Full Text AI-95-013

RESEARCH ON HANTAVIRUS AND OTHER EMERGING VIRAL THREATS

NIH GUIDE, Volume 24, Number 13, April 7, 1995

RFA:  AI-95-013

P.T. 34

Keywords: 
  Viral Studies (Virology) 
  Infectious Diseases/Agents 


National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  June 1, 1995
Application Receipt Date:  July 20, 1995

PURPOSE

The Virology Branch of the Division of Microbiology and Infectious
Diseases of the National Institute of Allergy and Infectious Diseases
(NIAID) invites applications for the establishment of Emerging
Viruses Research Groups (EVRG).  The purpose of this RFA is to
encourage multi-disciplinary, collaborative research on emerging
viral diseases in general, with a special emphasis on hantaviruses.
These research groups should develop coordinated basic and applied
research projects yielding new data that will enhance prediction,
prevention, treatment, and control of emerging and re-emerging viral
diseases threatening the U.S.  Furthermore, EVRGs must have at least
one of the component research projects dealing with hantaviruses,
with at least one other component project focused on another emerging
viral disease.  Since other initiatives are available to support
research on influenza, hepatitis, herpes, papilloma, respiratory
syncytial, measles, and retroviruses/HIV, projects on these viruses
will not be considered responsive to this RFA.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This Request
For Applications (RFA), Research on Hantavirus and other Emerging
Virus Threats, is related to the priority area of immunization and
infectious diseases.  Potential applicants may obtain a copy of
"Healthy People 2000" (Full Report:  Stock No. 017-001-00474-0 or
Summary Report:  Stock No. 017-001-00473-1) through the
Superintendent of Documents, Government Printing Office, Washington,
DC 20402-9325 (telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Research grant applications may be submitted by domestic non-profit
and for-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.  Foreign organizations are not eligible to apply, but may
be part of a collaborative arrangement in a domestic application.
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 program project (P01) grant.
This mechanism supports broadly based multi-disciplinary research
programs that have a well-defined central research focus or
objective.  An important feature of the program project is that the
interrelationships of the individual scientifically meritorious
projects will result in a greater contribution to the overall program
goals than if each project were pursued individually.  The program
project grant consists of a minimum of three interrelated individual
research projects that contribute to the program objective.  The
program project grant also can provide support for certain common
resources, termed 'cores.'  Such resources should be utilized by two
or more projects within the program project.

Responsibility for the planning, direction, and execution of the
proposed project will be solely that of the applicant.  The total
requested project period may not exceed four years.  The earliest
anticipated award date is April 1996.

FUNDS AVAILABLE

The estimated total funds (direct and indirect costs) available for
the first year of support for awards under this RFA will be $1.0
million.  In Fiscal Year 1996, the NIAID plans to fund two EVRGs.
The final number of awards to be made and level of support is
dependent upon the availability of funds and receipt of a sufficient
number of applications of high scientific merit.  The initial year's
total costs, including direct and indirect costs, should not exceed
$500,000 for each award except for the optimal remote sensing
projects (see special requirements).  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. 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 emergence of the AIDS epidemic and the appearance of hantavirus
in the Southwestern U.S. have demonstrated the vulnerability of the
U.S. to emerging viruses.  The NIAID recently co-funded two studies
by the Institute of Medicine dealing with emerging diseases (see:
Institute of Medicine:  Emerging Infections--Microbial Threats to
Health in the United States, National Academy Press; and The U.S.
Capacity to Address Tropical Infectious Disease Problems, National
Academy Press).  These studies warned that the threat posed by
disease-causing microbes may be expected to continue and intensify in
coming years.

Factors influencing the pattern of emergence and distribution of
infectious diseases in general include those associated with the
microbial agent itself, the agent's hosts and vectors, and the
environment in which agent and host interact.  However, for many
infectious agents, the specific factors contributing to emergence are
poorly understood.  Nonetheless, knowledge of these principles is
essential in planning strategies to prevent, treat, and control these
diseases.  The overall objective of this RFA is to gain new knowledge
about emerging viruses by supporting coordinated, multi- disciplinary
research programs.

