Full Text HL-94-005-B

IN VITRO INACTIVATION OF VIRUSES IN BLOOD COMPONENTS

NIH GUIDE, Volume 22, Number 42, November 19, 1993

RFA:  HL-94-005-B

P.T. 34

Keywords: 
  Blood/Blood Products/Transfusions 
  Viral Studies (Virology) 


National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  December 10, 1993
Application Receipt Date:  February 10, 1994

PURPOSE

The Transfusion Medicine Branch, Division of Blood Diseases and
Resources, National Heart, Lung, and Blood Institute (NHLBI), invites
grant applications to conduct basic and applied research on the
development of simple, cost-effective inactivation procedures to
destroy the infectivity of transfusion-transmitted viruses in blood
and blood components while maintaining the therapeutic effectiveness
of these preparations.

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), In Vitro Inactivation of
Transfusion-transmitted Viruses in Cellular Blood Components, is
related to the priority areas of HIV infection, and immunization and
infectious diseases.  Potential applicants may obtain a copy of
"Healthy People 2000" (Full Report:  Stock No. 017-001-00474-0) or
"Healthy People 2000" (Summary Report:  Stock No. 017-001-00473-1)
through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-782-3238).

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 or local
governments, and eligible agencies of the federal government.  Awards
in response to this RFA will be made to foreign institutions only for
research of very unusual merit, need, and promise, and in accordance
with PHS policy governing such awards.  Applications from minority
individuals and women are encouraged.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) individual
research grant award (R01) and is a one-time solicitation for new
applications.  Applicants, who will plan and execute their own
research programs, are requested to furnish their own estimates of
the time required to achieve the objectives of the proposed research
project.  Up to five years of support may be requested.  At the end
of the official award period, renewal applications may be submitted
for peer review and competition for support through the regular grant
program of the NHLBI.  It is anticipated that support for the present
program will begin July 1, 1994.  Administrative adjustments in
project period/or amount of support may be required at the time of
the award.  Since a variety of approaches would represent valid
responses to this announcement, it is anticipated that there will be
a range of costs among individual grants awarded.  All current
policies and requirements that govern the research grant programs of
the NIH will apply to grants awarded in connection with this RFA.

FUNDS AVAILABLE

It is anticipated that for fiscal year 1994, $1,500,000 will be
available for this initiative.  Approximately $750,000 of that amount
will be provided through an initiative of the Advanced Biomaterials
Program of the Federal Coordinating Council for Science, Engineering
and Technology (FCCSET).  It should be noted that award of grants
pursuant to this RFA is contingent upon receipt of funds for this
purpose.  It is anticipated that about six to eight new grants will
be awarded under this program.  The specific amount to be funded
will, however, depend on the merit and scope of the applications
received and on the availability of funds.  If collaborative
arrangements involve sub-contracts with other institutions, the NHLBI
Grants Operations Branch (telephone 301-594-7436) should be consulted
regarding procedures to be followed.

RESEARCH OBJECTIVES

Background

Recent progress in inactivating viruses in plasma derivatives has
been highly successful.  Safe and efficient inactivation procedures
have been developed and are now widely available.  One of these
methods, which was developed under NHLBI support, involves treatment
of material with organic solvent and detergent.  This approach has
been applied successfully to coagulation factor concentrates, immune
globulins, lymphokines and other growth factors.  Plasma derivatives
treated with solvent/detergent mixtures are now prepared in over 14
countries around the world.  Derivatives that are manufactured using
this method have shown no evidence of transmission of hepatitis B
virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus
(HIV) in studies designed to monitor the transmission of these
agents.

Conversely, attempts to develop inactivation procedures to destroy
the infectivity of viruses in blood and blood components have been
uniformly unsuccessful despite considerable research activity in this
area.  The fragile nature of cellular components, particularly plasma
membranes, make them extremely susceptible to disruption by virucidal
procedures.  As a result, the destruction of viral activity is often
accompanied by loss of cellular function.  Consequently, whole blood
and cellular components including red blood cell concentrates,
platelet concentrates, and leukocyte concentrates, continue to carry
a risk of virus transmission.  Current risks of being infected with a
unit of screened blood are 1 in 3,000 for HCV, 1 in 200,000 for HBV,
and 1 in 225,000 for HIV.  In addition, viruses such as the human
T-cell lymphotropic viruses (HTLV) types I and II, and
cytomegalovirus (CMV), also pose potential risks following the
transfusion of blood or blood components.  Despite advances in donor
selection and blood donor screening, it is unlikely that the risk of
transmission of these viruses will be completely eliminated without
the introduction of efficient virucidal or virus-removal procedures
that maintain cellular function.

