This Program Announcement expires on March 1, 2004, unless reissued.

NEW TECHNOLOGIES FOR HIV AND HIV VACCINE RELATED RESEARCH

Release Date:  February 22, 2001

PA NUMBER:  PA-01-055 (see Notice of Inactivation NOT-AI-04-009)

National Institute of Allergy and Infectious Diseases
 (http://www.niaid.nih.gov/)
National Institute of Dental and Craniofacial Research
 (http://www.nidcr.nih.gov)

Application Receipt Date:  STANDARD AIDS RECEIPT DATES

THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  IT 
INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS 
THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA.

PURPOSE

The National Institute of Allergy and Infectious Diseases (NIAID) and 
the National Institute of Dental and Craniofacial Research (NIDCR), 
National Institutes of Health (NIH), invites applications to conduct 
novel and innovative research in three target areas:  1) development of 
improved technologies for detecting HIV; 2) utilization of novel 
technologies to evaluate immune responses to HIV vaccines, as well as 
expansion of the range and scope of immune functions currently measured 
in HIV vaccine trials; and 3) utilization of novel technologies to 
measure and correlate immune responses that are responsible 
for/associated with the efficacy of non-HIV licensed vaccines.  

This program announcement (PA) is an expansion of a previously 
advertised PA entitled “Laboratory Methods to Assess Responses to HIV 
Vaccine Candidates” (PA-99-044).  This PA intends to complement the 
work conducted by the HIV Vaccine Trials Network (HVTN) and other 
programs supporting vaccine trials, as well as those conducting studies 
of animals receiving experimental HIV/SIV vaccines in prophylactic 
and/or therapeutic trials funded through programs in NIAID.  

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 Program 
Announcement (PA), “New Technologies for HIV and HIV Vaccine Related 
Research” is related to the focus area of “Immunization and Infectious 
Diseases.”  Potential applicants may obtain a copy of "Healthy People 
2010" at http://www.health.gov/healthypeople.

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 PA will use the National Institutes of Health (NIH) research 
project grant (R01, R03) award mechanism.  Responsibility for the 
planning, direction, and execution of the proposed project will be 
solely that of the applicant.  The total project period for an 
application submitted in response to this PA may not exceed five years.

Specific application instructions have been modified to reflect 
"MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined 
by the NIH. Complete and detailed instructions and information on 
Modular Grant applications can be found at
http://grants.nih.gov/grants/funding/modular/modular.htm.

A notice of modification and update (OD-00-046) regarding modular 
grants was released on 7/24/00 and can be found at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-046.html.

RESEARCH OBJECTIVES

This PA will support the use of novel and innovative technologies to: 
1) detect HIV, 2) quantitate and optimize measurement of immune 
responses to HIV and to candidate HIV vaccines, and 3) evaluate and 
quantitate immune responses responsible for the efficacy of licensed 
vaccines for other infectious diseases.  The ultimate objectives of 
this PA are first, to assist the development of sensitive, standardized 
assays for use in clinical HIV vaccine studies and second, to obtain a 
clearer understanding of the correlates of protection from HIV 
infection and immune-mediated control of disease progression so as to 
facilitate vaccine design.

Specifically, the PA encourages the development of new, highly 
sensitive technologies to permit the early recognition of HIV 
infection, and the detection of minimal levels of HIV replication and 
the differentiation from a transient infection that might arise in 
vaccinated individuals.  Current laboratory assays, such as 
neutralization, cytotoxic T cell assays, and proliferation assays, 
measure established immune responses in HIV-infected or vaccinated 
individuals.  However, there is no definitive evidence that these 
immune parameters are protective with regard to HIV infection or 
disease progression.  Hence, the PA also encourages the development of 
novel assays to determine the mechanism(s) of action of candidate HIV 
vaccines, and to identify and measure the responses that may correlate 
with vaccine-induced protection in a systematic, standardized way. The 
PA will also support the measurement of immune responses that are 
responsible for the efficacy of other licensed vaccines as a yardstick 
by which to evaluate the type of assays required for performing HIV 
vaccine trials and for quantitating the relevant immune responses. 

