Full Text AI-97-002
 
HUMAN IMMUNE RESISTANCE TO MALARIA IN ENDEMIC AREAS
 
NIH Guide, Volume 26, Number 27, August 15, 1997
 
RFA:  AI-97-002
 
P.T.


Keywords: 

 
National Institute of Allergy and Infectious Diseases
 
Letter of Intent Receipt Date:  August 20, 1997
Application Receipt Date:  October 28, 1997
 
APPLICATIONS IN RESPONSE TO THIS RFA MUST BE PREPARED USING A
MODIFIED (ABBREVIATED) GRANT APPLICATION FORMAT; SPECIFIC
INSTRUCTIONS FOR COMPLETING THE APPLICATION ARE IN "APPLICATION
PROCEDURES" BELOW.
 
PURPOSE
 
This initiative seeks to expand, through clinical studies conducted
under the cooperative agreement mechanism (U01), the understanding of
immunity to Plasmodium falciparum or P. vivax in humans.  Naturally
acquired or vaccine-elicited protective immunity may involve multiple
mechanisms, including cellular and humoral components, that target
different antigens from different parasite lifecycle stages, and that
may act in concert.  A number of immunologic assays exist for such
mechanisms.  Rapid, simple assays (e.g., ELISA, IFA, etc.) may
indicate prevalence, level and specificity of a particular immune
response, but to date have not proven predictive of immune
protection.  Functional assays (e.g., in vitro reduction in parasite
numbers or growth) provide an indication of biological activity;
none of these, however, has been rigorously evaluated as a surrogate
marker of protective immunity in defined, clinical populations (e.g.,
in longitudinal or case-control studies).   The availability of
reliable immunologic correlates of protection would facilitate
preclinical and clinical evaluation of candidate vaccine antigens and
substantially accelerate the vaccine development process.
 
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 RFA,
"Human Immune Resistance to Malaria in Endemic Areas" is related to
the priority areas of immunization and infectious diseases.
Potential applicants may obtain a copy of "Healthy People 2000" (Full
Report:  Stock No. 017-001-00474-0 or Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-0325 (telephone 202-512-1800).
ELIGIBILITY REQUIREMENTS
 
Applications may be submitted by domestic 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.
Because of the scope of research to be performed, it is expected that
foreign institutions will be active participants in the conduct of
research supported through awards made under this RFA; foreign
institutions, however, are not eligible to submit independent
applications directly.  Racial/ethnic minority individuals, women,
and persons with disabilities are encouraged to apply as Principal
Investigators.
 
MECHANISM OF SUPPORT
 
The administrative and funding mechanism to be used to undertake this
program will be the Cooperative Agreement (U01), an "assistance"
mechanism, rather than an "acquisition" mechanism, in which
substantial NIH scientific and/or programmatic involvement with the
awardee is anticipated during the performance of the activity.  Under
the cooperative agreement, the NIH purpose is to support and/or
stimulate the recipient's activity by involvement in and otherwise
working jointly with the award recipient in a partner role, but it is
not to assume direction, prime responsibility, or a dominant role in
the activity.  Details of the responsibilities, relationships, and
governance of a study funded under cooperative agreement(s) are
discussed later in this document under the section Terms and
Conditions of Award.
 
The total requested project period for applications submitted in
response to this RFA may not exceed five years.  At this time, the
NIAID has not determined whether and how this solicitation will be
continued beyond the present RFA.
 
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 million.  In Fiscal Year 1998 the NIAID plans to fund
approximately 3 awards. 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 and the receipt of a sufficient number of applications of
high scientific merit.  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
 
The World Health Organization has estimated that malaria claims the
lives of as many as 3 million people annually, most of these being
children living in sub-Saharan Africa.  There is no question that
vaccines against malaria are desperately needed, especially in light
of the current spread of drug resistant strains of the parasite.
 
Effective immunity to malaria has been observed in humans.  Many
infected individuals who have resided continuously for extended
periods of time in endemic areas eventually exhibit few or no
episodes of clinical malaria.  Moreover, although it is not
logistically feasible for widespread use, vaccination with
radiation-attenuated, infective sporozoite stage parasites has been
repeatedly shown to protect humans from subsequent experimental
challenge infection. Over the past decade, however, many candidate
malaria subunit vaccines that have proven effective in animal models
have failed to reproducibly elicit substantial protection in human
trials.
 
