LABORATORY METHODS TO ASSESS RESPONSES TO HIV VACCINE CANDIDATES

Release Date:  January 20, 1999

PA NUMBER:  PA-99-044

P.T.

National Institute of Allergy and Infectious Diseases

PURPOSE

The National Institute of Allergy and Infectious Diseases (NIAID), National
Institutes of Health (NIH), invites applications to conduct innovative research
to develop and improve technologies for evaluation of immune responses to HIV
vaccines and to expand the range and scope of immune functions currently measured
in vaccine trials.

This PA intends to complement the scope of vaccine research carried out in human
volunteers and animals receiving experimental HIV/SIV vaccines in prophylactic
and/or therapeutic trials funded through other programs.  Development of new
techniques that detect and quantitate changes in innate (non-specific) and HIV-
specific responses  will be fostered.

Research may include comparative analysis of samples acquired from individuals
infected with HIV or who have been exposed to, but not infected with HIV. 
Studies in animals, particularly primates that have received SIV/SHIV vaccines
are also encouraged. Applications to develop reagents (including non-clade B
based materials), to adapt assays to field conditions and to improve on cell
cryo-preservation methods are also appropriate.  The PA is not intended to
directly support the conduct of human or animal clinical trials.

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 PA, "LABORATORY METHODS TO ASSESS
RESPONSES TO HIV VACCINE CANDIDATES", is related to the priority area(s) of HIV
infection, and Immunization and Infectious. 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

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

Traditional research project grant (R01) applications may be submitted in
response to this PA.  Applicants may request up to five years of support.
Responsibility for the planning, direction, and execution of the proposed
research for all applicable mechanisms of support will be solely that of the
applicant.

RESEARCH OBJECTIVES

Background

The identification of immune correlates of resistance to HIV infection/disease
would greatly facilitate the development of HIV vaccines.  Planned HIV vaccine
efficacy trials in humans and challenge studies in animals provide opportunities
to determine such correlates.  However, the majority of the current assays to
evaluate immune responses to vaccines are complex, limited in scope, time
consuming, and difficult to quantitate.  Consequently, there is a need to develop
and improve immune assays to evaluate currently available vaccines and to guide
new product development.

Research Objectives and Scope

This PA encourages applications to develop new assays to evaluate immune
responses that are induced by HIV vaccines, to improve existing assays, to expand
the range of functional assays, to develop relevant cell cryo-preservation
methods, and to adapt and apply such assays to high through-put use under field
conditions.

This PA also encourages research on the development of appropriate assays to
study newly identified immune mechanisms. It is expected that the application of
these new assays may eventually yield information on the functional importance
of such mechanisms for resistance to HIV infection.

Important areas in need of research may include, but are not limited to: 

o  Novel approaches to increase the sensitivity and practicality of HIV
neutralization assays.

o  Development and adaptation of continuous cell lines that express CD4, HIV co-
receptors and other host genes as may be necessary for use in neutralization
assays.

o  Development of alternative cytotoxic T lymphocyte (CTL) assays, such as the
ELISPOT and "tetramer" assays, and comparisons of their sensitivity, 
specificity, reproducibility and precision with existing assays.

o  Tests to evaluate the magnitude and breadth of HIV-specific helper T cell
induction by vaccines (could include skin tests as well as laboratory assays).

o  Assays that reproduce the "in vivo" interactions between HIV-specific helper
T cells and CTLs or B cells.

o  Assays to evaluate the levels, patterns, function and significance of
cytokines and chemokines induced by HIV vaccines. 

o  Detection and quantification of vaccine-induced in vitro resistance of PBMCs
to HIV infection. 

o  Assays to evaluate the magnitude and potential function of HIV-specific
mucosal immune responses to vaccines.

o  Evaluation of HIV-specific antibody dependent cytotoxicity (ADCC) and other
antibody-mediated immune functions (agglutination, virolysis, infectivity
enhancement, etc.).

o  In vitro identification and quantification of HIV antigen-specific primed B
cells.

o  Enhancement of innate (non-specific) immune functions induced by HIV vaccines
and adjuvants and active against HIV or HIV-infected cells.

o  Further development of cryo-preservation methods that maintain cell function.

