ENHANCING VACCINE-ELICITED PROTECTIVE IMMUNITY IN MALARIA

Release Date:  February 19, 1999

RFA:  AI-99-006

P.T.

National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  March 22, 1999
Application Receipt Date:  May 20, 1999

THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA.

PURPOSE

The National Institute of Allergy and Infectious Diseases (NIAID), National
Institutes of Health (NIH) invites applications for research project (R01) grants
to conduct innovative research to advance fundamental understanding of eliciting
optimal protective immune responses with candidate malaria vaccines.  As part of
its Malaria Vaccine Development Plan, NIAID seeks to identify and validate
methods and strategies for improved antigen delivery, processing, and
presentation or enhancement of protective immunity with existing candidate
antigens.  Identification, characterization and evaluation of new candidate
vaccines, especially combination vaccines based on a rational strategy for
antigen inclusion, are also encouraged.

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, Enhancing Vaccine-Elicited
Protective Immunity in Malaria, is related to the priority area(s) 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 20402-9325 (telephone 202-512-1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign for-profit and non-profit
organizations; public and private institutions, such as universities, colleges,
hospitals, laboratories, units of State and local governments; and eligible
agencies of the Federal government.  Racial/ethnic minority individuals, women,
and persons with disabilities are encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

The mechanism of support will be the individual research project grant (R01). 
The total requested project period for an application submitted in response to
this RFA may not exceed five years.  However, specific application instructions
have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining
efforts being examined by the NIH. The modular grant concept establishes specific
modules in which direct costs may be requested as well as a maximum level for
requested budgets. Only limited budgetary information is required under this
approach. The just-in-time concept allows applicants to submit certain
information only when there is a possibility for an award. It is anticipated that
these changes will reduce the administrative burden for the applicants, reviewers
and Institute staff. Complete and detailed instructions and information on
Modular Grants can be found at
https://grants.nih.gov/grants/funding/modular/modular.htm.

Applications will request direct costs in $25,000 modules, up to a total direct
cost request of $250,000 per year. A typical modular grant application will
request the same number of modules in each year.

Application budgets will be simplified. Detailed categorical budget information
will not be submitted with the application; budget form pages of the application
kits will not be used. Instead, total direct costs requested for each year will
be presented. Information, in narrative form, will be provided only for Personnel
and, when applicable, for Consortium/Contractual Costs.  See section on
APPLICATION PROCEDURES below.

Additional narrative budget justification will be required in the application
only if there is a variation in the number of modules requested.

There will be no routine escalation for future years. In determining the total
for each budget year, applicants should first consider the direct cost of the
entire project period. Well-justified modular increments or decrements in the
total direct costs for any year of the project that reflect substantial changes
in expected future activities may be requested. For example, purchase of major
equipment in the first year may justify a higher overall budget in the first, but
not in succeeding years.

Other Support pages of the PHS 398 will not be submitted with the application. 
Information on research projects ongoing or completed during the last three years
of the principal investigator and key personnel will be provided as part of the
"Biographical Sketch." This information will include the specific aims, overall
goals and responsibilities and should include Federal and non-Federal support.
This information will be used by reviewers in the assessment of each individuals
qualifications for a specific role in the proposed project.

Following peer review, information about Other Research Support will be requested
by NIH from the applicant for applications being considered for award.

Additional budget information will be requested only under special circumstances.

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

Responsibility for the planning, direction, and execution of the proposed project
will be solely that of the applicant.

FUNDS AVAILABLE

It is anticipated that for fiscal year 2000, approximately $1 millions total
costs will be available for the first year of support for this initiative. Award
of grants pursuant to this RFA is contingent upon receipt of such funds for this
purpose. It is anticipated that up to 4 new grants will be awarded under this
program. Applicants may request up to 5 years of support. Direct costs will be
awarded in modules of $25,000, less any overlap or other necessary administrative
adjustments. Facilities and Administrative costs will be awarded based on the
negotiated rates.