The natural life cycle of many viruses is multi-faceted and in
addition to the virus, may include one or several reservoir or
amplifying hosts, and often an arthropod vector.  A change affecting
the interaction of these fundamental elements might lead to the
emergence or re-emergence of a viral disease.  Natural or man-made
changes to the environment typically impact on virus vectors or
hosts.  A recent example of the role of natural changes in the
environment contributing to the emergence of disease is the 1993
appearance of hantavirus in the Southwestern U.S.  It is now thought
that the virus in part emerged as a result of climatic and
environmental conditions favorable for increased infected rodent
populations.  Nonetheless, man-made changes to the environment also
lead to the emergence of disease.  There have been several accounts
of endemic viruses emerging and spreading as the result of such
changes as:  (a) development of dams and water projects resulting in
altered water distribution patterns, (b) deforestation and changing
land-use associated with the development of new communities, and (c)
the introduction of new virus-amplifying hosts or the expansion of
new vectors as the result of changing commercial practices.  An
example of the influence of man-made environmental changes is the
1987 epizootic of Rift Valley fever in the Senegal river basin, where
the emergence of the virus from low level, endemic circulation
closely coincided with beginning operation of a major new dam.  It is
thought that the virus emerged as a result of environmental changes
favorable for increased or altered mosquito vector populations, and
possibly changes in migration of herds of domestic animal hosts.
Historically, commerce has often brought new viruses, vectors, or
hosts into an area.  A classic example is the spread of yellow fever
in the western hemisphere in the 19th and early 20th century.
Impending expansion of worldwide commercial trade may facilitate the
emergence of new viruses, or increase the spread of previously known
viruses to a more receptive environment.

In some instances, viruses might emerge as the result of selection of
new genetic strains and variants with increased infectiousness,
virulence, or transmissibility  This has been well-established as a
cause for the emergence of new influenza outbreaks, and, in an
analogous fashion, probably contributes to the emergence of other
viruses, particularly, the bunyaviruses.

Unfortunately, until research leads to effective prevention/treatment
strategies, the initial population in which the virus emerges can be
disproportionately affected.  In the case of the emergence of
hantavirus, 34.3 percent of the 102 well-documented cases have
occurred in the Native American population, and the overall case
fatality rate has been 52 percent.

Major impediments in meeting these emerging virus threats are the
recent decrease in the number of researchers addressing
arthropod-borne and zoonotic viruses, and the formidable research
problems posed by the need for input from several disciplines.  This
RFA is intended to stimulate:  (1) basic and applied research that
will help formulate coordinated strategies for anticipating,
detecting, controlling, and preventing emergence or re-emergence of
viral diseases; and (2) basic and applied research on the virus, on
the infective process, and the host response to infection, which will
be useful in development of vaccines and antiviral drugs.

Objectives and Scope

The overall objective of this RFA is to stimulate and expand research
on emerging viruses by establishing multi-disciplinary, coordinated
research groups.  Unfortunately, gaps in the knowledge of emerging
viruses remain in several areas, and there are limited numbers of
researchers and laboratory groups studying these viruses.  Thus, it
is recognized that at this time, resources and basic data might not
be available for each EVRG to comprehensively approach a full range
of studies related to a virus.  For some viruses, such as dengue, a
relatively large amount of basic information exists, and focused
research questions and detailed experimental strategies can be
formulated.  However, other emerging viruses, such as hantaviruses,
have only recently been identified or implicated as a disease threat.
The goals of appropriate, state-of-the-art research for those viruses
will be less sophisticated, but no less important.  Thus, it is
anticipated that the general aims and the scope of research projects
proposed under this RFA might vary significantly.  Additionally, it
is unlikely that any one laboratory center could provide a
comprehensive research team; therefore, strong collaborative links
will probably be integral to a successful EVRG.  It is hoped that
this program eventually will help build a critical mass of
investigators with expertise in the varied laboratory, field, and
clinically-based lines needed for the comprehensive study of emerging
viral diseases.

EVRGs should be broadly-based multi-disciplinary research programs
that have a central research focus and a minimum of three inter-
related research projects around this central theme.  An important
feature of the EVRGs should be the synergy that results from
collaborative efforts.  Thus, the EVRGs are encouraged to include
coordinated multi-disciplinary projects.  Furthermore, EVRGs must
include at least one research project on hantaviruses and one other
component project focused on another emerging viral disease.  EVRG
Program Directors are encouraged to propose research projects within,
but not limited to, the general research areas listed below.  All
projects should be focused to yield new data significantly helpful in
prediction, prevention, treatment, or control of emerging viral
diseases.