As recommended in the Institute of Medicine Report, Malaria:
Obstacles and Opportunities (1991), further vaccine research would
benefit from identification of the underlying mechanisms of human
antimalarial immunity.  According to Dr. J.H.L. Playfair in Malaria -
Waiting for the Vaccine (1991), "It is unfortunately as true today as
ten years ago that we do not fully understand the mechanism(s) by
which immunity leads to protection against any stage of malaria.  One
consequence of this is that there is no reliable in vitro test that
would predict a successful outcome in any vaccine trial." In a follow
up report from the Institute of Medicine, Vaccines Against Malaria:
Hope in a Gathering Storm (1996), it was noted there are still no
reliable, validated in vitro correlates of protection, and as
described by Miller and colleagues ("The Need for Assays Predictive
of Protection in Development of  Malaria Bloodstage Vaccines,"
Parasitology Today, 1997), the need for such predictors is just as
great today.  This initiative therefore takes as its underlying
premise the idea that correlates of protective immunity in malaria
should be sought in humans, and that controlled clinical studies are
warranted to establish such correlates.
 
Historically, approaches that have defined mechanisms of acquired
resistance in humans have contributed substantively to the
development of synthetic vaccines for hepatitis B and a variety of
encapsulated bacteria (e.g, Streptococcus pneumoniae, Neisseria
meningitidis, and Haemophilus influenzae type B).  Because of the
geographic diversity and heterogeneous epidemiology of malaria,
however, it will be necessary to validate correlates observed in one
site as being relevant in other malaria endemic sites.  As correlates
are identified, NIAID Program Staff will work with investigators to
facilitate such multisite collaborations.  Although studies in animal
models are not within the purview of and will not be funded under
this RFA, NIAID Program Staff will work with investigators to set up
collaborations and access to capabilities that will facilitate
development of in vitro or animal models to allow screening for
induction of these protective responses.  Establishment of such
models should ease subsequent assessment of the protective potential
of malaria vaccine formulations.  Thus, this approach should not only
contribute to characterization of the mechanism(s) of protective
immunity, but also facilitate selection and prioritization of
recombinant candidate vaccines for malaria and lay important
foundations for future field testing of such vaccines.
 
Research Objectives and Scope
 
The objective of this initiative is to establish a core understanding
of the protective immune response to Plasmodium falciparum and
Plasmodium vivax in humans in endemic areas. Protective immunity may
be acquired either as a result of naturally occurring exposure to P.
falciparum or P. vivax or as a demonstrated result in future clinical
trials of candidate malaria vaccines.   In addition, it may be
possible to obtain insights into immune-mediated protection through
studies of patient populations participating in trials of other
interventions in malaria (e.g., bed net studies, nutritional
supplementation, drug efficacy studies).  Applicants are encouraged
either to undertake new clinical studies or enter into collaborations
with other investigators already involved in ongoing interventional
trials or clinical studies.  It is anticipated that these studies
will be carried out largely through collaborative arrangements or
subcontracts with one or more foreign investigators, institutions and
government agencies located in endemic areas.
 
Relevant research includes, but is not limited to, the following:
 
o Identification and correlation of humoral and cellular immune
responses associated with demonstrable resistance in human subjects
in endemic areas; such resistance may be reflected in reduced
infection, disease, or transmission
 
o Identification and correlation of humoral and cellular immune
responses associated with demonstrated differences in resistance of
trial participants in endemic areas to reinfection following
chemotherapy or other non-immunologic intervention; such resistance
may be reflected in reduced infection, disease, or transmission
 
o Identification, correlation and demonstration (validation) of
immunologic parameters associated with naturally acquired or
vaccine-elicited resistance in human subjects in endemic areas:  such
parameters might include recognition of specific antigen,
immunoregulatory genetic factors, production of certain cytokines,
elicitation of specific lymphocyte subpopulations or non-specific
immunologic effector mechanisms (e.g., iron binding proteins, nitric
oxide)
 
o Development of rapid, field applicable assays for such correlates
 
o Validation of demonstrated correlates of immunologic acquired
resistance in more than one endemic site through collaboration and
replicate studies
 
The areas outlined above are not intended to be all-inclusive.
 
TERMS AND CONDITIONS OF AWARD
 
The following terms and conditions will be incorporated into the
award statement and provided to the Principal Investigator as well as
the institutional official at the time of award.
 
