INTEGRATED PRECLINICAL/CLINICAL AIDS VACCINE DEVELOPMENT PROGRAM

Release Date:  March 6, 2000

PA NUMBER:  PAR-00-072

National Institute of Allergy and Infectious Diseases

Application Receipt Dates: June 13, 2000, 2001, 2002.

APPLICATIONS IN RESPONSE TO THIS PROGRAM ANNOUNCEMENT (PA) MUST BE PREPARED 
USING A MULTI-PROJECT GRANT APPLICATION FORMAT; SPECIFIC INSTRUCTIONS FOR 
COMPLETING THE APPLICATION ARE IN THE NIAID BROCHURE ENTITLED "INSTRUCTIONS 
FOR APPLICATIONS FOR MULTI-PROJECT AWARDS.”

PURPOSE

The National Institute of Allergy and Infectious Diseases (NIAID) of the 
National Institutes of Health (NIH) invites applications for research aimed 
at obtaining a safe and efficacious vaccine against HIV or AIDS.  NIAID 
supports the progressive stages of AIDS vaccine research and development 
including basic research, iterative product development, and clinical trials.  
NIAID supports AIDS prophylactic vaccine research and development via three 
grant programs. The Innovation Grant Program for AIDS Vaccine Research 
supports high risk/high impact early stage concept evaluation for projects 
with limited preliminary data.  The HIV Vaccine Research and Design (HIVRAD) 
Program supports multi-project investigator-initiated HIV vaccine design and 
development research.  The Integrated Preclinical/Clinical AIDS Vaccine 
Development (IPCAVD) Program supports iterative product development and 
optimization in the later stages of vaccine research and includes limited 
human studies.

This Program Announcement (PA) replaces PAR-97-056 and is a continuation of 
the Integrated Preclinical/Clinical AIDS Vaccine Development Program.  For an 
overview of these research programs and other information, visit the NIAID 
AIDS Vaccine Research Website at:  
http://www.niaid.nih.gov/daids/vaccine/default.htm
 
HEALTHY PEOPLE 2010

The Public Health Service (PHS) is committed to achieving the health 
promotion and disease prevention objectives of "Healthy People 2010," a PHS-
led national activity for setting priority areas.  This PA, “INTEGRATED 
PRECLINICAL/CLINICAL AIDS VACCINE DEVELOPMENT PROGRAM”, is related to the 
focus area(s) of immunization and infectious diseases, HIV infection, and 
sexually transmitted diseases.  Potential applicants may obtain a copy of 
"Healthy People 2010" at http://www.health.gov/healthypeople

ELIGIBILITY

Applications may be submitted by domestic 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.  In accordance with NIH policy, foreign institutions 
are not eligible for Program Project Grant (P01) awards.  However, for this 
initiative, NIAID has been granted an exception. Foreign institutions may 
apply for grants under this Program Announcement however all other 
restrictions on foreign grant applications will apply. Racial/ethnic minority 
individuals, women, and persons with disabilities are encouraged to apply as 
Principal Investigators.

MECHANISMS OF SUPPORT

Program project grant (P01) applications may be submitted in response to this 
announcement.  Program project grants support broadly based, 
multidisciplinary research programs that have a well-defined, central 
research focus or objective.  An important feature 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.  Standard NIH policy requires P01 
applications to consist of a minimum of three interrelated individual 
research projects that contribute to the program objective.  This type of 
award also can provide support for certain common resources termed cores.  
Such resources should be utilized by two or more projects within the award.  
An exception to standard policy has been granted for this program 
announcement such that fundable applications must have at least two (2) 
projects and one core. The total project period for P01 grants may not exceed 
five years.

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

Applicants for P01 grants must follow special application guidelines in the 
NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT 
AWARDS (April 1999); this brochure is available via the WWW at:
http://www.niaid.nih.gov/ncn/grants/multibron.htm
In the case of any discrepancies, this PA will supercede the instructions in 
the Brochure.

RESEARCH OBJECTIVES

Background

Vaccine research requires contributions from multiple fields including 
immunology, virology, animal models, and molecular biology. The IPCAVD 
program aims to foster the later stages of AIDS vaccine development that 
includes the transition of promising concepts from laboratory to clinic.

Research Objectives and Scope

As stated above, the overall goal of this PA is to support multidisciplinary 
research that will lead to a safe and protective AIDS vaccine.  As such, 
IPCAVD applications must include human clinical studies within the term of 
the award.

Studies responsive to this PA can include, but are not limited to: vaccine 
delivery and vector systems; methods of enhancing specific immune responses; 
dissection of viral and host contributions to immunity and combinations of 
these. Research directed toward optimization of existing vaccine concepts is 
also encouraged.
 