o  Expansion of research on viral changes and adaptations influencing
emergence.  Studies might address issues of viral evolution leading
to new or altered viruses with enhanced virulence or modified
transmissibility or infectivity.

o  Extension of research on ecologic and environmental factors
influencing disease emergence and distribution.  Studies might
include evaluation of:  the influence of natural, man-made, or
climate-induced environmental change on emerging viruses;  the
effects of alterations in host or vector population density and
distribution on viral diseases; and the influence of public health
practices, altered social/behavioral practices, or modern
technological developments on virus distribution.

o  Establishment of research programs focusing on susceptible hosts
and vectors and their roles during maintenance and emergence of
viruses.  Studies might include research on mechanisms of
pathogenesis, or the natural association of the virus with a vector
or host.  Projects also could include initial development of new
vaccines and antivirals for the protection of the individual from a
specific virus.  Studies might also lead to new prevention and
control strategies that can be employed at a community level to
ameliorate disease impact in the face of an epidemic.  For example,
an antiviral drug against flaviviruses might be useful, not only to
the individual, but also as a community public health tool to prevent
amplifying viremia in susceptible hosts and consequently reduce
disease spread during a dengue epidemic.

o  Establishment of projects for pre-clinical evaluation of newly
developed vaccines or antiviral therapies for emerging diseases.
These might involve: identification of suitable animal models of
disease to allow studies of potential prevention/treatment therapies;
preliminary evaluation of candidate vaccines or antivirals; and
initial development and testing of combinations of vaccines.

o  Development of research leading to improved surveillance of
emerging viruses.  The primary aim of the EVRGs will not be
surveillance per se, but research such as the development of improved
diagnostic reagents and assays.

Budget and Related Issues

Applications should budget appropriate funds to allow the Director of
each EVRG and all EVRG Project Leaders to attend one meeting annually
in Bethesda, MD with NIAID staff.

SPECIAL REQUIREMENTS

The P01 mechanism is used to support broadly-based multi-disciplinary
research programs that have a well-defined central research focus or
objective and a minimum of three inter-related research projects
around this central theme.  An important feature of the EVRGs
therefore is the synergy that results from collaborative efforts
among the interrelated individual scientifically meritorious
projects, resulting in a greater contribution to the overall program
goals than if each project were pursued independently. The
multi-project grant also provides support for certain common
resources, termed 'Cores,' which must be utilized by two or more
projects within the proposed program. EVRGs must have at least one
component research project dealing with hantaviruses and one or more
of the other projects in the program dealing with at least one other
emerging viral disease.

Recent advances in satellite remote sensing technology and in
computerized geographic information systems (GIS) have been applied
to the study of infectious diseases and their distribution.  These
tools have provided predictive data for purposes such as identifying
geographic areas where there is an increased risk of vector-borne
disease transmission.  Investigators seeking to employ remote sensing
in their studies of emerging viruses should clearly indicate this as
a separate project in the application.  This project will not be
considered one of the three qualifying component projects for the
Program  (P01).  This budget should be clearly identified and should
not be considered part of the $500,000 limit indicated above.  The
National Aeronautics and Space Administration will consider support
of these projects in conjunction with NIAID support of the EVRG.

Applicants are strongly encouraged to contact Dr. James Meegan at the
address listed under INQUIRIES below for more information.

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 and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990. The new policy contains some
provisions that are substantially different from the 1990 policies.

All investigators proposing research involving human subjects should
read the "NIH Guidelines For Inclusion of Women and Minorities as
Subjects in Clinical Research," which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513) and printed in
the NIH Guide for Grants and Contracts, Volume 23, Number 11, March
18, 1994.

Investigators also may obtain copies of the policy from Dr. Meegan,
listed under INQUIRIES below.  Dr. Meegan may also provide additional
relevant information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by June 1, 1995, a letter
of intent that includes a descriptive title of the overall proposed
research, the name, address, and telephone number of the EVRG
Director, a list of the key investigators and their institution(s),
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. Olivia Preble at the
address listed under INQUIRIES.

APPLICATION PROCEDURES

It is highly recommended that Dr.Meegan be contacted in the early
stages of the application. (see program contact in INQUIRIES below).
Before preparing an application, the applicant should carefully read
the new information brochure, "NIAID APPLICATION GUIDELINES FOR
MULTIPROJECT RESEARCH AWARDS."  Instructions for formatting the
application as outlined in the brochure must be followed carefully.
Failure to follow the instructions may result in unnecessary delays
in the review process.