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 92, and other HAS,
PHS, and NIH Grant Administration policy statements.
 
The administrative and funding instrument used for this program is
the cooperative agreement (U01), an "assistance"  mechanism rather
than an "acquisition" mechanism, in which substantial NIH scientific
and/or programmatic involvement with the awardee is anticipated
during the performance of the activity.  Under the cooperative
agreement, the NIH purpose is to support and/or stimulate the
recipient's activity by involvement in and otherwise working jointly
with the award recipient in a partner role, but it is not to assume
direction, prime responsibility, or a dominant role in the activity.
Consistent with this concept, the dominant role and prime
responsibility for the activity resides with the awardees for the
project as a whole, although specific tasks and activities in
carrying out the research will be shared among the awardees and the
NIAID Scientific Coordinator.
 
A.  Awardee Rights and Responsibilities
 
Awardees will have primary responsibility for defining the research
objectives, approaches and details of the studies within the
guidelines of the RFA and for performing the scientific activity.
Specifically, awardees have primary responsibility as described
below:
 
 1.  Research design and protocol development, including definition
of objectives and approaches, planning, implementation, participant
recruitment and follow-up, data collection, quality control, interim
data and safety monitoring, final data analysis and interpretation,
and publication of results.
 
2.  Establishing a mandatory Steering Committee composed of the
Principal Investigator, Project Directors for subcontracts, and the
NIAID Scientific Coordinator to coordinate and manage prospective
studies.  Following notification of award, awardee(s) will name in a
timely manner investigators to serve as members of the Steering
Committee which will meet periodically.
 
3.  Designating Study Protocol Chairs.  The Principal Investigator
shall designate a single Protocol Chairperson (if the P.I. does not
assume this role) for each proposed study protocol within the
research plan.  The Protocol Chairperson shall function as the
scientific coordinator for the proposed protocol and shall assume
responsibility for developing the proposed protocol and monitoring
study performance for the final, implemented protocol.  All proposed
protocols and modifications will be submitted by the Protocol
Chairperson to the Steering Committee for approval.
 
4.  Implementing the core data collection strategy and methods
collectively decided upon by the Steering Committee.  For each study
involving multiple institutions, it is the responsibility of each
awardee/site to ensure that data will be collected and submitted in a
timely way following such procedures as established by the Steering
Committee.  Additionally, individual investigators/sites must
demonstrate the ability to implement the strategy specifically
designed for their individual study population.
 
5.  Establishing mechanisms for quality control and monitoring.
Awardees are responsible for ensuring the accurate and timely
assessment of the progress of the study, including development of
procedures to ensure that data collection and management are:  (a)
adequate for quality control and analysis; (b) for clinical trials,
as simple as appropriate in order to encourage maximum participation
of clinicians and other providers and study subjects and to avoid
unnecessary expense; and (c) sufficiently staffed across the
participating institutions.  For studies involving multiple sites
(subcontractors), strategies for the analyses of pooled data will be
developed by the Steering Committee.
 
6.  Preparing and submitting interim progress reports, when
requested, to the NIAID Program Officer including, as a minimum,
summary data on protocol performance.  For a multi-site award, the
Steering Committee may require additional information from the
individual awardees/sites.  Such reports are in addition to the
annual awardee noncompeting continuation progress reports.
 
7.  Establishing procedures, where applicable, for all participating
institutions to comply with FDA regulations for studies involving
investigational agents or devices and to comply with the requirements
of 45 CFR Part 46 for the protection of human subjects.
 
8.  Cooperating in the reporting of the study findings.  The NIAID
will have access to and may periodically review all data generated
under an award.  Where warranted by appropriate participation, plans
for joint publication with NIAID of pooled data and conclusions, are
to be developed by the Principal Investigator or Steering Committee,
as applicable.  NIH policies governing possible co-authorship of
publications with NIAID staff will apply in all cases.  In general,
to warrant co-authorship, NIAID staff must have contributed to each
of following areas:  (a) design of the experiments or concepts being
tested; (b) performance of significant portions of the activity; and
(c) preparation and authorship of pertinent manuscripts.  The awardee
will retain custody of and have primary rights to the data developed
under these awards, subject to Government right of access consistent
with current HHS, PHS, and NIH policies.
 