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

Malaria continues to impose a tremendous health burden for people living in the
tropics, particularly in Africa.  It is estimated that half a billion people
worldwide are infected with malaria, and between 1.5 and 2.7 million people die
of this disease each year.  The situation is worsening, as drug resistant strains
of the most virulent form of malaria parasite, Plasmodium falciparum, have spread
to most endemic regions. At-risk groups include those in whom immunity has not
yet developed (young children in endemic areas, travelers, etc.) and those in
whom immunity has waned (pregnant women, the elderly and people from endemic
areas who have ceased to be routinely exposed to infection).

Since many of the poorest nations of the world are afflicted with malaria, to be
effective any intervention must be inexpensive, cost-effective, and relatively
easy to administer and maintain.  Historically, vaccines have been among the most
cost-effective and easily administered means of controlling infectious diseases,
but as yet no licensed vaccines exist for malaria.  Nevertheless, there are
reasons to believe that protective immunity against malaria can be elicited. 
Human populations residing in malaria endemic areas have been observed to acquire
immunity to clinical disease naturally over time.  Experimental vaccination with
attenuated malaria parasites has also been shown to result in effective immune
protection against challenge with malaria parasites.  Vaccines based on live,
attenuated or killed malaria parasites are economically and technically
impracticable; much of the current research, therefore, focuses on recombinant
or synthetic subunit vaccines.

The aforementioned observations and accumulating basic and clinical research
suggest that vaccines for malaria can be developed that could significantly
reduce morbidity and mortality as well as potentially reduce the spread of
infection.  A subunit vaccine against P. falciparum pre-erythrocytic stages has
recently demonstrated protective efficacy in a small clinical trial involving
experimental challenge of previously vaccinated volunteers (Stoute et al., N.
Engl. J. Med. 1997; 336:86-91), and a small trial of this vaccine is now ongoing
in a malaria endemic region.  An optimal vaccine would have the ability to elicit
protective immunity that not only blocks infection, but also prevents pathology
and inhibits transmission of parasites.  This would most likely require a
combination vaccine comprising subunits from different parasite stages.

Compared to vaccines for most acute bacterial or viral diseases, development of
malaria vaccines presents formidable obstacles in terms of parasite biology, host
immune responses, and both preclinical and clinical evaluation.  Four different
species of protozoan parasites cause human malaria; because of its severity,
however, most vaccine efforts have been directed to falciparum malaria. 
Furthermore, even parasite isolates of the same species but from different
geographic locations may be immunologically distinct.  Finally, malaria parasites
have complex life cycles, and, thus, distinct developmental stages, each of which
may have multiple antigens that could serve as targets of an immune response. 
Host immunity to malaria is likewise complex.  Naturally occurring immunity is
slow to develop and wanes rapidly.  Multiple different immune responses, both
humoral and cellular, appear capable of contributing to protective immunity,
although to date, no immune response predictive of protection in humans has been
clearly identified or validated.

In 1997, NIAID developed a Research Plan for Malaria Vaccine Development
(http://www.niaid.nih.gov/Dmid/malvacdv/toc.htm).  This Plan aims to accelerate
research leading to the development of a vaccine to reduce mortality and
morbidity resulting from malaria.  The NIAID Plan provides for:

o  Improved access to well characterized research materials o  Increased
discovery and preclinical testing of new vaccine candidates o  Enhanced capacity
for production and evaluation of candidate malaria vaccines
o  Establishment of clinical research and trial preparation sites in endemic
areas

Over the past two years, NIAID has sought to implement this plan systematically
through solicitations for expanded clinical research, creation of a malaria
reagent repository, and expansion of facilities for vaccine production and
evaluation.  This RFA addresses another important component of the NIAID plan,
involving research on characterization of candidate vaccine antigens and
identification and validation of superior strategies and technologies for
vaccination. Recent advances in immunology, as well as molecular and cellular
biology, have led to an improved understanding of potential mechanisms of
protective immunity and of the biology of the malaria parasite.  New insights
into the role of antigen processing and presentation in the development of immune
responses, along with a more comprehensive appreciation of the immunoregulatory
effects of cytokines, need to be studied in relation to enhancing vaccine-
elicited protective immunity, especially for currently identified vaccine
candidates. Furthermore, the information expected to come from genetic sequencing
projects will likely reveal a wealth of new antigens for future studies.  Focused
efforts are necessary to determine whether these fundamental discoveries can be
targeted to the development of new prevention or intervention strategies. This
initiative should be considered as a component of the overall NIAID Research Plan
for Malaria Vaccine Development, with an opportunity for promising research to
be expanded and pursued collaboratively in the context of other Institute-
supported programs.