Applications can include preclinical research, vaccine production, and 
clinical testing. However, preclinical research alone, without clear, 
feasible, and realistic plans for progressing to human testing within the 
period of award, will not be considered responsive to this PA. Applicants 
must delineate discrete goals, milestones, and criteria that can be used to 
evaluate progress toward a testable vaccine.  If preclinical evaluation of 
the concept, according to these milestones, demonstrates that further studies 
should not be pursued, funding for those latter phases of the project will 
not be released.
 
Applicants may also request funds for production of clinical grade 
(manufactured under Food and Drug Administration (FDA)-Good Laboratory 
Practices (GLP) guidelines) vaccine and subsequent in vivo testing. 
Applicants seeking to move from preclinical research to lot production must 
detail the goals, milestones, and criteria, which will be reviewed by the 
Scientific Review Group (SRG), to justify the release of funds for this 
purpose.

Since human studies will require the filing of an IND application with the 
FDA, certain regulatory requirements must be met prior to the release of 
funds to initiate this part of the study. Additionally, information that may 
be useful in improving or refining the vaccine may arise during these 
clinical studies. The applicant should address how the results of the 
clinical evaluations will be used to either improve the vaccine concept or 
advance it through further human testing.
 
Applicants must address the following issues in their application regarding 
human studies: design of the clinical trial, plans for recruitment, 
enrollment, education and follow-up of clinical subjects, including attention 
to the possibility of social harms and discrimination arising from vaccine-
induced positive screening tests that may be interpreted incorrectly as HIV 
infection, plus documentation of compliance with all applicable federal 
(FDA), state and local laws and regulations governing clinical research. The 
completeness and feasibility of these plans will be reviewed by the SRG.

Investigators are encouraged to discuss clinical evaluation of their 
candidate vaccines by the NIAID-supported HIV Vaccine Trials Network (HVTN) 
with NIAID Program Staff. For clinical trials, NIAID Program Staff can 
arrange for review of data by the AIDS Vaccine Data and Safety Monitoring 
Board, which reviews data for HVTN trials. Funds available under this PA are 
for small-scale early phase clinical studies. Investigators interested in 
pursuing NIAID support for large-scale human vaccine trials should contact 
the HVTN (see below for contact information).

Vaccine research focused solely on therapeutic application is not responsive 
to this announcement. The safety evaluation of immunogens in infected animals 
or people may be included if these studies directly support the development 
of a prophylactic vaccine.  For information on programs that support 
therapeutic vaccine development please contact program staff.
 
The participation of the private sector is strongly encouraged because of its 
unique infrastructure, experience in product manufacture and development, and 
capital resources.  These capabilities are considered to be especially 
appropriate and valuable for collaborative studies in this area.  For 
example, a pharmaceutical or biotechnology company might participate in an 
individual project that provides testing of a preclinical concept and 
sufficient production of a vaccine when the product is needed to conduct 
studies.

SPECIAL REQUIREMENTS 

All awardees are strongly encouraged to attend an NIAID-sponsored annual 
meeting on AIDS vaccine research and development and may include a request 
for travel funds for this purpose.

Patent Coverage
 
Since applications may involve several institutions, including the private 
sector, complex patent situations may arise. To avoid delays in the 
implementation of new vaccines for HIV related to intellectual property 
issues, each multi-project group is to provide a plan as part of the 
application, detailing 1) the approach, agreed to by all parties, to be used 
for obtaining patent coverage and for licensing, where appropriate, and, 2) 
the procedures to be followed for the resolution of legal problems that 
potentially may develop.

Attention is drawn to the reporting requirements of 35 U.S.C. Parts 200-212 
and 37 CFR Part 401 or FAR 55.227-11. Instructions were also published in the 
NIH GUIDE FOR GRANTS AND CONTRACTS, Vol. 19, No. 23, June 22, 1990. Note that 
non-profit organizations (including universities) and small business firms 
retain the rights to any patent resulting from Government grants or 
cooperative agreements.
 
It is also noted that a Presidential memorandum of February 18, 1983, 
extended to all business concerns, regardless of size, the first option to 
the ownership of rights to inventions as provided in P.L. 96-517. As a result 
of this memorandum, the relationships among industrial organizations and 
other participants are simplified, since all Group members can now be full 
partners in the research and in any inventions resulting there from. The 
specific patenting arrangements among the institutions may vary and could 
include joint patent ownership, exclusive licensing arrangements, etc. 
Applicants are encouraged to develop an arrangement that is most suitable for 
the Group's particular circumstances.
 
The agreement among the institutions comprising the Group, signed and dated 
by the organizational officials authorized to enter into patent arrangements 
for each Group member and member institution, must be delivered prior to 
submission of the application to Dr. Steve Bende, at the address listed under 
INQUIRIES. A copy of the patent agreement should also be submitted with the 
application. If the Group wishes to place all inventions and discoveries 
resulting from these studies within the public domain, a letter to that 
effect must be submitted to Dr. Bende in lieu of the patent agreement. The 
letter must be co-signed by the Principal Investigator, each of the Project 
Leaders, and each of the business officials representing the respective 
institutions.
 
