EVOLUTION OF INFECTIOUS DISEASES

Release Date:  December 18, 1998

RFA NUMBER:  GM-99-005

P.T.

National Institute of General Medical Sciences
National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  February 01, 1999
Application Receipt Date:  March 17, 1999

PURPOSE

The goal of this joint NIGMS/NIAID Request for Applications (RFA) is to encourage
development of a predictive science of infectious diseases by applying the
perspectives, theories, and methods of population and evolutionary biology to
important issues of disease emergence, prevention and treatment.  To achieve this
goal, this RFA seeks collaborations between two major groups of scientists: (1)
those with expertise in population and evolutionary biology and molecular
phylogenetics, including mathematical modeling and complexity theory; (2)
infectious disease experts such as clinicians, epidemiologists, immunologists,
microbiologists, veterinarians, or plant pathologists.  NIGMS and NIAID
anticipate that this RFA will be released again within a year.

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, Evolution of Infectious Diseases,
is related to one or more of the priority areas.  Potential applicants may obtain
a copy of "Healthy People 2000" at http://www.crisny.org/health/us/health7.html.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and non-profit
organizations, public and private, 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

This RFA will use the National Institutes of Health (NIH) research project grant
(R01) and program project grant (P01).  Foreign institutions are not eligible for
program projects.  Supplements to existing NIH grants will also be considered. 
Responsibility for the planning, direction, and execution of the proposed project
will be solely that of the applicant.  The anticipated award date is September
1, 1999.

FUNDS AVAILABLE

The NIGMS and NIAID intend to commit approximately $5 million in FY 99 to fund
16-20 new grants in response to this RFA.  An applicant may request a project
period of up to 5 years and a budget for direct costs of up to $1 million for 5
years, excluding indirect costs on consortium arrangements.  Because the nature
and scope of the research proposed may vary, it is anticipated that the size of
each award will also vary.  Although the financial plans of the NIGMS and NIAID
provide support for this program, awards pursuant to this RFA are contingent upon
the availability of funds and the receipt of a sufficient number of applications
of outstanding scientific and technical merit.

RESEARCH OBJECTIVES

Background

Population dynamics and evolutionary processes are fundamental to virtually all
aspects of infectious diseases, including their emergence or re-emergence as
public health threats, their prevention and their treatment.  The ability of an
infectious species to colonize plant or animal hosts, to proliferate, to cause
disease, and to spread depends on a variety of factors, such as its genetic
characteristics, its life history, and its mode of transmission, all of which can
be modified by evolutionary forces.  Ecological and environmental factors also
play an important role in the development of infectious diseases.  The ability
of a host species to prevent and control infections similarly depends on its
innate defense system (including immune defenses), its behavior, its environment,
and human intervention.  Population dynamics, including population density,
migration, population subdivision, and competition for resources, affect the
evolution of both pathogens and hosts, including humans.

Evolutionary biology, in combination with molecular biology, genetics,
systematics, immunology, mathematics, and other disciplines, will contribute
significantly to our ability to develop a predictive science of infectious
diseases.  For example, identifying the origins and host ranges of infectious
agents requires a variety of molecular, genetic, mathematical, and evolutionary
tools.  Intervention to prevent or treat infections by behavior modification,
control of vectors, vaccination, chemotherapy or other means influences a variety
of dynamic evolutionary processes in individual hosts, communities of hosts, and
communities of pathogenic organisms.  Understanding the conditions under which
interventions fail (e.g., antibiotic resistance or live vaccines' reversion to
virulence) and designing protocols to prevent these failures requires application
of evolutionary and ecological principles.  Multidisciplinary approaches,
including evolution and ecology, are also essential for anticipating the
conditions under which new infectious diseases will emerge and old ones will re-
emerge.

While there is widespread understanding that population, ecological and
evolutionary dynamics are central to understanding, preventing and treating
infectious diseases and anticipating their emergence and re-emergence, research
into these aspects of infectious diseases has been limited.  With a few
exceptions, the quantitative and comparative perspectives of population and
evolutionary biology and mathematical modeling are rarely employed in infectious
disease research or in the design of protocols to prevent and treat infections. 
The goal of this initiative is to remedy this situation by supporting
collaborations among scientists with expertise in evolutionary and population
biology, including phylogenetics; scientists with expertise in infectious
disease; and scientists with expertise in mathematical modeling, computer
science, and complexity theory.