Over the past five years, investigators supported under an NHLBI RFA
program have explored a number of different approaches to inactivate
or remove viruses from blood and blood components including the use
of UV-C irradiation, filtration, hydrolyzed diol epoxides, ozone,
halogenated oxidizing agents, and photoactive dyes for viral
sterilization of fresh frozen plasma, red blood cell concentrates,
and platelet concentrates.  Removal of leukocytes by filtration was
shown to reduce CMV transmission to susceptible patients; however,
elimination of HIV-infected cells by this method was incomplete, and
filtration could not be expected to remove cell-free virus.  The use
of UV or ionizing irradiation is attractive because of its
simplicity; however, the dose of gamma-irradiation used to inactivate
lymphocytes is not sufficiently virucidal, and the virucidal doses
are generally cell-destructive.  UV irradiation was found to
inactivate HIV under conditions generally favorable to platelets.
However, important caveats on the use of UV remain; viral sensitivity
to UV treatment seems to depend on the size of the viral genome and
whether it is single or double stranded and, apparently, suboptimal
doses for viral inactivation induce virus activation and/or
replication. Hydrolyzable compounds such as beta-propriolactone have
proved highly virucidal but failed to destroy sufficient virus under
conditions tolerated by cellular components.  The use of ozone has
been shown to inactivate HIV but virucidal doses often cause
hemolysis.  Promising results have been obtained with the treatment
of whole blood and red blood cells with photodynamically active dyes.
Cell-associated virus has been known to be inactivated by these
procedures under conditions where uninfected cells maintain their
functional integrity.  Techniques need to be developed to allow
ultraviolet light or other energy sources to penetrate to all
circulating elements.  This approach will require methods to move
blood through narrow pathways and perhaps the development of new
plastics that facilitate the penetration of light.  There is also a
need to evaluate and contrast the advantages of continuous flow
irradiation with batch irradiation of intact red blood cell
concentrates and platelet concentrates.  This evaluation should
include the extent of viral inactivation and the impact of
irradiation on cellular integrity immediately following treatment and
during storage under standard blood bank conditions.

While significant progress has been made under the previous RFA
program toward the development of inactivation procedures, additional
research is urgently needed to better understand the mode of action
of these as well as other virucidal reagents and procedures so as to
apply and optimize their use in a blood banking environment.
Furthermore, studies on the removal of viruses from biological
materials in ways that permit the treated products to be used
clinically are also needed and are an important goal of this RFA.
Possible approaches include viral adherence to affinity columns; use
of monoclonal antibodies for in vitro neutralization;
absorption-filtration procedures; centrifugal removal of viruses; and
use of filters for leukodepletion.

In summary, transfusion practices continue to carry a small but
unacceptable risk of infection from transfusion-transmitted viruses.
The solution to this problem is the development of inactivation or
virus removal procedures that do not destroy the functional integrity
of blood or blood components.  Some procedures are currently
available such as the use of photochemicals that inactivate nucleic
acids and destroy virus infectivity with minimal effects on nucleic
acid-free red cells and platelets.  What is needed are technological
advances that would permit the use of photochemicals and inactivation
procedures in an efficient cost-effective  fashion that is compatible
with the operation of a large-scale blood center.  Other forms of
viral inactivation that maintain the functional integrity of blood
components also need to be pursued.  This program encourages basic
and applied research on the development and evaluation of procedures
to remove or destroy the infectivity of transfusion-transmitted
viruses in blood and blood components while maintaining the
therapeutic effectiveness of these preparations.

Exclusions:  Epidemiological studies, large-scale clinical trials,
and large multi-project grant applications (program project grants)
are specifically excluded from this RFA.

SPECIAL REQUIREMENTS

Upon initiation of the program, the NHLBI will sponsor annual
meetings to encourage the exchange of information among investigators
who participate in this program.  In the preparation of the budget
for the grant application, applicants should request additional
travel funds for one meeting each year to be held in Bethesda,
Maryland.  Applicants should also include a statement in the
applications indicating their willingness to participate in such
meetings.

STUDY POPULATIONS

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

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements will be required to include minorities and
women in study populations so that research findings can be of
benefit to all persons at risk of the disease, disorder or condition
under study; special emphasis should be placed on the need for
inclusion of minorities and women in studies of diseases, disorders
and conditions which disproportionately affect them.  This policy is
intended to apply to males and females of all ages.  If women or
minorities are excluded or inadequately represented in clinical
research, particularly in proposed population-based studies, a clear
compelling rationale should be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues should be addressed in developing a research
design and sample size appropriate for the scientific objectives of
the study.  This information must be included in the form PHS 398
(rev. 9/91) in Sections 1-4 of the Research Plan AND summarized in
Section 5, Human Subjects.  Applicants are urged to assess carefully
the feasibility of including the broadest possible representation of
minority groups.  However, NIH recognizes that it may not be feasible
or appropriate in all research projects to include representation of
the full array of United States racial/ethnic minority populations
(i.e., Native Americans, Blacks, and Hispanics).  The rationale for
studies on single minority population groups should be provided.