The research studies may be conducted within a single laboratory or in
conjunction with other laboratories at the same or different institutions
specializing in different research areas. Applicants are strongly encouraged to
establish collaborations with individuals or institutions having relevant
expertise and access to human volunteers or experimental animals receiving HIV
or SIV candidate vaccines.

Potential applicants are encouraged to contact the program staff listed under
INQUIRIES for guidance concerning the organization and scope of the proposed and
the preparation of the application. Program staff may be able to facilitate
contact with appropriate investigators conducting vaccine-related clinical or
preclinical studies.

o  Investigators should, prior to application, arrange for access to samples from
existing clinical and cohort studies, such as those conducted by the HIVNET and
AVEG, through the existing "Material Transfer Agreements" of these organizations. 
It is the responsibility of the applicants to establish and fully document any
collaborative arrangements with such networks or with other collaborators prior
to the submission of grant applications.  Program staff listed under INQUIRIES
may assist by suggesting relevant clinical trials of vaccines, human cohorts'
studies, non-human primate studies, or reagent resources.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and their
subpopulations must be included in all NIH supported biomedical and behavioral
research projects involving human subjects, unless a clear and compelling
rationale and justification are provided that inclusion is inappropriate with
respect to the health of the subjects of the purpose of the research.  This
policy results from the NIH Revitalization Act of 1993 (Section 492B of Public
Law 103-43).

All investigators proposing research involving human subjects should read the
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical
Research", which have been published in the Federal Register of March 28, 1994
(FR 59 14508-14513) and the NIH Guide for Grants and Contracts, Vol. 23, No. 11,
March 18, 1994, which is available via the www at:
http://www.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 Participating 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://www.nih.gov/grants/guide/notice-files/not98-024.html

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

SPECIAL REQUIREMENTS

Awardees will be invited to attend a meeting to present the progress of the work
funded under this program.  Details of this meeting will be provided post-award. 
Thus, applicants should include in their budget request funds for the PI to
attend one two-day meeting per year in the Washington, D.C. area.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
4/98) and will be accepted on the standard AIDS application deadlines as
indicated in the application kit.

Application kits are available at most institutional offices of sponsored
research and may be obtained 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
http://www.nih.gov/grants/forms.htm.

For purposes of identification and processing, item 2 on the face page of the
application must be marked "YES".  The PA number and the PA title must also be
typed in section 2.

The completed, signed original and five legible, single-sided copies of the
application must be sent or delivered to:

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

Applicants from institutions that have a General Clinical Research Centers (GCRC)
funded by the NIH National Center for Research Resources may wish to identify the
Center as a resource for conducting the proposed research.  If so, a letter of
agreement from the GCRC Program Director must be included in the application
material.

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS referral
guidelines. Upon receipt, applications will be reviewed for completeness by the
NIH Center for Scientific Review.  Incomplete applications will be returned to
the applicant without further consideration.  Applications will be reviewed for
scientific and technical merit by study sections of the Center for Scientific
Review, NIH, in accordance with the standard NIH peer review procedures.  As part
of the initial merit review, applications will receive a written critique and
undergo 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
appropriate national advisory 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 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.

AWARD CRITERIA

Applications will compete for available funds with all other favorably
recommended applications.  The following will be considered when making funding
decisions: quality of the proposed project as determined by peer review, program
balance among research areas of the program announcement, and availability of
funds.

INQUIRIES

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

Inquiries regarding programmatic (research scope and eligibility) issues may be
directed to:

Jorge Flores, M.D.
Division of AIDS
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 2A11
Bethesda, MD  20892-7640
Telephone: (301) 435-3758
FAX:  (301) 402-3684
Email:  jf30t@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Jackie Johnson
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4C16 - MSC 7610
Bethesda, MD  20892-7610
Telephone:  (301) 402-5936
FAX:  (301) 480-3780
Email:  jj19e@nih.gov

AUTHORITY AND REGULATIONS

This program is supported under authorization of the Public Health Service Act,
Sec. 301(c), Public Law 78-410, as amended.  The Catalogue of Federal Domestic
Assistance Citations are No. 93.855 - Immunology, Allergy, and Transplantation
Research and No. 93.856 - Microbiology and Infectious Disease Research. 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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