A particular goal of this PA is to include the application of genome-
wide expression profiling (chip, microarray or Serial Analysis of Gene 
Expression [SAGE]) technologies to clinical research studies of vaccine 
design, development, and evaluation, in any of the three targeted 
areas.  It is known that the susceptibility to acute infection with 
many pathogens is influenced by the host’s genetic background.  For 
example, in HIV infection, individuals lacking CCR5 surface expression 
are highly resistant to viral infection.  Genetic variation that may 
influence host-pathogen interactions has implications for understanding 
human immune cell function, designing rationale preventive vaccines, 
and for predicting vaccine efficacy in population-based studies. In 
addition, oligonucleotide/cDNA arrays may allow comprehensive high-
throughput screening of the effects of HIV infection or immunization 
(genetic, physiologic, pathologic, etc.) on gene expression in tissues 
and specific cell populations of interest.  Additionally, it is not 
known to what extent the viral vaccine strain genotype/phenotype must 
match circulating viruses in order to afford protection.  Techniques 
that allow rapid/thorough characterization of isolates in break-through 
infections would expedite an understanding of this issue. 

Research projects responsive to this PA may include comparative 
analyses 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.  The measurement and correlation of vaccine-induced 
protective responses in individuals immunized with licensed vaccines 
such as Hepatitis B for the determination of the relevance and 
importance of establishing similar assays for HIV vaccine studies is 
also encouraged.  Applications are encouraged to develop reagents 
(including non-clade B-based materials), to optimize or validate 
existing assays, or to adapt current assays such that they are simple, 
sensitive and easily transferable to international locations where 
future efficacy trials will be conducted.  The PA will not directly 
support the conduct of human trials or animal vaccine studies.

Scientific areas considered responsive to this PA may include, but are 
not limited to: 

o  the development of novel, highly sensitive technologies to identify, 
characterize and quantitate HIV in blood and tissues , including 
lymphoid and oral tissues, saliva and gingival fluid.  

o  the identification of new genetic or immune markers for immune 
responses to HIV, and exploration of their potential ability to serve 
as surrogates for protection from infection, disease progression or 
transmission to others

o  the comparison of candidate HIV vaccines to proven, efficacious, 
licensed, vaccines against other infectious diseases according to key 
immune parameters (e.g. kinetics, longevity, breadth of responses) 
using state-of-the art assays, such as ELISPOT

o  the development of assays to evaluate the magnitude and breadth of 
HIV-specific CD4 cell responses induced by vaccines that may be 
associated with improved prognosis in infected individuals

o  the development of laboratory assays that mimic the "in vivo" 
interaction between HIV-specific helper T cells and CTLs or B cells

o  the development or optimization of existing assays to evaluate and 
validate the magnitude and potential function of HIV-specific immune 
response (mucosal, systemic cellular, humoral) to HIV vaccine 
candidates in humans or experimental animals

o  the development of tissue culture assays to identify and quantify 
HIV antigen-specific primed B cells and distinguish effector cells from 
the memory pool

o  the development of innovative uses of DNA genome technology 
applicable to HIV clinical vaccine studies (e.g. HLA typing, subtyping 
the HIV genome, monitoring host gene expression in cell types or 
tissues post-infection or immunization)

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.  Human specimens 
to be used in these studies should be collected under appropriate 
informed consent processes.  Applicants are strongly encouraged to 
establish collaborations with individuals or institutions having 
relevant expertise in the ethical issues involving the use of fresh and 
stored human biological materials for research.

Investigators should, prior to application, arrange for access to 
samples from existing clinical and cohort studies, such as those 
conducted by the HVTN or Prevention Trials network (PTN), through the 
existing "Material Transfer Agreements" of these organizations.  It is 
the responsibility of the applicant to establish and fully document any 
collaborative arrangements with such networks or with other 
collaborators prior to the submission of a grant application.  

Potential applicants are encouraged to contact the program staff listed 
under INQUIRIES for guidance concerning the organization and scope of 
the proposed research and the preparation of the application. Program 
staff may be able to facilitate contact with appropriate HVTN or PTN 
investigators, as well as investigators performing DAIDS-supported 
preclinical studies in experimental animals.  Program staff also may 
assist by suggesting reagent resources as well as by coordinating the 
comparative testing and validation of immunological assays by supplying 
appropriate samples from DAIDS-sponsored clinical networks.   

