Full Text AI-95-004


NIH GUIDE, Volume 23, Number 40, November 18, 1994

RFA:  AI-95-004

P.T. 34

  Immune System 
  Prenatal Factors 

National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  January 15, 1995
Application Receipt Date:  March 15, 1995


The National Institute of Allergy and Infectious Diseases (NIAID) of
the National Institutes of Health (NIH) invites applications for
basic studies on maternal immunization that will lead to passive,
protective immunization of infants against infectious pathogens.  The
applications should present plans for altering the structure of
antibody molecules, either by methods of protein chemistry or
manipulation of antibody-encoding genes, that will (a) improve the
efficiency with which antibody molecules are transported into the
fetus via the placenta and/or into the newborn via breast milk; (b)
prolong the metabolic half-lives of antibodies, both in mother and
infant; and/or (c) improve the efficacy of antibodies to protect the
infant from pathogenic microorganisms.  Applications that deal with
antibodies against known, critical antigens (those likely to elicit
protective antibodies) of infant pathogens, or propose to identify
such antigens, are of particular interest.


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), Maternal Antibodies for Passive Infant
Immunization, is related to the priority areas of family planning,
educational and community-based programs, maternal and infant health,
HIV infection, sexually transmitted diseases, immunization and
infectious diseases and clinical prevention services.  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).


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 or
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.  Racial/ethnic
minority individuals, women, and persons with disabilities are
encouraged to apply as Principal Investigators.


The mechanisms of support will be the individual research project
grant (R01) and the FIRST (R29) award.  The total project period for
applications submitted in response to this RFA may not exceed five
years; foreign applications may not request more than three years of
support.  Responsibility for the planning, direction, and execution
of the proposed project will be solely that of the applicant.

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


The estimated funds available for the total (direct and indirect)
first-year costs of all awards made under this RFA will be $500,000.
In Fiscal Year 1995, the NIAID plans to fund approximately three
R01/R29s.  The NIH is currently limiting annual inflationary
increases to no more than four percent for future years of awards.
The usual PHS policies governing grants administration and management
will apply.  This level of support is dependent on the receipt of a
sufficient number of applications of high scientific merit.  Although
this program is provided for in the financial plans of the NIAID,
awards pursuant to this RFA are contingent upon the availability of
funds for this purpose.  Funding beyond the first and subsequent
years of the grant will be contingent upon satisfactory progress
during the preceding years and availability of funds.

The National Institute of Child Health and Human Development (NICHD)
is also interested in research concerned with protective immunization
in infants.  Applications that are of mutual interest may be given
secondary assignment to the NICHD in accordance with Division of
Research Grants (DRG) referral guidelines.



Maternal immunization to elicit antibodies that can be transported to
the fetus, and/or to the newborn via colostrum and breast milk, is an
approach that has been utilized for years to prevent tetanus in
infants, particularly in developing nations.  Research performed in
the 1950s and 1960s showed that maternal-to-fetal transfer of
antibodies occurs in a variety of common domestic and laboratory
animals, the exact route of transport varying with the type of
placenta, the nature of the embryonic membranes and other factors.
It was found that transplacental transport varies with the class of
immunoglobulin, molecules of class IgG being most efficiently
transported.  In the case of colostrum immunoglobulins of classes IgA
and IgG predominate.  In recent years, there has been little
additional research concerned with maternal-infant transfer of
immunoglobulins except for a few studies on Fc receptors on cells of
the trophoblast.  Fc receptors involved in transport of
immunologlobulins across gut epithelium of the infant have attracted
attention recently.

At the present time, NIAID supports research concerned with natural
transfer of antibodies from mother to fetus and newborn, in
particular: (1) maternal to fetal transfer of antibodies of different
isotypes that are elicited by conjugated and unconjugated vaccines of
Hemophilus influenzae type b, unconjugated pneumococcal
polysaccharide vaccines, and group B streptococcal vaccines; and (2)
transfer of antibodies in colostrum following maternal immunization
with a subunit of respiratory syncytial virus.  However, more
attention is needed on methods of enhancing the efficiency of
maternal-fetal and maternal-neonatal transfer of antibodies,
prolonging the persistence of antibody molecules in both maternal and
newborn circulation, and enhancing the efficacy of antibodies that
enter the infant.  In short, up-to-date approaches and methods of
molecular and cellular immunology, along with progress in identifying
and engineering key antigenic components of organisms responsible for
infections in infants, are necessary to ensure that maternal
immunization will result in protection of the newborn from

Research Objectives and Scope

The objective of this RFA is to support basic research (in animal or
human subjects) that will lead to procedures for active or passive
maternal immunization to endow mothers with antibodies that:  (a)
persist in the maternal circulation, (b) are transported efficiently
to the fetus and/or infant via the placenta and breast milk, and (c)
provide strong protection against infection with microorganisms that
are pathogenic in infants.  Support will be provided for the
development and pre-clinical testing of modified antibody molecules
suitable for:  (a) injection into pregnant women and efficient
transfer across the placenta and into the fetus, (b) injection into
lactating females and efficient transport into colostrum and thus
into the newborn, and (c) oral administration to newborns and infants
and efficient transport across intestinal epithelium and into the
circulation.  NOTE:  Studies focused on the Human Immunodeficiency
Virus (HIV) and its sequelae are NOT within the scope of this RFA.