Applications are to be submitted on the standard research grant
application form PHS 398 (rev. 9/91).  These application forms may be
obtained from the institution's office of sponsored research or its
equivalent and from the Office of Grants Information, Division of
Research Grants, National Institutes of Health, 5333 Westbard Avenue,
Room 449, Bethesda, MD 20892, telephone (301) 710-0267.

The RFA label available in the PHS 398 (rev. 9/91) 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 2a 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 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 courier or express mail)

At the time of submission, two additional exact copies of the grant
application and five sets of appendix material must also be sent to:

Dr. Olivia Preble
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C-19
6003 Executive Boulevard MSC 7610
Bethesda, MD  20892-7610
Bethesda, MD  20852 (for express mail/courier service)

Applications must be received by July 20, 1995.  All components,
subparts and sections of the application must be collated into the
application, and the packages sent to the DRG and to the NIAID must
each be complete in themselves.  Applications that do not conform to
the instructions contained in PHS 398 (rev. 9/91) application kit
will be returned to the applicant.

Current NIH policy permits a component research project of a
multiproject grant application to be concurrently submitted as a
traditional individual research project (R01) application.  If,
following review, both the multiproject application and the R01
application are found to be in the fundable range, the investigator
must relinquish the R01 and will not have the option to withdraw from
the multiproject grant.  This is an NIH policy intended to preserve
the scientific integrity of a multiproject grant, which may be
seriously compromised if a strong component project(s) is removed
from the program.  Investigators wishing to participate in a
multiproject grant must be aware of this policy before making a
commitment to the EVRG Director and awarding institution.

The original and three copies of the applications that are sent to
the DRG must be received as a single package from the program
director and conform to the instructions contained in PHS 398 (rev.
9/91) application kit otherwise the application will be returned to
the applicant.

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the GCRC as a resource for conducting
the proposed research.  If so, a letter of agreement from either the
GCRC program director or principal investigator could be included
with the application.

REVIEW CONSIDERATIONS

Review Method

Upon receipt, applications will be reviewed for completeness by the
Division of Research Grants (DRG) for completeness and for
responsiveness by NIAID staff.  Incomplete and non-responsive
applications will be returned to the applicant without further
consideration or review.

Applications that are complete and responsive may be subjected to a
triage by a peer review group to determine their scientific merit
relative to other applications received in response to this RFA.  The
NIAID will remove from competition those applications judged to be
non-competitive for award and will notify the EVRG Directors and
institutional business officials.

Those applications judged by the reviewers to be competitive for
award will be further 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 review criteria are stated in the NIAID GUIDELINES FOR
MULTIPROJECT RESEARCH AWARDS.  In addition, the following criteria
will apply:

o  the scientific and technical significance, merit, and originality
of the research projects and anticipated contributions to the
understanding of hantavirus and other emerging viral diseases;

o  the scientific expertise and experience of the EVRG Director, the
Project Leaders and key project and core personnel;

AWARD CRITERIA

Funding decisions will be made on the basis of scientific and
technical merit as determined by peer review, program balance, and
availability of funds.

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Dr. James M. Meegan
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
Solar Building, Room 3A-15
6003 Executive Boulevard MSC 7630
Bethesda, MD  20892-7630
Telephone:  (301) 496-7453
FAX:  (301) 402-0659
Email:  jm75v@nih.gov

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

Dr. Olivia Preble
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C-19
6003 Executive Boulevard MSC 7610
Bethesda, MD  20892-7610
Telephone:  (301) 496-8208
FAX:  (301) 402-2638
Email:  op2t@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Mary Ledford
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B-24  MSC 7610
Bethesda, MD  20892-7610
Telephone:  (301) 496-7075
FAX:  (301) 480-3780
Email:  ml28g@nih.gov

Schedule

Letter of Intent Receipt Date:  June 1, 1995
Application Receipt Date:       July 20, 1995
Scientific Review Date:         November 1995
Advisory Council Date:          January 1996
Earliest Award Date:            April 1, 1996

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.856 Microbiology and Infectious Diseases Research.
Awards are made under the authority of the Public Health Service Act,
Section 301 (42 USC 241) and administered under PHS grants policies
and Federal Regulations, most specifically at 42 CFR Part 52 and 45
CFR Part 74.  This program is not subject to the intergovernmental
review requirements of the 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, 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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