SPECIAL REQUIREMENTS

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

TERMS AND CONDITIONS OF AWARD

When clinical studies or trials are a component of the research 
proposed, NIAID policy requires that studies be monitored commensurate 
with the degree of potential risk to study subjects and the complexity 
of the study.  Terms and Conditions of Award will be included with 
awards.  NIAID policy was announced in the NIH Guide on February 24, 
2000 and is available at: 
http://grants.nih.gov/grants/guide/notice-files/NOT-AI-00-003.html.  
The full policy including terms and 
conditions of award is available at: 
http://www.niaid.nih.gov/ncn/pdf/clinterm.pdf

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 UPDATED "NIH Guidelines For Inclusion of Women and Minorities 
as Subjects in Clinical Research," published in the NIH Guide for 
Grants and Contracts on August 2, 2000 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); a 
complete copy of the updated Guidelines are available at: 
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm.  
The revisions relate to NIH-defined Phase III clinical trials and 
require:  a) all applications or proposals and/or protocols to provide 
a description of plans to conduct analyses, as appropriate, to address 
differences by sex/gender and/or racial/ethnic groups, including 
subgroups if applicable; and b) all investigators to report accrual, 
and to conduct and report analyses, as appropriate, by sex/gender 
and/or racial/ethnic group differences.

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

URLS IN NIH GRANT APPLICATIONS OR APPENDICES

All applications and proposals for NIH funding must be self-contained 
within specified page limitations.  Unless otherwise specified in an 
NIH solicitation, internet addresses (URLs) should not be used to 
provide information necessary to the review because reviewers are under 
no obligation to view the Internet sites.  Reviewers are cautioned that 
their anonymity may be compromised when they directly access an 
Internet site.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 
(rev. 4/98) and will be accepted at the standard 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 301/435-0714, email: 
GrantsInfo@nih.gov.  In addition, the application kits can be found on 
the following URL: http://grants.nih.gov/grants/forms.htm.

Applicants planning to submit an investigator-initiated new (type 1), 
competing continuation (type 2), competing supplement, or any 
amended/revised version of the preceding grant application types 
requesting $500,000 or more in direct costs for any year are advised 
that he or she must contact the Institute or Center (IC) program staff 
before submitting the application, i.e., as plans for the study are 
being developed. Furthermore, the application must obtain agreement 
from the IC staff that the IC will accept the application for 
consideration for award. Finally, the applicant must identify, in a 
cover letter sent with the application, the staff member and Institute 
or Center who agreed to accept assignment of the application. 

This policy requires an applicant to obtain agreement for acceptance of 
both any such application and any such subsequent amendment. Refer to 
the NIH Guide for Grants and Contracts, March 20, 1998 at 
http://grants.nih.gov/grants/guide/notice-files/not98-030.html

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS

BUDGET INSTRUCTIONS

Modular Grant applications will request direct costs in $25,000 
modules, up to a total direct cost request of $250,000 per year. 
(Applications that request more than $250,000 direct costs in any year 
must follow the traditional PHS 398 application instructions.)  The 
total direct costs must be requested in accordance with the program 
guidelines and the modifications made to the standard PHS 398 
application instructions described below:

PHS 398

o  FACE PAGE:  Items 7a and 7b should be completed, indicating Direct 
Costs (in $25,000 increments up to a maximum of $250,000) and Total 
Costs [Modular Total Direct plus Facilities and 
Administrative(F&A)costs] for the initial budget period Items 8a and 8b 
should be completed indicating the Direct and Total Costs for the 
entire proposed period of support.

o  DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form 
Page 4 of the PHS 398. It is not required and will not be accepted with 
the application.

o  BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete 
the categorical budget table on Form Page 5 of the PHS 398.  It is not 
required and will not be accepted with the application.

o  BUDGET NARRATIVE JUSTIFICATION - Prepare a Modular Grant Budget 
Narrative page. (See 
http://grants.nih.gov/grants/funding/modular/modular.htm for sample 
pages.) At the top of the page, enter the total direct costs requested 
for each year.  This is not a Form page.

Under Personnel, provide budget narrative for ALL personnel by 
position, role and level of effort.  This includes consultants and any 
“to be appointed” positions.  No individual salary information should 
be provided.  However, the applicant should use the NIH appropriation 
language salary cap and the NIH policy for graduate student 
compensation in developing the budget request.

For Consortium/Contractual costs, provide an estimate of total costs 
(direct plus facilities and administrative) for each year, each rounded 
to the nearest $1,000.  List the individuals/ organizations with whom 
consortium or contractual arrangements have been made, the percent 
effort of all personnel, and the role on the project.  Indicate whether 
the collaborating institution is foreign or domestic.  The total cost 
for a consortium/contractual arrangement is included in the overall 
requested modular direct cost amount.  Include a Letter of Commitment 
or Intent if there is or is to be a subcontract/ consortium.

