Full Text AI-93-016

AID/NIAID PROGRAM:  FUNDAMENTAL MALARIA VACCINE STUDIES

NIH GUIDE, Volume 22, Number 27, July 30, 1993

RFA:  AI-93-016

P.T. 34

Keywords: 
  Vaccine 
  0715151 


National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  September 1, 1993
Application Receipt Date:  November 10, 1993

PURPOSE

This initiative seeks to expand basic and clinical research on those
aspects of malaria immunology and pathogenesis most relevant to vaccine
candidate identification, characterization, and development.  For many
years both the United States Agency for International Development (AID)
and the National Institute of Allergy and Infectious Diseases (NIAID)
have independently supported fundamental studies of malaria immunology
in recognition that such studies serve as the scientific foundation for
malaria vaccine development efforts.  This initiative, which focusses
on basic research investigations on the role of malaria antigens in
potential protection of individuals from malaria infection or disease,
represents a new collaborative program between these two government
agencies to foster accelerated development of effective malaria
vaccines.  Studies of human immune responses to malaria, studies in
relevant animal models, and studies of the cellular and molecular basis
of immunity are all of interest under this initiative.  The ultimate
goal of this program is to develop vaccines that will reduce
malaria-associated morbidity and mortality, especially in children in
endemic areas.

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), AID/NIAID Program:  Fundamental Malaria Vaccine
Studies, is related to the priority area of immunization and infectious
diseases.  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 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit and non-profit
organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State or local governments, and
eligible agencies of the Federal government.  Applications from
minority individuals and women are encouraged.  Foreign institutions
are not eligible to submit applications.

MECHANISM OF SUPPORT

Support for this program will be through the Cooperative Agreement
(U01), which is an interactive assistance relationship of ongoing
collaboration between NIAID staff and the investigators.  The nature of
NIAID program involvement is further described under Terms of Award;
Awardee Rights and Responsibilities; Nature of Participation of NIAID
Staff.  The awardee will be responsible for the planning, direction and
execution of the proposed project and interrelated activities.  The
award will be administered under PHS grants policy as stated in the
Public Health Service Grants Policy Statement, DHHS Publication No.
(OASH) 90-50,000, revised October 1, 1990.  The total project period
for applications submitted in response to this RFA may not exceed three
years.  The earliest possible award date is September 1, 1994.

Reissuance of this RFA is uncertain at the present time.  If, by the
end of the second year of the award, AID's continued support of the
AID/NIAID Joint Program is unclear and NIAID has therefore not
announced its intent to reissue the RFA, incumbents of U01s should
contact program staff before preparing a recompeting application to
seek advice on the most appropriate method of application submission.

FUNDS AVAILABLE

The estimated level of support (total direct and indirect costs) for
the entire program for the first year is $800,000.  The NIAID
anticipates making four awards.

RESEARCH OBJECTIVES

Background

As recently described in the Institute of Medicine (IOM) Report,
Malaria:  Obstacles and Opportunities, the outlook for malaria control
is grim.  Today 2.1 billion persons worldwide are at risk, and an
estimated 270 million are infected.  Each year, there are more than 100
million clinical cases and one to two million deaths.  The number of
malaria cases worldwide is rising, most notably those due to Plasmodium
falciparum, the parasite species responsible for the most dangerous
form of the disease.  As a result of the rapid emergence of drug
resistance of Plasmodium spp. and the widespread insecticide resistance
of mosquitoes responsible for transmitting the disease, there are now
fewer tools to effectively control malaria than there were even 20
years ago.  Since the current means to effectively control, prevent,
and treat malaria are both inadequate and in jeopardy, the IOM
Committee recommended "sustained support for research to identify
mechanisms and targets of protective immunity and to exploit the use of
novel scientific technologies to construct vaccines that induce
immunity against all relevant stages of the parasite life cycle."

