RFA-AI-03-028: PARTNERSHIPS FOR VACCINE AND DIAGNOSTIC DEVELOPMENT

PARTNERSHIPS FOR VACCINE AND DIAGNOSTIC DEVELOPMENT

RELEASE DATE: June 9, 2003 (see clarification NOT-AI-03-050)

RFA: AI-03-028

National Institute of Allergy and Infectious Diseases (NIAID)
(http://www.niaid.nih.gov)

CATALOGUE OF FEDERAL DOMESTIC ASSISTANCE NUMBERS:
No. 93.855, Immunology, Allergy, and Transplantation Research
No. 93.856, Microbiology and Infectious Diseases Research

LETTER OF INTENT RECEIPT DATE: August 23, 2003
APPLICATION RECEIPT DATE: September 24, 2003

THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism(s) of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS RFA

Research of the National Institute of Allergy and Infectious Diseases (NIAID),
National Institutes of Health, strives to understand, treat and ultimately
prevent the myriad infectious, immunologic, and allergic diseases that
threaten millions of human lives. The NIAID Division of Microbiology and
Infectious Diseases (DMID) supports extramural research to control and prevent
diseases caused by virtually all infectious agents. This includes basic
biomedical research, such as studies of microbial physiology and antigenic
structure; applied research, including the development of diagnostic tests;
and clinical trials to evaluate experimental drugs and vaccines.

This Partnership program will use the cooperative agreement (U01) funding
mechanism to support the development and testing of products for selected
human infectious diseases of public health importance. A key component of the
Partnership initiatives is the development of appropriate partnerships among
government, academia, and the biotechnology, chemical or pharmaceutical
industries.

This RFA is specifically focused on:

A) Development of vaccines against group A streptococci (GAS);
B) Development of vaccines against group B streptococci (GBS);
C) Development of vaccines against Helicobacter pylori;
D) Development of point of care diagnostics for GAS; and
E) Development of point of care diagnostics for GBS.

PARTNERSHIPS

A key component of this initiative is the development of appropriate
partnerships between the government and industry. For the purpose of this
RFA, "industry" is defined as large and small, domestic or foreign,
pharmaceutical, biotechnology, bioengineering, and chemical companies. Since
academic organizations are often the source of new candidate products, this
RFA can also support a partnership between industry and a collaborator(s) as
necessary from academic or non-profit research organizations. The involvement
of an academic or non-profit research organization is NOT a requirement;
therefore industry does not need a collaborator to submit an application to
this program.

All projects must demonstrate substantive involvement by the industry partner.
For the purpose of this RFA, "substantive involvement" is defined as the
commitment of any one or more of the following resources: funds; personnel; or
in-kind contributions of materials and/or reagents, including but not limited
to chemical libraries, GMP chemical synthesis or recombinant protein
production, provision of animal or other laboratory models and assays,
subcontracts, data management resources and regulatory support. The Principal
Investigator of the project may be affiliated with either industry or academic
organization (if academia is part of a partnership with industry). See
information under Eligible Institutions below.

The Partnership Program is intended to support all phases of development of a
candidate product or platform technology including, but not limited to, early
validation, pre-clinical stages, pilot lot production, regulatory
requirements, and, where appropriate, limited clinical evaluation. The NIAID
recognizes that the inherent nature and demands of the product development
process may require funding large, complex grants with interdependent specific
aims. Furthermore, some aspects of the product development process (e.g.,
production of GLP and cGMP product) are inherently not innovative.
Recognizing that product development is often an iterative and sequential
process, and that steps early in the process may not be successful and may
need to be modified or reworked, NIAID staff, through the cooperative
agreement grant mechanism, will be actively involved in evaluating the
milestones of awardees and determining whether additional investment in the
development is warranted.

RESEARCH OBJECTIVES

Background

In late 2000, the NIAID convened a panel of experts to discuss the role and
nature of NIAID/industry collaborations in antimicrobial drug development for
public health needs and to learn how NIAID could better facilitate and engage
industry and academia in these endeavors ("Summit on Drug Development for
Infectious Diseases."). One of the recommendations from this meeting was a
continued pursuit of innovative opportunities to form partnerships with the
private sector for the control of a number of infectious diseases with public
health importance. A report of this meeting is available at
http://www.niaid.nih.gov/dmid/drug/. Since 2002, NIAID has identified a
diverse set of priority areas for partnership solicitations that have included
Partnerships for Novel Therapeutic, Diagnostic and Vector Control Strategies
in Infectious Diseases (PAR-02-026, http://grants.nih.gov/grants/guide/pa-
files/PAR-02-026.html) and Partnerships: Hepatitis B and Vector Borne
Diseases Control (RFA-AI-03-003, http://grants.nih.gov/grants/guide/rfa-
files/RFA-AI-03-003.html). NIAID is also using this mechanism to solicit
applications related to biodefense. The need to support the research
specified by the current RFA has been emphasized by the NIAID-convened review
of its Group A Streptococcal Program in 1998 and the Analysis and Action Plan
for the National Vaccine Advisory Committee that was prepared in response to
the Institute of Medicine's report, "Vaccines for the 21st Century". This
plan is available at http://www.cdc.gov/od/nvpo/pubs/iomreport.htm (November
2002) and includes information related to the development of vaccines for GAS,
GBS and H. pylori.