B.  NIAID Staff Responsibilities
 
NIAID staff assistance will be provided by the Host Immunity Program
Officer, Parasitology and International Programs Branch, DMID/NIAID,
who will serve as NIAID's Scientific Coordinator.  The NIAID
Scientific Coordinator will have substantial scientific/programmatic
involvement during the conduct of this activity through technical
assistance, advice and coordination above and beyond normal program
stewardship for grants, as described below.
 
It is expected that the dominant role and prime responsibility for
the activity will reside with the awardee(s) for the project as a
whole.  However, specific tasks and activities will be shared among
the awardee(s) and the NIAID Program Officer.  The NIAID Program
Officer will be the contact for all facets of the scientific
interaction with the awardee(s).  As required for the coordination of
activities and to expedite progress, the NIAID Program Officer may
designate additional NIAID staff to provide advice or assistance to
the awardee on specific scientific, technical, or management issues.
The NIAID Program Officer shall retain overall programmatic
responsibility for the award(s) and will clearly specify to the
awardee(s) the name(s) and role(s) of any such additional individuals
and the lines of reporting authority.
 
NIAID Extramural Program staff responsibilities will include:
 
1. NIAID Scientific Coordinator will provide access to and use of,
when appropriate, reagents and assays, and other resources available
through NIAID contractors and awardees. NIAID staff may provide
assistance by suggesting and/or facilitating the selection of sources
or resources, including provision of biological supplies (e.g., DNA
primers, genetically engineered or recombinant proteins).
 
2. NIAID Scientific coordinator will provide assistance and guidance,
when appropriate, in  complying with regulatory guidelines.  For
example, NIAID currently offers, through the Clinical and Regulatory
Affairs Branch, DMID,  guidance on Good Clinical Practice  and
development of  Investigational New Drug Applications for clinical
trials.
 
3. The NIAID Scientific Coordinator will participate in Steering
Committee meetings.
 
4. The NIAID Scientific Coordinator will participate in clinical
study design, management and technical performance so as to ensure
comparability of data obtained with similar efforts being supported
by NIAID and non-NIH partner agencies participating in the
Multilateral Initiative Against Malaria (MIM).
 
5. The NIAID Scientific Coordinator will serve as a liaison with
research efforts being undertaken by non-NIH partner agencies
participating in the MIM.
 
6. For multi-institutional protocols, through participation on the
Steering Committee and with the agreements of the Principal
Investigator(s), the NIAID Scientific Coordinator may coordinate
activities among awardees by assisting in the design, development,
and coordination of a common research or clinical protocol and
statistical evaluations of data; in the preparation of questionnaires
and other data recording forms; and in the publication of results.
 
7. The NIAID Scientific Coordinator will provide information on
opportunities for collaborations, such as:
 
a. Principal Investigators may not have immediate access to the
discoveries stemming from malaria projects supported by other
Government agencies, or from NIAID-supported projects that are not
directly related to malaria but are germane to the overall goals of
the RFA.  For example, NIAID, USAID and the United States Army
Medical Research and Development Command (USAMRDC) have a  Memorandum
of Agreement to cooperate in malaria vaccine development.   NIAID
staff will facilitate the development of cooperation between
Principal Investigators and other Institute, USAID or USAMRDC
supported researchers and contractors in order to develop promising
new leads more rapidly. NIAID's Scientific Coordinator will
facilitate such access by suggesting and encouraging collaboration
with appropriate Principal Investigators.
 
b. NIAID Scientific Coordinator may facilitate access to other
populations and population-based information available through
NIAID-supported researchers in the International Collaborations in
Infectious Disease Research Program (ICIDR) and the Tropical Medicine
Research Centers (TMRC).  These populations and data may prove a
valuable resource to allow investigators to extend studies beyond or
outside those originally proposed.  NIAID staff will suggest and
encourage further collaborations which may profit from access to
ICIDR and TMRC facilities and populations.  Similarly, NIAID staff
will suggest and encourage further collaborations with other special
programs within NIAID, including domestic facilities and
investigators in the Tropical Disease Research Units, the
university-based Cooperating Groups of the International Centers for
Tropical Disease Research, and the Vaccine and Treatment Evaluation
Units.
 
c. Through a number of new international initiatives, including the
Multilateral Initiative in Malaria (MIM), and the US-European Union
(EU) Transatlantic Agenda, and international task forces , e.g., the
US-EU task forces on  biotechnology and emerging diseases,  NIAID
staff are frequently aware of relevant programs supported by other
agencies, and will transmit this information to Principal
Investigators to enable them to take advantage of these opportunities
to strengthen their programs.  NIAID staff currently maintain close
interactions with international agencies such as the World Health
Organization (WHO), the Pan-American Health Organization, the World
Bank, and the United Nations Development Program, and agencies of
other governments, such as International Cooperation with Developing
Countries (INCO-DC)  Program of the Commission of the European
Communities (CEC).
 