Progress in this area will require the application of modern
molecular biology.  Presumably, the combining sites of the antibody
or antibody-like molecules should be derived from authentic human
antibodies.  Alternatively, combining sites of monoclonal murine
antibodies that are minimally immunogenic in humans might be
satisfactory.  An example of a worthwhile approach might be the
construction and expression of a gene that would encode single-chain
molecules having:  (a) Fv segments of heavy and light Ig chains, of
the same or different epitope specificities at either end; (b) a
linker segment consisting of an epitope of the key microbial antigen,
or an analog of an adhesion molecule that would prevent attachment of
antibody-coated microorganisms to epithelial cells.  Such a molecule
would require further refinement to, at least, ensure its efficiency
of secretion or transplacental transfer and its non-immunogenicity.

The ultimate objective of the research to be supported under this RFA
is to obtain the knowledge needed to be able to prepare antibodies
that are specific for key antigens of microbial pathogens and have
the following properties:

o  are secreted into colostrum and breast milk and/or traverse the
placenta with high efficiency;

o  possess combining sites of optimum affinity;

o  are microbicidal, prohibit growth of target microorganisms or
interfere with their attachments (adherence) to host epithelial

o  bear idiotopes (or introduced epitopes) that mimic one or more
epitopes of the critical microbial antigen;

o  have prolonged metabolic half-lives both in the maternal and fetal
or neonatal environment;

o  are, themselves, non-antigenic in humans; and

o  produce no harmful side-effects either in the pregnant or
lactating female or in the fetus or newborn.


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 has been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513), and reprinted
in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume
23, Number 11.

Investigators may obtain copies from these sources or from the
program staff or contact person listed below.  Program staff may also
provide additional relevant information concerning the policy.


Prospective applicants are asked to submit, by January 15, 1995, 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 NIH staff to estimate the potential review workload
and to avoid conflict of interest in the review.  The letter of
intent is to be sent to Dr. Olivia Preble at the address listed under


Applications are to be submitted on the standard research grant
application form PHS 398 (rev. 09/91).  These application forms may
be obtained from the institution's office for sponsored research or
its equivalent, or from the Grants Information Office, Division of
Research Grants, National Institutes of Health, 5333 Westbard Avenue,
Room 449, Bethesda, Maryland 20892, telephone (301) 710-0267.  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
typed in.

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
contacts in INQUIRIES below.)  Applications that do not conform to
the instructions contained in PHS 398 (rev. 09/91) application kit,
will be judged nonresponsive 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)
award applications must include at least three sealed letters of
reference attached to the face page of the original application.
FIRST applications submitted without the required number of reference
letters will be considered incomplete and will be returned without

Applications must be received by March 15, 1994.  Applications
received after the receipt date will be returned without review.  The
Division of Research Grants (DRG) will not accept any application in
response to this RFA that is essentially the same as one currently
pending initial review, unless the applicant withdraws the pending
application.  This does not exclude the submission of substantial
revisions of an application already reviewed.  These applications
must, however, include an introduction addressing the previous

Submit a signed, typewritten original of the application, including
the checklist, and three signed, exact, single-sided photocopies, 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 all five sets of the appendix must also be sent to
Dr. Olivia Preble 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 could be included
with the application.


Upon receipt, applications will be reviewed for completeness by the
NIH Division of Research Grants (DRG) and for responsiveness by NIAID
staff.  Incomplete and 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 (triage) 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 promptly notified.
The second level of review will be provided by the National Advisory
Allergy and Infectious Diseases Council.  Review, Council and award
dates can be found in SCHEDULE, below.

Review Criteria

o  scientific, technical, or medical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;

o  availability of the resources necessary to perform the research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research;

o  adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plans for the recruitment and retention of subjects will also be

The initial review group will also examine the provisions for the
protection of human and animal subjects and the safety of the
research environment.


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.


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

Direct inquiries regarding programmatic issues to:

Joseph F. Albright, Ph.D.
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4A25
6003 Executive Boulevard
Bethesda, MD  20892-7640
Telephone:  (301) 496-1886
FAX:  (301) 402-2571
Email:  JA250@NIH.GOV

Carole A. Heilman, Ph.D.
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
Solar Building, Room 3B06
6003 Executive Boulevard
Bethesda, MD  20892-7630
Telephone:  (301) 496-5305
FAX:  (301) 496-8030
Email:  CH25V@NIH.GOV

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

Olivia T. Preble, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C19
6003 Executive Boulevard
Bethesda, MD  20892-7610
Telephone:  (301) 496-8208
FAX:  (301) 402-2638
Email:  OP2T@NIH.GOV

Direct inquiries regarding fiscal matters to:

Mr. Carl Lucas
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B28
6003 Executive Boulevard
Bethesda, MD  20892-7610
Telephone:  (301) 496-7075
Email:  CL37E@NIH.GOV


Letter of Intent Receipt Date:  January 15, 1995
Application Receipt Date:       March 15, 1995
Scientific Review Date:         June 1995
Advisory Council Date:          September 1995
Earliest Award Date:            September 1995


The NIAID program is described in the Catalog of Federal Domestic
Assistance, No. 93.855 - Immunology, Allergy and Transplantation
Research.  Awards for NIAID will be made under the authority of the
Public Health Service Act, Title IV, Part A, (Public Law 78-410, as
amended by Public Law 99-158, 42 USC 241 and 285) and administered
under PHS grants 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

The Public Health Service (PHS) 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


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