-infected cells (Cheynier et  al., 6th Int. Conf. AIDS,
Abst. F.A. 73, 2:108).  Also, lymphoproliferative responses
to HIV antigens have been reported to be more common in
infants of infected mothers than in infants of uninfected
mothers (Borkowsky, W. AIDS Res. Human Retroviruses 6:673,
1990).  These studies suggest that an infant may protect
itself via an active cell-mediated immune response.  Cell-
mediated immune suppression of viral replication by other
than cytotoxic mechanisms has been reported, but this
phenomenon has not yet been investigated in newborn infants
of seropositive mothers.  Likewise, there is limited
information regarding the innate susceptibility of infants'
lymphocytes or monocytes to infection by HIV.
 
II.  OBJECTIVES AND SCOPE
 
Transmission of the AIDS virus to infants occurs in about
20-35% of children born of HIV-1 infected mothers.  Recent
studies suggest that protective immunity may, in some
mothers, prevent viral transmission to the infant.  In
addition, preliminary data suggest that there may be cell-
mediated immunity against HIV in infants of infected
mothers. There is a pressing need to determine if an immune
response on the part of either mother or infant can protect
the infant from intrauterine or perinatal infection and/or
predict which babies will be infected.  Maternal immunity
might protect the infant by reducing the quantities of
infectious virus, by altering the transport of virus across
the placenta, or a resistant state might be created in the
fetus or infant.  (Alternatively, immune mechanisms might, in
certain circumstances, facilitate the transfer of HIV-1 to
the fetus or promote infection of the fetus.)   Applications
are invited that seek to develop innovative techniques for
diagnosis prior to eight weeks of age and/or to determine
the factors that influence perinatal transmission in order
to design potential vaccines and immune-based therapy of
infected mothers and/or their infants.  Approaches to this
question may include, but are not limited to, the following:
 
A.     Mother:  Identify the correlates of immunity in
       pregnant women that appear to be protective for their
       infants, particularly in relationship to the quantity
       and quality of virus infecting the mother.
 
       1.   Humoral immunity:  Define the specificity for
            viral subunits and epitopes of antibodies in
            HIV-1 seropositive women that correlate with
            non-transmission of HIV-1 to infants.  Define
            other characteristics, such as isotype and
            avidity of antibodies, that may contribute to
            their biological activity.
 
       2.   Cell-mediated immunity:  Determine if cellular
            immunity in infected mothers is correlated with
            non-transmission of HIV-1; and, if so, identify
            the effector cells responsible for the
            immunity, their specific targets, and potential
            mechanisms of action.
 
B.     Compare immune reactions to HIV-1 of infected and
       uninfected infants (less than eight weeks of age)
       born of HIV-infected mothers, including, but not
       limited to:
 
       1.   Humoral Immunity:  specificity, isotype,
            avidity, source, and biologic activities (such
            as cytotoxicity, neutralization, or arming of
            infant effector cells for ADCC).
 
       2.   Cell-mediated immunity:  inhibition of viral
            replication by effector cells or molecules,
            destruction of virus-infected cells by natural
            killer cells, cytotoxic T lymphocytes or
            effector cells for antibody-dependent cell-
            mediated cytotoxicity that may be "armed" with
            maternal anti-HIV-1 antibodies.  If such immune
            mechanisms are identified, it will be essential
            to define their specificity for viral subunits
            and epitopes.
 
       3.   Identification and assessment of maternally
            derived cells in infants in order to determine
            if transplacental passage of infected cells
            contributes to the transmission of HIV
            infection in the presence of a potentially
            protective immune response in the mother.
 
C.     To develop and evaluate novel methods for early
       diagnosis during gestation and in infants less than
       eight weeks of age by means including, but not limited
       to:
 
       1.   Development and evaluation of reliable and
            practical immunologic, virologic, and/or
            molecular-biological techniques for diagnosis
            of HIV infection in infants during the first
            eight weeks of life;
 
       2.   Development of safe and reliable methods for
            prenatal diagnosis of HIV infection; and
 
       3.   Design and implementation of studies to
            determine the timing and frequency of HIV
            transmission from mother to offspring during
            gestation and the intrapartum period.
 