Scientific Objectives

This initiative includes those areas of infectious disease research where
population dynamics and evolutionary processes clearly play an important role. 
Proposals for research projects responsive to this announcement may address
either broad evolutionary questions  that may ultimately be relevant to
infectious diseases or the implications of evolution and population dynamics in
specific diseases.  The study of model systems may be instructive in either case. 
Applicants must clearly explain how proposed approaches and perspectives are
expected to contribute to development of a predictive science of infectious
diseases.

Studies which combine theoretical and empirical approaches to investigations of
the evolution of infectious diseases and their prevention and treatment are
especially encouraged.  Also encouraged are projects whose evolutionary focus
will lead to a predictive science of the sources, prevention, and treatment of
existing, emerging, or reemerging infectious diseases.  Model systems, including
plant systems, will be considered when they are used to address fundamental
problems of the population biology and evolution of disease.

Responsive applications must employ approaches typical of population and
evolutionary studies, such as mathematical modeling, phylogenetics, and
cladistics, as well as in vitro and in vivo experiments that address interrelated
elements an infectious system (host, pathogen, vector and environment, as
appropriate).  Within the areas of investigation described below, relevant
applications would focus on one or more of the stated specific aspects:

1.   Population and/or evolutionary studies related to the causes and sources of
infectious diseases.
o  Genetic variation and structure of pathogen populations and the genetic
relationships between commensal and pathogenic members of closely related taxa
o  Population analyses of the contributions and sources of the vertical and
horizontal transfer of genes and accessory elements coding for virulence
determinants, host range and specificity, and drug resistance
o  Genetic factors (pathogen, host or vector) responsible for geographic and
temporal variation in disease frequency and severity

2.   Population and/or evolutionary studies related to the interactions between
hosts and pathogens.
o  Contribution of population dynamic and evolutionary processes to the
pathogenesis and virulence of infecting organisms
o  Establishment of model systems to explore the relationship between the
evolution of pathogenic organisms and factors affecting host susceptibility,
including ecological, social and other environmental factors

3.   Population and/or evolutionary studies related to the consequences of
intervention strategies.
o  Within-host population dynamics related to intervention strategies, including
reversion to virulence of live vaccines (as opposed to outgrowth of existing
unattenuated organisms), as well as evolution of resistance following
antimicrobial chemotherapy or vaccination
o  Establishment of model systems (either in vitro systems, or in vivo systems
involving non-human pathogens and/or animal or plant hosts) to predict the
ecological and evolutionary consequences of programs involving host behavior,
vaccination, antimicrobial chemotherapy, and other intervention strategies on
pathogen, host, and vector populations

4.   Population and/or evolutionary studies related to the factors contributing
to variation in pathogen virulence and host susceptibility to infections and
their consequences.
o  Establishment of model systems to explore the environmental, physiological and
genetic factors responsible for generating and maintaining variation in pathogen
and host populations, including co-evolutionary pressures.

5.   Population and/or evolutionary studies related to the natural history of
pathogenic organisms.
o  Evolutionary basis of the normal range of pathogenic organisms' habitats and
hosts
o  Establishment of model systems to explore the molecular basis of host barriers
that must be overcome by pathogens in order to extend their ranges
o  Establishment of model systems to explore the molecular, individual, and
population dynamics of extending the niche or host range of a pathogen.

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 is 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," which have been published in the Federal Register of March 28, 1994
(FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23,
Number 11, March 18, 1994 available on the web at: 
http://grants.nih.gov/grants/guide/notice-files/not94-105.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 is available at the following URL address:
http://grants.nih.gov/grants/guide/notice-files/not98-024.html

Investigators also may obtain copies of these policies from the program staff
listed under INQUIRIES.  Program staff may also provide additional relevant
information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes a
descriptive title of the proposed research, the name, address, and telephone
number of the Principal Investigator, the identities of other key personnel and
participating institutions, and the number and title of the RFA in response to
which the application may be submitted.  Although a letter of intent is not
required, is not binding, and does not enter into the review of a subsequent
application, the information that it contains allows program staff to estimate
the potential review workload and avoid conflict of interest in the review.