Federal regulation clause 37-CFR-401 and HHS Inventions regulations at 45 CFR 
Parts 6 and 8 require that NIH be informed of inventions and licensing 
occurring under NIH funded research. Invention and licensing reports must be 
submitted to the Extramural Invention Reports Office at 301 435 1986.
 
Terms of Award

On February 24, 2000, NIAID announced its expanded policies on MONITORING OF 
CLINICAL TRIALS AND STUDIES in the NIH Guide at: 
http://grants.nih.gov/grants/guide/notice-files/NOT-AI-00-003.html.

Applications and awards with component clinical trials and studies must 
adhere to these policies including the terms and conditions of award; see 
http://www.niaid.nih.gov/ncn/pdf/clinterm.pdf 

Phased Release of Funds:

For awards including vaccine pilot lot production, release of funds for this 
purpose will be contingent on successful accomplishment of milestones and 
criteria proposed by the applicant. Release of funds for clinical research 
will be contingent on successful accomplishment of milestones and criteria 
for preclinical evaluation of the product and plans for its production and 
availability of funds.

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 at: 
http://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: http://grants.nih.gov/grants/guide/notice-files/not98-024.html

Investigators may obtain copies from these sources or from Dr. Steve Bende 
(listed in INQUIRIES below) who may also provide additional relevant 
information concerning the policy.

APPLICATION PROCEDURES

Applicants for P01 grants must follow special application guidelines in the 
NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT 
AWARDS (April 1999); this brochure is available at: 
http://www.niaid.nih.gov/ncn/grants/multibron.htm

Where differences exist, instructions in this Program Announcement take 
precedence over instructions in the Multi-Project Awards Brochure, which 
takes precedence over the standard PHS 398 instructions.

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) 435-
0714, email: Grantsinfo@nih.gov  Applications are also available at: 
http://grants.nih.gov/grants/forms.htm.

All applications in response to this PA must include detailed rather than 
modular budgets.

For purposes of identification and processing, item 2a on the face page of 
the application must be marked "YES" and the PA number as stated on the title 
page of this Program Announcement and the words "INTEGRATED 
PRECLINICAL/CLINICAL AIDS VACCINE DEVELOPMENT PROGRAM" must be typed in.

Applications must be received by June 13 of the 3 years of the PA.  
Applications that are not received as a single package on the receipt date or 
that do not conform to the instructions contained in PHS 398 (rev. 4/98) 
Application Kit (as modified in, and superseded by, the NIAID BROCHURE 
ENTITLED "INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS"), will be 
judged non-responsive and will be returned to the applicant.  

It is required that the appropriate NIAID program contact be consulted before 
submitting the application to obtain approval for acceptance of applications 
requesting direct costs $500,000 or more in any year of the proposed grant.  
(See program contact under INQUIRIES).

Submit a signed, typewritten original of the application, including the 
checklist; the original of the appendices (if any); and three signed, exact, 
single-sided photocopies of the application (no copies of the appendices), 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 mail or courier service)

At the time of submission, two additional exact copies of the grant 
application and all five copies of any appendix materials must be sent to Dr. 
Dianne Tingley at the address listed under INQUIRIES.
  
Concurrent submission of an R01 and a Component Project of a Multi-project 
Application:  Current NIH policy permits a component research project of a 
multi-project grant application to be concurrently submitted as a traditional 
individual research project (R01) application.  If, following review, both 
the multi-project 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 multi-project grant.  This is an NIH policy 
intended to preserve the scientific integrity of a multi-project grant, which 
may be seriously compromised if a strong component project(s) is removed from 
the program.  Investigators wishing to participate in a multi-project grant 
must be aware of this policy before making a commitment to the Principal 
Investigator and awarding institution.

GCRC INSTITUTIONS

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 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

Review Procedures

Applications will be assigned to NIAID on the basis of established NIH 
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.

P01 applications that are complete and responsive to this PA will be 
evaluated for scientific and technical merit by an appropriate peer review 
group convened by the NIAID.

Review Criteria

The NIAID brochure "INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT 
AWARDS”(April 1999) states the general review criteria for P01 applications. 
Additional review criteria specific to this PA are:

For preclinical evaluation of vaccine concepts/strategies reviewers will 
consider:
 
A.  The overall scientific and technical merit of the proposed vaccine study 
with regard to impact on the AIDS epidemic.
 
B.  Appropriateness and adequacy of the experimental approach and the 
methodology proposed to carry out the research, specifically including the 
feasibility of the applicant's plans, and the availability of necessary 
facilities to conduct the research. In addition, the goals and milestones to 
be met for progression through to production and in vivo trial will be 
reviewed for adequacy, feasibility, and likelihood of attainment during the 
period of the grant.
 