Research Objectives and Scope

NIAID seeks to foster innovative research to develop methods for improved antigen
delivery/presentation or enhancement of protective immunity with existing
candidate vaccine antigens, as well as to identify and characterize new candidate
vaccines.  It is anticipated that the bulk of this research will be pursued at
the preclinical level, and will involve the use of appropriate animal models of
malaria.  Investigators anticipating studies involving human subjects should
contact the Program Officer (see "INQUIRIES" below) for additional guidance.

Relevant research includes, but is not limited to, the following:

o  Identification and validation of antigens as promising candidate vaccines to
prevent infection, disease and/or transmission
o  Evaluation, in animal models, of vaccines based on combinations of antigens
o  Identification, validation and optimization of appropriate formulations (e.g.
delivery systems, adjuvants) of candidate vaccines that can elicit long-lasting
protective immunity in animal models
o  Characterization and quantitative assessment of specific effector mechanisms
of protective immunity operating in these models
o  Identification and evaluation of innovative strategies and mechanisms to
sustain protective effector mechanisms and/or boost waning responses
o  Development of in vitro assays that could serve as correlates of vaccine
efficacy for future clinical trials

The areas outlined above are not intended to be all-inclusive.

SPECIAL REQUIREMENTS

Principal Investigators should budget for a trip to attend an annual, three day
meeting sponsored by NIAID in the Washington DC area.  These meetings will allow
investigators to meet with other participants capable of providing access to
relevant information, technologies and/or patient populations.  It is expected
that such meetings will foster collaboration between basic and clinical
researchers, and expedite clinical applications of research findings where
appropriate.

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
sub-populations must be included in all NIH supported biomedical and behavioral
research projects involving human subjects, unless a clear, compelling rationale,
and justification are provided that inclusion is inappropriate with respect to
the health of the subjects or 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", 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 which is available via the WWW. at:
https://grants.nih.gov/grants/guide/notice-files/not94-100.html

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them.  This
policy applies to all initial (Type 1) applications  submitted for receipt dates
after October 1, 1998.

All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects" that was published in the NIH Guide for Grants
and Contracts, March 6, 1998, and which is available at the following URL
address:  https://grants.nih.gov/grants/guide/notice-files/not98-024.html

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 March 22, 1999, 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.
B.F. Hall at the address listed under INQUIRIES.

APPLICATION PROCEDURES

Applicants are strongly encouraged to contact NIAID program staff listed under
INQUIRIES with any questions regarding the responsiveness of their proposed
project to the goals of this RFA.

The research grant application form PHS 398 (rev. 4/98) is to be used in applying
for these grants.  Application kits are available at most institutional offices
of sponsored research and from the Division of Extramural Outreach and
Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC
7910, Bethesda, MD 20892-7910, telephone (301) 710-0267,
email:GrantsInfo@nih.gov.  Applications are also available on the World Wide Web
at:  https://grants.nih.gov/grants/forms.htm.

BUDGET INSTRUCTIONS

The total direct costs must be requested in accordance with the program
guidelines and the modifications made to the standard PHS 398 application
instructions described below:

o  FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in
$25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total
Direct plus Facilities and Administrative (F&A) costs] for the initial budget
period. Items 8a and 8b should be completed indicating the Direct and Total Costs
for the entire proposed period of support.

o  DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4
of the PHS 398. It is not required and will not be accepted with the application.

o  BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the
categorical budget table on Form Page 5 of the PHS 398. It is not required and
will not be accepted with the application.

o  NARRATIVE BUDGET JUSTIFICATION - Use a Modular Grant Budget Narrative page.
(See https://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At
the top of the page, enter the total direct costs requested for each year.

o  Under Personnel, List key project personnel, including their names, percent
of effort, and roles on the project. No individual salary information should be
provided.