Research should focus on the relationship of the maternal
immune response to viral strains prevalent in the population
and/or actually present in the pregnant woman.  Research
designed to find out if infants harbor immunological
"escape" variants, i.e., viruses that are not susceptible to
inhibition, neutralization, or elimination by maternally
derived antibodies, will be considered responsive to this
RFA.  Emphasis should be on a search for immune responses
that are not easily evaded by variation in the sequence of
viral proteins, e.g., responses that neutralize, inhibit, or
destroy viruses of many different strains.
 
Collaborations between scientists and/or institutions are
encouraged but not required for response to this
announcement.  Access to a patient population and, if
appropriate, a pre-existing sample collection that is
sufficient to allow evaluation of hypotheses must be
demonstrated.  For proposals focused on serological studies,
access to a pre-existing sample collection, including viral
isolates, where relevant, must be demonstrated.  For studies
of cell-mediated immunity, a limited budget for sample
preparation will be allowed, but access to an appropriate
cohort for sample collection must be demonstrated.
Collaborations with well-designed and executed prospective
epidemiologic and clinical studies can be expected to
provide well characterized clinical specimens. The use of
funds from these grants to support the actual conduct of
clinical trials will not be allowed, but plans are
encouraged for immunologic and virologic assessment of
samples from women and infants enrolled in epidemiology or
therapy trials, provided that the trials are supported by
other funds.
 
SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF
NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN
CLINICAL RESEARCH STUDY POPULATIONS
 
The following is the NIH and ADAMHA policy regarding the
inclusion of women and minorities in study populations.
Applications that are responsive to this RFA will, by definition,
meet the requirement for inclusion of women.  The inclusion of
minorities must be addressed in application submitted responding
to this RFA.
 
NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical
research grants and cooperative agreements will be 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
should 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 should 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 should be addressed in
developing a research design and sample size appropriate for the
scientific objectives of the study.  This information should be
included in the form PHS 398 in Section 2, A-D of the Research
Plan AND summarized in Section 2, E, Human Subjects.
Applicants/offerors 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 includes 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.
 
For foreign awards, the policy on inclusion of women applies
fully; since the definition of minority differs in other
countries, the applicant must discuss the relevance of research
involving foreign population groups to the United States'
populations, including minorities.
 
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 award grants or cooperative agreements that do not comply
with these policies.
 
III.  MECHANISM OF SUPPORT
 
This RFA will use the R01 mechanism.  The NIAID has allocated
$3,000,000 (total costs) for the initial year of funding
applications received in response to this RFA, with the
relative level of support between epidemiologic and
immunologic studies to be determined by Program Staff.  The
number of awards to be made is dependent upon receipt of a
sufficient number of applications of high scientific merit
and upon the availability of funds.   The earliest possible
award date is September 27, 1991.  If NIAID determines
that there is a sufficient continuing program need, this RFA
will be reissued.
 
IV.  MINIMUM REQUIREMENTS FOR APPLICATION
 
Any domestic or foreign institution, university, medical
college, hospital, laboratory, or other public, private, or
for-profit institution is eligible.  Applications may
request up to four years of support.
 