AID has supported malaria research for over 25 years in recognition
that such studies serve as the scientific foundation of vaccine
development efforts, and the current AID Malaria Vaccine Development
Program has a continuing interest in support of fundamental research on
this topic.  The ultimate goal of AID's Malaria Vaccine Program is to
develop vaccines that will reduce malaria-associated morbidity and
mortality, especially in children and pregnant women in less developed
countries.  Likewise, NIAID has a long history of supporting research
efforts on malaria immunology and cell biology.  AID and NIAID have
thus long shared complementary interests in malaria research,
especially in the areas of malaria immunology and vaccine development.
In light of these shared interests, NIAID and AID have worked
cooperatively in the past in efforts aimed at production and clinical
evaluation of candidate vaccines.

This initiative represents a new collaborative effort between the NIAID
and AID's Malaria Vaccine Development Program.  It has been
increasingly recognized that the scientific basis of vaccine
development is extremely complex and requires sustained scientific
support of technical assistance to, and cooperation with, investigators
from the earliest stages of vaccine discovery through the later phases
of vaccine design, production, and testing.

The need for investigators' awareness of, and efficient access to,
current information and resources to accelerate vaccine development is
now widely accepted.  In particular, rapid dissemination of information
and results from all stages of vaccine development among investigators
is necessary to expedite vaccine development.  In appreciation of these
factors and in an effort to overcome those barriers impeding
investigators' progress in this area, AID and NIAID have agreed to form
a new cooperative program dedicated to malaria vaccine development.

Scope of Research

The objective of this RFA is to stimulate innovative new research that
will provide information critical to determining the potential value of
various antigens as components of malaria vaccines.  All applications
should be directly related to development of vaccines against P.
falciparum (this may include studies of rodent models which make use of
analogous plasmodial species).

Basic research projects, including studies of clinical material, are
sought that emphasize investigations of the following:

o  pre-erythrocytic antigens, excluding the circumsporozoite protein
(CSP):  studies of liver-stage antigens are particularly encouraged;

o  blood-stage antigens, excluding the merozoite surface antigen
MSP-1/gp195 and cytoadherence antigens;

o  parasite antigens thought to participate in the pathogenesis of the
severe manifestations of the disease, especially those manifestations
that occur in children (for example, antigens thought to stimulate the
production of cytokines such as tumor necrosis factor).

All applications must clearly describe how the information obtained
from the proposed research will assist in achieving the goal of
reducing malaria-associated mortality and morbidity, especially in
children in endemic areas:  applications not related to the
identification and characterization of potential components of a
vaccine against P. falciparum will be considered non-responsive.

SPECIAL REQUIREMENTS

Awardee Rights and Responsibilities; Nature of Participation of NIAID
Staff

Successful applicants will be invited to participate in the AID/NIAID
Joint Malaria Vaccine Program.  Each Principal Investigator would
represent his/her program at meetings organized jointly by AID and
NIAID.  These meetings, which are expected to take place annually in
the Washington, DC area and to last no more than three days, will be
held to share advances in malaria vaccine research among the
participants of the AID/NIAID Joint Program and other NIAID- and
AID-supported activities, to discuss research needs and opportunities
in malaria vaccine research, and to develop collaborations and
multi-center studies.  Principal Investigators should include funds to
attend these meetings in their budget requests.

Under the Cooperative Agreement, a partnership relationship exists
between the recipient of the award and the NIAID according to the terms
and conditions stated below.  Investigators are expected to define
research objectives and methods in accord with their own interests and
perceptions of novel and exploitable approaches to research that
ultimately are likely to contribute to the accelerated discovery and
development of malaria vaccines.

Terms and Conditions

It is the primary responsibility of each Principal Investigator to
define objectives and approaches, and to plan, conduct, analyze, and
publish results, interpretations, and conclusions of their studies.
The awardee will retain custody of and primary rights to data generated
under this cooperative agreement.  The Government, however, shall
retain rights of access to such data.  Accordingly, the NIAID Program
Officer and the AID Malaria Vaccine Program Officer may periodically
review and generate internal reports from data and progress reports
developed under this cooperative agreement.