For Consortium/Contractual costs, provide an estimate of total costs (direct plus
facilities and administrative) for each year, each rounded to the nearest $1,000.
List the individuals/organizations with whom consortium or contractual
arrangements have been made, the percent effort of key personnel, and the role
on the project. Indicate whether the collaborating institution is foreign or
domestic. The total cost for a consortium/ contractual arrangement is included
in the overall requested modular direct cost amount.

Provide an additional narrative budget justification for any variation in the
number of modules requested.

o  BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by
reviewers in the assessment of each individual's qualifications for a specific
role in the proposed project, as well as to evaluate the overall qualifications
of the research team. A biographical sketch is required for all key personnel,
following the instructions below. No more than three pages may be used for each
person. A sample biographical sketch may be viewed at:
https://grants.nih.gov/grants/funding/modular/modular.htm
- Complete the educational block at the top of the form page; - List current
position(s) and then previous positions;
- List selected peer-reviewed publications, with full citations; - Provide
information, including overall goals and responsibilities, on research projects
ongoing or completed during the last three years.

o  CHECKLIST - This page should be completed and submitted with the application.
If the F&A rate agreement has been established, indicate the type of agreement
and the date. It is important to identify all exclusions that were used in the
calculation of the F&A costs for the initial budget period and all future budget
years.

o  The applicant should provide the name and phone number of the individual to
contact concerning fiscal and administrative issues if additional information is
necessary following the initial review.

Applicants not conforming to these guidelines will be considered unresponsive to
this RFA and will be returned without further review.

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.  For purposes of identification and processing, item 2 on the
face page of the application must be marked "YES" and the RFA number "AI-99-006"
and the words "Enhancing Vaccine-Elicited Protective Immunity in Malaria" must
be entered on the face page.

Submit a signed, typewritten original of the application, including the
checklist, and five signed, exact, single-sided photocopies, in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

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.

Applications must be received by May 20, 1999.  Applications not received as a
single package on the receipt date or not conforming to the instructions
contained in PHS 398 (rev. 4/98) Application Kit (as modified in, and superseded
by, the special instructions above, for the purposes of this RFA), will be judged
non-responsive and will be returned to the applicant.

The Center for Scientific Review (CSR) will not accept any applications in
response to this RFA that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending application.  The CSR
will not accept any application that is essentially the same as one already
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

Upon receipt, applications will be reviewed for completeness and adherence to the
Special Instructions above by CSR and for responsiveness by NIAID staff.
Incomplete and/or non-responsive applications will be returned to the applicant
without review.  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 CSR in accordance with the review criteria stated below. 
As part of the initial merit review, a process will be used by the initial review
group in which applications receive a written critique and under go a process in
which only those applications deemed to have the highest scientific merit,
generally the top half of the applications under review, will be discussed,
assigned a priority score, and receive a second level review by the National
Advisory Allergy and Infectious Diseases Council.

Review Criteria

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 or advance
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,
minorities and their subgroups, and children 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.

The personnel category will be reviewed for appropriate staffing based on the
requested percent effort. The direct costs budget request will be reviewed for
consistency with the proposed methods and specific aims.  Any budgetary
adjustments recommended by the reviewers will be in $25,000 modules.  The
duration of support will be reviewed to determine if it is appropriate to ensure
successful completion of the requested scope of the project.

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.  The
earliest anticipated date of award is April 1, 2000.

INQUIRIES

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:

Dr. B.F. Hall
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 3A09
Bethesda, MD  20892-7630
Telephone:  (301) 496-2544
FAX:  (301) 402-0659
Email:  bh24q@nih.gov

Direct inquiries regarding fiscal matters to:

Maryellen Connell
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4B27
Bethesda, MD  20892
Telephone:  (301) 402-5576
Fax: (301) 480-3780
Email:  mc40u@nih.gov

Schedule

Letter of Intent Receipt Date:  March 22, 1999
Application Receipt Date:       May 20, 1999
Scientific Review Date:         October 1999
Advisory Council Date:          February 2000
Earliest Award Date:            April 2000

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance Nos.
93.856 and 93.855.  Awards are made under authorization of the Public Health
Service Act, Sec. 301 (c), Public Law 78-410, as amended.  The 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 Public Health Service 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 routine 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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