For production of clinical grade vaccine product, reviewers will consider:
 
A.  Appropriateness of the scientific rationale for advancing to the vaccine 
production stage, and suitability of the proposed milestones and criteria to 
be attained in order to merit funding. The SRG will judge the suitability of 
such criteria. If satisfactory proof that these criteria and milestones have 
already been met is supplied, funds to produce vaccine product will be 
released at the time of grant award.
 
B.  Completeness and feasibility of the plan to produce the vaccine. This 
includes adherence to any and all federal (FDA), state, and local regulations 
for the production of clinical grade material.
 
For clinical studies, reviewers will consider:
 
A.  Scientific, technical, and clinical significance and originality of the 
proposed research.
 
B.  The completeness of plans for the design of the clinical trial, plans for 
recruitment, enrollment, education and follow-up of clinical subjects.  This 
includes the safety, monitoring, and possibility of social harms and 
discrimination arising from vaccine-induced positive screening tests that may 
be interpreted incorrectly as HIV infection, and other harms such as true HIV 
infection as the result of vaccination, and compliance with all applicable 
Federal, State and local laws and regulations governing clinical research 
will be reviewed by the SRG. Appropriateness of the proposed criteria and 
milestones to be met to permit release of funds and progression of the study 
to the clinical phase.

For all applications:
 
A.  Leadership and research experience of the Principal Investigator and key 
staff in the areas of proposed research. For clinical-grade vaccine 
production, the track record and facilities of the proposed producer. For 
clinical trials research, the leadership, scientific ability and 
administrative competence of the applicant for the development, 
implementation and management of pilot clinical trials, and for effective 
interaction with designated NIAID staff.
 
B.  Adequacy of the proposed means for protecting against adverse effects of 
the research upon humans, animals or the environment, where such are 
involved.

C.  Justification of the usefulness of the core facilities to the various 
research projects, including the administrative core, if applicable. Each 
core unit must provide essential facilities or service for two or more 
approved individual projects.

D.  A sound institutional administrative and organizational structure that 
facilitates attainment of the objective(s) of the program, including fiscal 
responsibility and management capability to assist the PI and staff in 
following PHS policy.

The initial review group will also examine:  the adequacy of plans to include 
children and both genders and minorities and their subgroups as appropriate 
for the scientific goals of the research and plans for the recruitment and 
retention of subjects.

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 announcement, and 
availability of funds.  The NIAID gives special consideration for funding, 
including award of grants beyond the established NIAID percentile and 
priority score paylines, to scientifically meritorious applications in 
response to Program Announcements.

INQUIRIES

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

Requests for the NIAID brochure “INSTRUCTIONS FOR APPLICATIONS FOR MULTI-
PROJECT AWARDS” as well as inquiries regarding programmatic (research scope, 
eligibility and responsiveness) issues may be directed to:

Steve Bende, Ph.D.
Division of AIDS
National Institute of Allergy and Infectious Diseases
6700-B Rockledge Drive, Rm. 4107, MSC 7628
Bethesda, MD 20892-7628
Telephone: (301) 435-3756
Fax:  (301) 435-6511
Email:  sb22k@nih.gov

Direct inquiries regarding review issues to:
 
Dr. Dianne Tingley
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6700-B Rockledge Dr. Room 2148, MSC 7616
Bethesda, MD  20892-7616
Bethesda, MD  20817 (for express/courier service)
Telephone:  (301) 496-0818
FAX:  (301) 402-2638
Email:  dt15g@nih.gov

Direct inquiries regarding fiscal matters to:

Jane Unsworth
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6700-B Rockledge Drive, Rm. 2128, MSC 7614
Bethesda, MD 20892-7614
Telephone: (301) 402-6824
Fax: (301) 480-3780
Email: ju3a@nih.gov

Direct inquiries regarding the HVTN to:

Dr. Jorge Flores
Division of AIDS
National Institute of Allergy and Infectious Diseases
6700-B Rockledge Drive, Rm. 4154, MSC 7628
Bethesda, MD 20892-7628 (301) 
Telephone: (301) 435-3758
Fax:       (301) 435-6511
Email:     jf30t@nih.gov

AUTHORITY AND REGULATIONS

This program is supported under authorization of the Public Health Service 
Act, Sec. 301 (c) and 405 (42 USC 241 and 284).  The Catalogue of Federal 
Domestic Assistance Citations are Sec. 93.856, Microbiology and Infectious 
Diseases Research, and No. 93.855 - Immunology, Allergy, and Transplantation 
Research.  Awards will be administered under PHS grants policies and Federal 
Regulations 42 CFR Part 52 and 45 CFR Part 74 and 94.  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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