C.  Collaborative Responsibilities
 
In addition to the interactions defined above, awardees and NIAID
Scientific Coordinator shall share responsibility for the following
activities:
 
Steering Committee.  A Steering Committee organized by the Principal
Investigator, Project Directors for Subcontracts, and the NIAID
Scientific Coordinator will be the main oversight body of the study.
 
The Steering Committee has primary responsibility to design research
activities, establish priorities, develop common protocols and
manuals, questionnaires and other data recording forms, establish and
maintain quality control among awardees, review progress, monitor
patient/subject accrual, coordinate and standardize data management,
and cooperate on the publication of results.  Major scientific
decisions regarding the core data will be determined by the Steering
Committee.  The Steering Committee will document progress in written
reports to the NIAID Program Officer and will provide periodic
supplementary reports upon NIAID request.
 
The Steering Committee usually will meet at least twice yearly.
 
A Chairperson, other than the NIAID Scientific Coordinator, will be
selected by vote of the members.  The Chairperson is responsible for
coordinating the Committee activities, for preparing meeting agendas,
and for scheduling and chairing meetings.
 
D.  Arbitration
 
Any disagreement that may arise on scientific/programmatic matters
(within the scope of the award) between award recipients and the
NIAID may be brought to arbitration.  An arbitration panel will be
composed of three members -- one selected by the Steering Committee
(with the NIAID member not voting) or by the individual awardee in
the event of an individual disagreement, a second member selected by
the NIAID, and the third member with expertise in the relevant area
and selected by the two prior members will be formed to review any
scientific or programmatic issue that is significantly restricting
progress.  While the decisions of the Arbitration Panel are binding,
these special arbitration procedures will in no way affect the
awardee's right to appeal an adverse action in accordance with PHS
regulations at 42 CFR Part 50, subpart D, and HAS regulations at 45
CFR Part 16.
 
Cooperative agreements are subject to the administrative requirements
outlined in OMB circulars A-102 and A-110.  All pertinent HAS, PHS,
and NIH grant regulations, policies and procedures, with particular
emphasis on PHS regulations at 42 CFR Part 52 and HAS regulations at
45 CFR Part 74, are applicable. These special terms and conditions
pertaining to the scope and nature of the interaction between the
NIAID and the investigators will be incorporated in the Notice of
Grant Award.  However, these terms will be in addition to, not in
lieu of, the customary programmatic and financial negotiations that
occur in the administration of cooperative agreements.
 
STUDY POPULATIONS
 
Populations participating in research supported through awards made
under this RFA must be located in geographic areas with documented,
substantial malaria.
 
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 are
provided that inclusion is inappropriate with respect to the health
of the subjects of the purpose of the research.  This policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43).  All investigators proposing research involving human
subjects should read the "NIH Guidelines for Inclusion of Women and
Minorities as Subjects in Clinical Research", which have been
published in the Federal Register of March 28, 1994 (FR 59
14508-14513) and the NIH Guide for Grants and Contracts, Vol. 23, No.
11, March 18, 1994.
 
For studies involving foreign populations, the NIH policy on
inclusion of women in research conducted outside the U.S. is the same
as that for research conducted in the U.S.  With regard to population
of the foreign country, the definition of minority groups may be
different than in the U.S.  If these is a scientific rationale for
examining subpopulation group differences within the foreign
population, investigators should coniser designing their studies to
accommodate these differences.
 
Investigators may obtain copies from these sources or from Dr. B.F.
Hall (listed in INQUIRIES below) who may also provide additional
relevant information concerning the policy.
 
LETTER OF INTENT
 
Prospective applicants are asked to submit, by August 20, 1997, 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. Madelon Halula at the address listed
under INQUIRIES.
 
APPLICATION PROCEDURES
 
APPLICATIONS IN RESPONSE TO THIS RFA MUST BE PREPARED USING A
MODIFIED (ABBREVIATED) GRANT APPLICATION FORMAT; SPECIFIC
INSTRUCTIONS ARE PRESENTED BELOW.
 