Provide an additional narrative budget justification for any variation 
in the number of modules requested.

o  BIOGRAPHICAL SKETCH - The Biographical Sketch provides information 
used by reviewers in the assessment of each individual's qualifications 
for a specific role in the proposed project, as well as to evaluate the 
overall qualifications of the research team.  A biographical sketch is 
required for all key personnel, including consultants, following the 
instructions below.  No more than three pages may be used for each 
person.  A sample biographical sketch may be viewed at:  
http://grants.nih.gov/grants/funding/modular/modular.htm

-  Complete the educational block at the top of the form page
-  List position(s) and any honors
-  Provide information, including overall goals and responsibilities, 
on research projects ongoing or completed during the last three years
-  List selected peer-reviewed publications, with full citations

o  CHECKLIST - This page should be completed and submitted with the 
application.  Applicant institutions should calculate the Facilities 
and Administration (F&A) costs using the current negotiated F&A rate, 
less exclusions, for the initial budget period and all future budget 
periods.  It is not necessary to list the exclusions on the Checklist 
nor anywhere in the application.  If the F&A rate agreement has been 
established, indicate the type of agreement and the date.  All 
appropriate exclusions must be applied in the calculation of the F&A 
costs for the initial budget period and all future budget years.

o  The applicant should provide the name and phone number of the 
individual to contact concerning fiscal and administrative issues if 
additional information is necessary following the initial review.  

The title and number of the program announcement must be typed on line 
2 of the face page of the application form and the YES box must be 
marked.

Applications not received as a single package on the receipt date or 
not conforming to the instructions, including page limitations and font 
size, contained in PHS 398 Application Kit (rev. 4/98) will be judged 
non-responsive and will be returned to the applicant.

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)

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established NIH referral 
guidelines.  Applications will be evaluated for scientific and 
technical merit by an appropriate scientific review group convened in 
accordance with the standard NIH peer review procedures.  As part of 
the initial merit review, all 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 
applications under review, will be discussed, assigned a priority 
score, and receive a second level review by the appropriate national 
advisory council or board.

Review Criteria

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health. 
In the written comments reviewers will be asked to discuss the 
following aspects of the application 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 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 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?

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

Additional scientific/technical merit criteria specific to the 
objectives of the PA and the mechanism used must be included if they 
are to be used in the review.

AWARD CRITERIA

Applications will compete for available funds with all other 
recommended applications.  The following will be considered in making 
funding decisions:  Quality of the proposed project as determined by 
peer review, availability of funds, and program priority.

INQUIRIES

Inquiries are encouraged.  The opportunity to clarify any issues or 
questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Patricia D’Souza, Ph.D.
Vaccine Prevention and Research Program
Division of AIDS
National Institute of Allergy and Infectious Diseases
Room 4152, MSC-7628
6700-B Rockledge Drive
Bethesda, MD 20892-7628
Telephone: (301) 496-8379
FAX: (301) 402-3684
Email: PD6N@NIH.GOV

Dennis F. Mangan, Ph.D.
Chief, Infectious Diseases and Immunity Branch
Division of Extramural Research, 
National Institute of Dental and Craniofacial Research 
Blg. 45, Room 4AN-32F
Bethesda, MD 20892-6402
Phone: 301 594-2421 
Fax: 301 480-8318
Email: Dennis.Mangan@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Jeannette Gordon
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 3222, MSC-7614
6700-B Rockledge Drive
Bethesda, MD 20892-7614
Telephone: (301) 496-7075
FAX: (301) 480-3780
Email: jg82s@nih.gov

Martin R. Rubinstein
Division of Extramural Research
National Institute of Dental Research
Building 45, Room 4AN-44A
Bethesda, MD  20892-6402
Telephone:  (301) 594-4800
Fax:  301 480-8301
Email:  Martin.Rubinstein@nih.gov

AUTHORITY AND REGULATIONS 

This program is described in the Catalog of Federal Domestic Assistance 
No. 93.856, (Microbiology and Infectious Diseases Research) and 
No.93.121 (Oral Diseases and Disorders Research.)  Awards are made 
under authorization of Sections 301 and 405 of the Public Health 
Service Act as amended (42 USC 241 and 284) and administered under NIH 
grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 
and 92. 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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