Customary NIAID programmatic and stewardship responsibilities will be
assumed by the NIAID Malaria Vaccine Program Officer.  In addition, the
NIAID anticipates substantial scientific and programmatic involvement
during the performance of a Cooperative Agreement.  Awardees will be
offered the opportunity to participate in the full network of AID and
NIAID Programs to support malaria vaccine development, including
vaccine production and testing.  The NIAID Program Officer will serve
as a focal point for input from AID Staff concerning programmatic
objectives and will work closely with the Joint Program investigators.
The role of the NIAID Program Officer, however, will be to facilitate
and not to direct the activities.  During performance of this award,
the NIAID Program Officer, in coordination with the AID Program
Officer, may work with the AID/NIAID Joint Program Principal
Investigators to provide appropriate assistance and advice concerning:

o  the design and planning of research activities;

o  selection of sources or resources, including provision of biological
supplies (e.g., DNA constructs, genetically engineered or recombinant
proteins), or reagent production facilities (e.g., cGMP facilities)
available through NIAID or AID sources;

o  identification, selection, and provision of appropriate clinical
testing facilities;

o  development of collaborative research efforts with principal
investigators supported by other NIAID and AID programs;

o  coordination, collection and/or evaluation of data;

o  technical and management performance of AID/NIAID Joint Program
activities;

o  preparation of publications.

NIAID will support and enhance coordination among the components of the
AID/NIAID Joint Program through:

o  facilitation of information exchange between AID/NIAID Joint Program
PI's, other members of AID's Malaria Vaccine Development Program, and
the NIAID's International Center for Tropical Diseases Research (ICTDR)
network, which includes the International Collaborations in Infectious
Diseases (ICIDR) and Tropical Medicine Research Centers (TMRC) located
in endemic areas, and Tropical Disease Research Units (TDRU), as well
as other investigators and agencies engaged in tropical disease
research;

o  provision of new research reagents and technologies or of other
important resources and information that may not otherwise be available
to the individual AID/NIAID Joint Program Principal Investigators;

In the event that research supported by the Cooperative Agreement
results in development of a prophylactic, therapeutic, or other medical
intervention, the NIAID will retain the option to cross-file or
independently file an application for investigational clinical trial,
i.e., an Investigational New Drug Application (INDA) to the United
States Food and Drug Administration.  Reports of data generated by the
AID/NIAID Joint Program that are required for inclusion in the INDAs
and for cross-filing purposes will be submitted in final draft form by
the Principal Investigator to the NIAID Malaria Vaccine Program Officer
upon request.

Arbitration Panel

It is anticipated that decisions in all activities outlined within this
RFA will be reached by consensus of the Principal Investigators and
that the NIAID Program Officer will be given the opportunity to offer
input during this process.  The manner of reaching this consensus and
the final decision-making authority will rest with the Principal
Investigator.  If any difference of opinion arises, an arbitration
panel, composed of one person designated by NIAID, one person
designated by the Principal Investigator, and a third member selected
by these two, will be established to review any scientific/programmatic
issue that is significantly restricting progress.  This arbitration
process in no way affects the right of an award recipient to appeal
post award administrative decisions in accordance with PHS regulations
at 42 CFR Part 50, Subpart D, and HHS regulations at 45 CFR Part 16.

These special Terms of Award are in addition to, and not in lieu of,
otherwise applicable OMB administrative guidelines, HHS Grant
Administration Regulations at 45 CFR Part 74, and other HHS, PHS, and
NIH grant administration policy statements.  NIH reserves the right to
withhold funds if any of the terms of the award not be implemented.

Applicants must describe plans to accommodate these stated program
requirements, criteria and staff involvement.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements are 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 must 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 must 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 must be addressed in developing a research design
and sample size appropriate for the scientific objectives of the study.
This information must be included in the form PHS 398 (rev. 9/91) in
Sections 1-4 of the Research Plan AND summarized in Section 5, Human
Subjects.  Applicants 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 is defined as 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 studies conducted overseas, 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 research groups to the United States' populations,
including minorities.

If the required information is not contained within the application,
the application will be returned.

Peer review groups need adequate information about the composition of
proposed study populations in all applications involving human
subjects.  To avoid delays in review of such applications, the NIAID
advises that, as a minimum, the application should contain demographic
data about clinic and/or in-patient population from which study
subjects will be drawn:  average hospital admissions per year;
percentage distribution of Black/Hispanic/other minority/non-minority
populations; gender; etc.  Studies using non-hospital populations, such
as community-based studies, should provide similar data about
populations in the area or region from which the study subjects will be
drawn.  In the absence of current data, historical demographic
information and/or previous recruitment data for similar studies from
the proposed study sites should be provided.