Applications are to be submitted on the grant application form PHS
398 (rev. 5/95).  Applications submitted in response to this RFA may
present their research plan in up to 25 pages.  Application kits are
available at most institutional offices of sponsored research and may
be obtained from the Office of Extramural Outreach and Information,
National Institutes of Health, 6701 Rockledge Drive, MSC 7910,
Bethesda, MD 20892-7910, telephone (301)710-0267, email:
asknih@odrockm1.od.nih.gov.
 
For purposes of identification and processing, item 2a on the face
page of the application must be marked "YES" and the RFA number
"(enter number)" and the words "HUMAN IMMUNE RESISTANCE TO MALARIA IN
ENDEMIC AREAS" must be entered on the face page.
 
Applications must be received by October 28, 1997.  Applications that
are not received as a single package on the receipt date or that do
not conform to the instructions contained in PHS 398 (rev. 5/95)
Application Kit (as modified in, and superseded by, the special
instructions below, for the purposes of this RFA), 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.
 
If the application submitted in response to this RFA is substantially
similar to a grant application already submitted to the NIH for
review, but that 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 that is
essentially identical to one that has already been reviewed cannot be
submitted in response to this RFA .  This does not preclude the
submission of substantial revisions of applications already reviewed,
but such applications must include an introduction addressing the
previous critique.
 
It is highly recommended that the NIAID program contact be consulted
before submitting the letter of intent and during the early stages of
preparation of the application.  (See program contacts under
INQUIRIES).
 
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
6701 Rockledge Drive, Room 1040 - MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express mail or courier service)
 
At the time of submission, two additional exact copies of the grant
application and all five sets of any appendix material must be sent
to Dr. Madelon Halula 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.
 
SPECIAL INSTRUCTIONS FOR COMPLETION OF APPLICATIONS IN RESPONSE TO
THIS RFA
 
A status report on NIH reinvention activities was provided in the NIH
GUIDE (Volume 24, Number 40) of November 24, 1995.  Two of these
activities are:  (1) the use of "Just-in-Time" grant applications;
and (2) modular budget requests and funding.
 
Both "Just-in-Time" and "Modular Budgeting" are to be used for
applications in response to this RFA.
 
JUST-IN-TIME GRANT APPLICATIONS.  The basic principle of
"Just-in-Time" is to simplify and reduce the administrative and
paperwork burdens of preparing an NIH grant application without
compromising the initial review group determination of scientific
merit or reasonableness of the proposed budget.  To that end, the
quantity of information and the amount of detail required is reduced
in "Just-in-Time" applications.
 
MODULAR GRANTS.  Applications are submitted and/or awards made with
direct costs in modules (multiples) of a given amount ($25,000 for
this RFA), with work proposed within these incremental categories.
The model involves using pre-established funding levels for awards
and acknowledging that grantees can and do rebudget post-award.  This
process eliminates the need for many budget details, thereby reducing
administrative burden on both NIH staff and grantee organizations and
simplifying cost management by NIH program staff.
 
RESEARCH PLAN CONTENT AND PAGE LIMIT.
 
Sections a - d of the Research Plan may not exceed 25 pages for each
proposed research study.  It is anticipated that each applicant will
propose one or two multi-site studies.  Additionally, each applicant
shall describe procedures for identifying future collaborative
studies.
 
SPECIFIC INSTRUCTIONS
 
The following are specific instructions for sections of the PHS 398
(rev. 5/95) application form, which are to be completed differently
than usual (that is, in the "Just-in-Time" and "Modular Grant"
format).  Some sections in the application are modified and should
not be completed.  If the application receives a score in the
fundable range, additional information will be requested.  For all
other items in the application, follow the usual instructions on
pages 5-20 of the PHS 398 booklet.
 
Form DD, Page 4.  Do NOT complete this page.
 
Form EE, Page 5.  Budget for Entire Proposed Project Period and
Justification:
 
General:  Budget - Only summary budget information is to be provided;
initial budget period (first year) direct costs must be requested as
a multiple of $25,000. Justification - only minimal information on
personnel (name, role on project, percentage effort, and brief
justification) is requested; only unusual research resources need to
be briefly justified.
 