V.  LETTER OF INTENT
 
Prospective applicants are asked to submit by March 15,
1991, a letter of intent that includes a descriptive title
and a description (not to exceed one page) of the proposed
research.  The letter of intent is requested in order to
provide an indication of the number and scope of
applications to be reviewed.
The letter of intent
is not binding, nor is
it a requirement for submission of an application.  The
letter of intent should be sent to:
 
Patricia E. Fast, M.D., Ph.D.
Vaccine Research and Development Branch
Division of AIDS, NIAID
6003 Executive Blvd., Room 203E
Bethesda, MD  20892
FAX:  (301) 480-5703
 
VI.  CONSEQUENCES OF LACK OF RESPONSIVENESS TO THE RFA
 
Applications that are judged to be incomplete for review or
nonresponsive to this RFA will be removed from consideration
by NIH staff upon receipt and returned to the applicants.
Because applications that do not address areas of program
relevance will also be considered nonresponsive, potential
applicants are strongly encouraged to discuss their research
plans with program staff before completing their
applications.
 
VII.  REVIEW METHOD AND PEER REVIEW CRITERIA
 
Those applications that are complete and responsive may be
subjected to a triage by a peer review group to determine
their scientific merit relative to the other applications
received in response to this RFA.  The NIH will withdraw
from competition those applications judged by triage to be
noncompetitive and notify the applicant and institutional
business official.
 
Those applications judged to be competitive will be further
reviewed for scientific and technical merit by an initial
review group convened by the Division of Research Grants,
NIH.  The second level of review will be provided by the
National Advisory Allergy and Infectious Disease Council at
its September 1991 meeting.
 
Awards will be based on scientific and technical
significance, originality, adequacy of research experience,
commitment, and time availability of the Principal
Investigator and other key personnel, adequacy of
facilities, and reasonable cost.
 
VIII.  METHOD OF APPLYING
 
A.  Receipt Date:
 
The deadline for receipt of applications is May 7, 1991.
Applications received after this date will be considered
not responsive to this RFA and will be returned without
review.
 
B.  General
 
1.  The research grant application form PHS-
398 (rev. 10/88) must be used in applying.  These
forms are available at most institutional business
offices and from the Division of Research Grants,
National Institutes of Health, 9000 Rockville Pike,
Westwood Building, Room 449,
Bethesda, Maryland  20892.
 
Submit a signed, typewritten original of the application,
including the Checklist, and twenty-three (23) signed,
exact, single-sided photocopies, in one package to:
 
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**
 
2.  TO ASSURE THE IDENTIFICATION OF YOUR APPLICATION
WITH THIS RFA:
 
a.  The application form should have "HIV IN MOTHERS
AND INFANTS: IMMUNITY AND EARLY DIAGNOSIS (RFA AI-91-
06)" typed on line 2 of the face page of the
application.
 
b.  The RFA label provided with the instructions must
be affixed to the bottom of the face page.  Failure
to use this label could result in delayed processing
of your application so that it may not reach the
Review Committee in time for review.
 
IX.  INQUIRIES
 
Additional clarification regarding applications related to
immunity to HIV infection may be obtained from:
 
Patricia E. Fast, M.D., Ph.D.
Vaccine Research and Development Branch, DAIDS, NIAID
6003 Executive Blvd., Room 203E
Bethesda, MD  20892
Telephone:  (301) 496-8200
FAX:      (301) 480-5703
 
Additional clarification regarding applications related to
early diagnosis may be obtained from:
 
Rodney Hoff, D.Sc., M.P.H.
Epidemiology Branch, DAIDS, NIAID
6003 Executive Blvd., Room 241P
Bethesda,  MD 20892
Telephone:  (301) 496-6177
FAX:      (301) 402-1506
 
This program is described in the Catalog of Federal Domestic
Assistance, 93.856 - Microbiology and Infectious Diseases
Research and 93.855 - Allergy, Immunology and
Transplantation Research.  Grants are awarded under the
authority of the Public Health Service Act, Title IV,
Section 301 as amended, Public Law 78-410; Public Law 97-
219; Public Law 99-158; Public Law 99-500; and Report 99-711
to accompany HR 5233 and administered under PHS grant
policies and Federal Regulations 42 CFR 52 and 45 CFR Part
74.  This program is not subject to the intergovernmental
review requirements of Executive Order 12372 or Health
Systems Agency review.