The letter of intent is to be sent to the Dr. Irene Eckstrand at the address
listed under INQUIRIES by the letter of intent receipt date listed in the heading
of this RFA.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used in applying
for these grants.  These forms 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 301/435-0714, email: GrantsInfo@nih.gov.

The RFA label available in the PHS 398 (rev. 4/98) application form must be
affixed to the bottom of the face page of the 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.  In addition, the RFA title and
number must be typed on line 2 of the face page of the application form and the
YES box must be marked.

Submit a signed, typewritten original of the application, including the
Checklist, and five signed, 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)

Applications must be received by the application receipt date listed in the
heading of this RFA.  If an application is received after that date, it will be
returned to the applicant without review.

The Center for Scientific Review (CSR) will not accept any application in
response to this RFA that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending application.  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 by CSR and for
responsiveness by NIGMS and NIAID staff.  Incomplete applications will be
returned to the applicant without further consideration.  If the application is
not responsive to the RFA, NIH staff will contact the applicant to determine
whether to return the application to the applicant or submit it for review in
competition with unsolicited applications at the next review cycle.

Applications that are complete and responsive to this RFA will be evaluated for
scientific and technical merit in accordance with the criteria stated below by
an appropriate initial review group of the CSR.  As part of the initial merit
review, applications will receive a written critique and may undergo a process
in which only those applications deemed to have the highest scientific merit will
be discussed and assigned a priority score.  Scored applications will receive a
second level of review by the appropriate National Advisory Council.

Review Criteria

The goal of this RFA is to stimulate useful collaborations among scientists from
different fields focused on developing a predictive science of infectious
disease.  In the written review, comments on the following aspects of the
application will be made in order to judge the likelihood that the proposed
research will have a substantial impact on the pursuit of this goal.  Each of
these criteria will be addressed and considered in the assignment of the overall
score.

(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)?  Are the nature and
quality of the collaborations appropriate for the proposed research?

(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?

In addition to the above criteria, in accordance with NIH policy, all
applications will also be reviewed with respect to the following:

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

o  The reasonableness of the proposed budget and duration in relation to the
proposed research

o  The adequacy of the proposed protection for humans, animals or the
environment, to the extent they may be adversely affected by the project 
proposed in the application.

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

Schedule

Letter of Intent Receipt Date:    February 1, 1999
Application Receipt Date:         March 17, 1999
Peer Review Date:                 June - July 1999
Council Review:                   September - October 1999
Earliest Anticipated Start Date:  December 1, 1999

AWARD CRITERIA

Applications will compete with all other approved applications for available
funds.  The following will be considered in making funding decisions:
o  the quality of the proposed project as determined by peer review;
o  balance among the projects in addressing a variety of experimental approaches;
o  likelihood that the proposed research will lead to significant advances in our
knowledge of the evolution of infectious diseases;
o  promise of the proposed studies to accomplish the goals of this RFA by
increasing knowledge of the evolution of infectious disease;
o  adequacy of plans to make data and material developed as a result of the
proposed research accessible to the biomedical research community in a timely
manner; and
o  availability of funds.

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. Irene Anne Eckstrand
Division of Genetics and Developmental Biology
National Institute of General Medical Sciences
45 Center Drive, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-0943
FAX:  (301) 480-2228
Email:  Irene_Eckstrand@nih.gov

Dr. Stephanie James
Parasitology and International Programs Branch
National Institute of Allergy and Infectious Diseases
Solar Building, Room 3A-10
Rockville, MD  20892
Telephone:  (301) 496-2544
FAX:  (301) 402-0659
Email:  sj13y@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Marcia Cohn
Grants Management Office
National Institute of General Medical Sciences
45 Center Drive, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-3918
FAX:  (301) 480-1969
Email:  cohnm@nigms.nih.gov

Ms. Mary Kirker
Grants Management Branch
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B-23
Telephone:  (301) 496-7075
FAX:  (301) 480-3780
Email:  mkirker@mercury.niaid.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance Nos.
93.821, 93.859, 93.862, and 93.856.  Awards are made under authorization of the
Public Health Service Act, as amended and administered under PHS grants policies,
the NIH Grants Policy Statement (October 1, 1998), 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.

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, and 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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