Budget (top half of page 5):
 
o  Complete the TOTAL DIRECT COST line entries for all requested
budget periods (years) and the TOTAL DIRECT COST FOR ENTIRE PERIOD OF
SUPPORT entry.  Except for Direct and Indirect Consortium/Contractual
Costs, do not provide separate budgets for the individual budget
categories.
 
o  Requested TOTAL DIRECT COSTS for the INITIAL BUDGET PERIOD must be
a multiple of $25,000.  Generally, first year costs should be
increased by four percent annually thereafter.
 
Justification (bottom of page 5 with continuation sheets as
necessary):
 
o  Personnel - list the name, role on project, and percent effort for
all project personnel and provide a brief narrative justification for
each person.
 
o Research Resources - provide a brief narrative justification for
any unusual significant resources included in the budget requested
for this project.
 
o  Additional (future) Year Budgets - for each ADDITIONAL YEARS OF
SUPPORT REQUESTED, briefly justify annual changes that are more than
or less than four percent increases from the preceding year.
 
Form FF - Page 6 - Biographical Sketch:  For all key personnel
provide biographical sketches that do not exceed TWO PAGES and
include the following information:
 
o  Name, Position Title, Education/Training.  Complete these sections
as instructed in the PHS 398 booklet.
 
o  list previous positions directly relevant to this application.
 
o  list selected peer-reviewed publications (with full citation)
directly relevant to this application.
 
o  provide information on ongoing research grants and completed
research projects relevant to this application; list title, principal
investigator, funding source, and role for each project cited.
 
Form GG - Page 7 - Other Support:  Do not complete.  (Any required
information will be requested from successful applicants prior to
grant award.)
 
Form HH - Page 8 - Resources and Environment:  Complete selected
item(s) only if proposed research requires specialized unique
resources for which availability must be documented.
 
Research Plan (Booklet Pages 15-19):  Note:  Items a - d MAY NOT
EXCEED TWENTY FIVE (25) PAGES.  Applications with research plans that
exceed 25 pages will be returned without review.
 
o  Item a - Specific Aims (typically less than one page): List in
priority order the broad, long range objectives of the proposed
project and describe concisely and realistically the hypothesis to be
tested and what the specific research described in this application
is intended to accomplish.
 
o  Item b - Background and Significance (typically one page):  The
background and significance has been established by the NIAID in
setting aside funds for the release of this RFA.  Use this section to
describe how the proposed research will contribute to meeting the
goals and objectives of the RFA and explain the rationale for the
selection of the general methods and approaches proposed to
accomplish the specific aims.
 
o  Items c - d:  Complete as instructed on pages 15-17 of the PHS 398
booklet, noting the reduced page limit stated above.  The following
is general guidance for information to be presented in this section:
 
-  preliminary studies pertinent to the application.
-  rationale for each particular set of experiments.
-  general methods that will be utilized.  Provide specific details
ONLY for those techniques that are unique, or where a significant
departure from a generally accepted technique is important for the
reviewers to know.
-  outcome measures that will be used to assess the success or
failure of each set of experiments.
-  potential pitfalls in the experimental design and alternative
studies that will be done if the proposed experiment(s) fail.
 
o  Items e - f:  Complete as described on pages 17-18 of PHS 398
booklet.
 
o  Item h - Consortium, Contractual Arrangements (one page only):
Provide brief explanation (not to exceed one page) of the scientific,
fiscal, and administrative arrangements made with collaborating
organizations.
 
o  Item I - Consultants/Collaborators:  Biographical sketches should
conform to the brief format described for Form FF (page 6), above.
 
Appendix (PHS 398 Booklet - Page 24)  Complete as instructed.
 
Forms II and JJ - Checklist:  Do not complete.  Information will be
requested by NIAID only from applicants being considered for funding.
 
If you or your business office has any questions regarding these
special instructions, E-mail, call, FAX, or write the NIAID staff at
the addresses listed under INQUIRIES.
 
REVIEW CONSIDERATIONS
 
Upon receipt, applications will be reviewed for completeness and
adherence to the Special Instructions above by the NIH DRG and for
responsiveness by NIAID staff; those judged to be incomplete will be
returned to the applicant without review.  Those considered to be
non-responsive will be returned without review.
 
Those applications that are complete and responsive may be subjected
to a triage by an NIAID peer review group to determine their
scientific merit relative to other applications received in response
to this RFA.  The NIAID will withdraw from competition those
applications judged to be non-competitive for award and will notify
the applicant and institutional business officials.
 