For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology, (and
preventive strategies), diagnosis, or treatment of diseases,
disorders or conditions, including but not limited to clinical
trials.

The usual NIH policies concerning research on human subjects also
apply. Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including
minorities.

If the required information is not contained within the application,
the application will be deferred until the information is provided.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the
selected study population is inadequate, it will be considered a
scientific weakness or deficiency in the study design and will be
reflected in assigning the priority score to the application.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not award
grants or cooperative agreements that do not comply with these
policies.

LETTER OF INTENT

Prospective applicants are asked to submit, by December 10, 1993, 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.  Such letters are requested
only for the purpose of providing an indication of the number and
scope of applications to be received; therefore their receipt is
usually not acknowledged.  A letter of intent is not binding, and it
will not enter into the review of any application subsequently
submitted, nor is it a necessary requirement for the application.

This letter of intent is to be sent to:

Acting Chief, Centers and Special Projects Review Section
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 553
Bethesda, MD  20892
Telephone:  (301) 594-7448
FAX:  (301) 594-7407

APPLICATION PROCEDURES

Applications are to be submitted on the research grant application
form PHS 398 (rev. 9/91).  This form is available in an applicant
institution's office of sponsored research 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.  Use the conventional format for research
grant applications and ensure that the points identified in the
section on REVIEW CONSIDERATIONS are fulfilled.

To identify the application as a response to this RFA, check "YES" on
Item 2a of page 1 of the application and enter the RFA number and
title:  IN VITRO INACTIVATION OF VIRUSES IN BLOOD COMPONENTS: HL
94-005-B

The RFA label available in the PHS 398 application kit must be
affixed to the bottom of the face page of the original copy 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.

Send or deliver the completed application and three signed, exact
photocopies to the following, making sure that the original
application with the RFA label attached is on top:

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

Send an additional two copies of the application to the Chief,
Centers and Special Projects Review Section at the address listed
under LETTER OF INTENT.  It is important to send these two copies at
the same time as the original and three copies are sent to the
Division of Research Grants.  Otherwise the NHLBI cannot guarantee
that the application will be reviewed in competition for this RFA.

Applications must be received by February 10, 1994.  If an
application is received after that date, it will be returned to the
applicant without review.  The Division of Research Grants (DRG) will
not accept any application in response to this announcement that is
essentially the same as one currently pending initial review, unless
the applicant withdraws the pending application.  The DRG 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 the
DRG and responsiveness by the NHLBI.  Incomplete applications will be
returned to the applicant without further consideration.  If the
application is not responsive to the RFA, NHLBI 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 may be triaged by an NHLBI peer review group on the
basis of relative competitiveness.  The NIH will withdraw from
further competition those applications judged to be non-competitive
for award and notify the applicant Principal Investigator and
institutional official.  Those applications judged to be competitive
will undergo further scientific merit review.  Those applications
that are complete and responsive will be evaluated in accordance with
the criteria stated below for scientific/technical merit by an
appropriate peer review group convened by the Division of Extramural
Affairs, NHLBI.  The second level of review will be provided by the
National Heart, Lung, and Blood Advisory Council.

Review criteria

The factors to be considered in the evaluation of scientific merit of
each application will be similar to those used in the review of
traditional research grant applications, including the novelty,
originality, and feasibility of the approach; the training,
experience and research competence of the investigator(s); the
adequacy of the experimental design; the suitability of the
facilities; and the appropriateness of the requested budget to the
work proposed.

AWARD CRITERIA

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

Awards in response to this RFA will be made to foreign institutions
only for research of very unusual merit, need, and promise, and in
accordance with PHS policy governing such awards.

INQUIRIES

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

Inquiries regarding this Request for Applications may be directed to:

Dr. Luiz H. Barbosa
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
Federal Building, Room 504
Bethesda, MD  20892
Telephone:  (301) 496-1537
FAX:  (301) 402-4843

For fiscal and administrative matters, contact:

Ms. Jane R. Davis
Blood Diseases and Resources Grants Management Section
National Heart, Lung, and Blood Institute
Westwood Building, Room 4A11
Bethesda, MD  20892
Telephone:  (301) 594-7436
FAX:  (301) 594-7492

AUTHORITY AND REGULATIONS

The programs of the Division of Blood Diseases and Resources, NHLBI,
are described in the Catalog of federal Domestic Assistance number
93.839.  Awards will be 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 42 CFR
Part 52 and CFR Part 74.  This program is not subject to the
intergovernmental review requirements of Executive Order 12372, or to
Health Systems Agency review.

.

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