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 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.

LETTER OF INTENT

Prospective applicants are asked to submit, by September 1, 1993, a
letter of intent that includes a descriptive title of the proposed
research, the names and affiliations of proposed key investigators, and
the number and title of the RFA in response to which the application
may be submitted.  The letter of intent is requested in order to
provide an indication of the number and scope of applications to be
reviewed.  This does not commit the sender to submit an application,
nor is it a requirement for submission of an application.

The letter of intent is to be sent to Dr. Olivia Preble at the address
listed under INQUIRIES.

APPLICATION PROCEDURES

Applications are to be submitted on form PHS 398 (rev. 9/91), the
standard application form for research grants.  Application kits are
available at most institutional offices of sponsored research and may
be obtained from the Office of Grants Information, Division of Research
Grants, National Institutes of Health, Westwood Building, Room 449,
Bethesda, MD 20892, telephone 301/594-7428.  Applicants must adhere to
the format and requirements specified in the PHS 398 application kit.

For purposes of identification and processing, mark "yes" in item 2a on
the face page of the application and type in the RFA number AI-93-016
and the title "AID/NIAID Program:  Fundamental Malaria Vaccine
Studies."  The RFA label available in the form PHS 398 must be affixed
to the bottom of the face page of the original application.  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.

The signed, typewritten original of the application, including the
Checklist, and three exact single-sided copies must be sent to:

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

At the time of submission, two additional copies must be sent to Dr.
Olivia Preble at the address listed under INQUIRIES.

To ensure their review, applications must be received by both the
Division of
Research Grants and Dr. Olivia Preble by November 10, 1993.
Applications not received on the receipt date will be considered
non-responsive and will be returned to the applicant.  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.

REVIEW CONSIDERATIONS

Review Procedures

Applications will be reviewed by DRG staff for completeness and by
NIAID staff to determine administrative and programmatic responsiveness
to this RFA.  Those judged to be incomplete or non-responsive will be
returned to the applicant without review.  Those considered complete
and responsive may be subjected to a triage review by an NIAID peer
review group to determine their scientific merit relative to the other
applications submitted in response to this RFA.  This triage may be
conducted before or during the initial review committee meeting.  The
NIAID will withdraw from competition those applications judged by the
triage peer review group to be noncompetitive for award and will so
notify the applicant investigator and the institutional business
official.

Those applications judged to be competitive for award will be reviewed
for scientific and technical merit by a Review Committee convened by
the Division of Extramural Activities, NIAID.  The second level of
review will be provided by the National Advisory Allergy and Infectious
Diseases Council.

Review Criteria

The factors to be considered in scientific review of the application
are:

1.  Scientific merit of research approach, design, and methodology as
well as the potential scientific, technical, or medical significance of
the proposed research.

2.  Research experience and competence of the Principal Investigator(s)
and other staff to conduct the proposed studies.

3.  Adequacy of the time (effort) that the Principal Investigator(s)
and staff would devote to the proposed studies.

4.  Adequacy of facilities, including, if relevant to the proposed
research, adequacy of the clinical facilities and patient availability
for clinical studies.

AWARD CRITERIA

In selecting applications for funding, while scientific merit is of
primary consideration, applications will also be evaluated for program
relevance and program balance.

INQUIRIES

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:

B. Fenton Hall, M.D., Ph.D.
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
Solar Building, Room 3A-36
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-7115
FAX:  (301) 402-0804
E-mail:  [email protected]

Address the letter of intent and direct any questions regarding review
procedures to:

Olivia Preble, Ph.D.
Microbiology and Immunology Review Section
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C-20
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-8208
FAX:  (301) 402-2638

Direct inquiries regarding fiscal matters to:

Mr. Todd Ball
Grants Management Branch
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B-35
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-7075
FAX:  (301) 480-3780

Schedule

Letter of Intent Receipt Date:  September 1, 1993
Application Receipt Date:       November 10, 1993
Scientific Review Date:         March 1994
Council Meeting Date:           June 1994
Earliest Award Date:            September 1, 1994

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance
No. 93.856, Microbiology and Infectious Disease Research.  Awards are
made under authorization 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 review.

.

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