Those applications judged by the reviewers 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 five criteria to be used in the evaluation of grant applications
are listed below.  To put those criteria in context, the following
information is contained in instructions to the peer reviewers.
 
The goals of NIH-supported research are to advance our understanding
of biological systems, improve the control of disease, and enhance
health.  The reviewers will comment on the following aspects of the
application in their written critiques in order to judge the
likelihood that the proposed research will have a substantial impact
on the pursuit of these goals.  Each of these criteria will be
addressed and considered by the reviewers in assigning the overall
score weighting them as appropriate for each application.  Note that
the application does not need to be strong in all categories to be
judged likely to have a major scientific impact and thus deserve a
high priority score.  For example, an investigator may propose to
carry out important work that by its nature is not innovative but is
essential to move a field forward.
 
1.  Significance.  Does this study address an important problem? If
the aims of the application are achieved, how will scientific
knowledge be advanced?  What will be the effect of these studies on
the concepts or methods that drive this field?
 
2.  Approach.  Are the conceptual framework, design, methods, and
analyses adequately developed, well-integrated, and appropriate to
the aims of the project?  Does the applicant acknowledge potential
problem areas and consider alternative tactics?
 
3.  Innovation.  Does the project employ novel concepts, approaches
or method?  Are the aims original and innovative? Does the project
challenge existing paradigms or develop new methodologies or
technologies?
 
4.  Investigator.  Is the investigator appropriately trained and well
suited to carry out this work?  Is the work proposed appropriate to
the experience level of the principal investigator and other
researchers (if any)?
 
5.  Environment.  Does the scientific environment in which the work
will be done contribute to the probability of success?  Do the
proposed experiments take advantage of unique features of the
scientific environment or employ useful collaborative arrangements?
Is there evidence of institutional support?
 
The initial review group will also examine: the appropriateness of
proposed project budget and duration; the adequacy of plans to
include both genders and minorities and their subgroups as
appropriate for the scientific goals of the research and plans for
the recruitment and retention of subjects; the provisions for the
protection of human and animal subjects; and the safety of the
research environment.
 
AWARD CRITERIA
 
Funding decisions will be made on the basis of scientific and
technical merit as determined by peer review, program balance, and
the availability of funds.  In addition, consideration will be given
to geographic distribution.  The earliest anticipated date of award
is August 1998.
 
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 (eligibility and
responsiveness) issues to:
 
Dr. B. F. Hall
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
Solar Building, Room 3A09
6003 Executive Boulevard
Bethesda, MD  20892-7630
Telephone:  (301) 496-2544
FAX:  (301) 402-0659
E-Mail:  BH24Q@NIH.GOV
 
Direct inquiries regarding review issues and special instructions for
application preparation; address the letter of intent to; and mail
two copies of the application and all five sets of appendices to:
 
Madelon Halula, 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) 402-2636
FAX:  (301) 402-2638
E-Mail: mh30x@nih.gov
 
Direct inquiries regarding fiscal matters to:
 
Todd Ball
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B35
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-7075
Fax:  (301) 480-3870
E-mail:  tb22j@nih.gov
 
Schedule
 
Letter of intent receipt date: August 20, 1997
Application receipt date:        October 28, 1997
Scientific review date:        February, 1998
Advisory Council date:         June, 1998
Earliest award date:           August, 1998
 
AUTHORITY AND REGULATIONS
 
This program is supported under authorization of the Public Health
Service Act, Sec. 301 (c), Public Law 78-410, as amended.  The
Catalogue of Federal Domestic Assistance Citation is (Sec. 93.856,
Microbiology and Infectious Diseases Research, or No. 93.855 -
Immunology, Allergy, and Transplantation Research, or both, as
appropriate).  Awards will be administered under PHS grants policies
and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74.  This
program is not subject to the intergovernmental review requirements
of Executive Order 12372 or Health Systems review.
 
The PHS strongly encourages all grant and contract recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products. In addition, Public Law 103-227, the Pro-Children Act of
1994, prohibits smoking in certain facilities (or in some cases, any
portion of a facility) in which regular or routing education,
library, day care, health care or early childhood development
services are provided to children.  This is consistent with the PHS
mission to protect and advance the physical and mental health of the
American people.
 
.

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