Investment by industry in the commercialization of products for the control of
a number of infectious diseases of public health importance remains limited.
This initiative is meant to help stimulate industry participation in
decreasing the medical impact of these targeted important diseases for which
effective new control measures and diagnostics are lacking. This program is
seeking applications that propose to:

A. Development of a vaccine against GAS

GAS cause a broad spectrum of disease that ranges from uncomplicated
pharyngitis and skin infections to life threatening invasive illnesses that
includes pneumonia, bacteremia, necrotizing fasciitis, streptococcal toxic
shock syndrome (STSS) and nonsuppurative sequelae consisting of acute
rheumatic fever (ARF) and post streptococcal glomerulonephritis (PSGN).
Streptococcal pharyngitis has been and continues to be one of the most common
childhood illnesses throughout the world. Skin infections caused by GAS are a
particular problem in tropical and subtropical climates and summer months of
temperate or northern climates. Outbreaks of necrotizing fasciitis and STSS
with significant rates of morbidity and mortality among otherwise healthy
individuals were first reported in the 1980's in the U.S., Europe and Japan
and have continued into the 21st century. Although the incidence of ARF has
varied in the U.S.- decreasing in the 70's, reappearing in the 80's and
limited to Utah and occasional outbreaks in the 90's-this disease continues to
be a serious public health problem in developing countries. Recurrent
infections with GAS following ARF result in rheumatic fever and rheumatic
heart disease (RF/RHD), requiring costly resources for medical and surgical
treatment. RF/RHD is the major cause of heart disease in children around the
world. Post infectious glomerulonephritis (GN) is the most common form of GN
in children and GAS are the most frequent infectious etiology. The frequency
and severity of PSGN seems to be diminishing in the U.S. and epidemics have
been rare since 1965. However, sporadic outbreaks of PSGN continue to be
reported in developing countries and close communities with poor hygiene.
Although penicillin is the treatment of choice for GAS infections, macrolides
are used for patients who are hypersensitive to penicillin. In recent years,
resistance to macrolides among group A streptococci is an increasing problem
worldwide The high burden of disease from streptococcal infections and the
emergence of antibiotic resistance emphasizes the need for a safe and
efficacious vaccine.

B. Development of a vaccine against GBS

In the 1970's Group B Streptococci (GBS) emerged as the most important
infectious cause of neonatal morbidity and mortality and pregnancy-related
morbidity. Two syndromes in infants had been recognized: early onset disease
(primarily sepsis, pneumonia and bacteremia within the first 7 days of life)
and late onset disease (primarily meningitis between 7 and 90 days of age).
GBS are vertically transferred from a colonized mother during delivery and can
cause invasive disease. Neonatal disease prevention strategies in the United
States have focused on the identification of vaginal and rectal colonization
in pregnant women and the use of antibiotics during labor and delivery in
those women who are colonized. Although there has been a decrease in the
incidence of early onset neonatal infections (65%) and invasive GBS infections
in pregnant girls and women (21%), the incidence of late onset GBS disease in
infants has not changed. While this strategy is effective, it is an interim
solution. It has not been able to eliminate GBS disease and encourages the
widespread use of antibiotics with related concerns that include emergence of
drug resistance in GBS. Recent data indicate that 15% of GBS isolates are
resistant to clindamycin and 21% to erythromycin. Although the incidence of
invasive GBS disease has recently decreased in the neonates, there has been an
increase in the incidence of invasive GBS disease in non-pregnant adults. The
majority of these cases occur in adults with significant underlying conditions
such as diabetes, neurological impairment, breast cancer and cirrhosis.
Common clinical manifestations of GBS disease in adults include skin and soft
tissue infections, bone and joint infections, and pneumonia. Meningitis and
endocarditis are less common but when present are associated with serious
morbidity and mortality. The case fatality rate is higher in adults than in
neonates and adults over the age of 65 are at the highest risk of dying from
invasive GBS disease. A GBS vaccine would benefit pregnant women, neonates,
and adults with underlying medical conditions.

C. Development of a vaccine against H. pylori

Helicobacter pylori infects the stomach of more than 50% of the human
population worldwide. It is now firmly established that persistent infection
can cause chronic gastritis, peptic ulcer disease, and in some individuals,
gastric adenocarinoma and gastric B cell lymphoma. Neither the mechanism of
transmission nor the relative susceptibility factors are known. Infection is
usually acquired during childhood, especially in people living in developing
countries and in low socioeconomic populations. Current treatment is based on
the use of a proton-pump inhibitor and relatively long-term antibiotic
therapy. Although this treatment is efficacious, its limitations include
problems with patient compliance and antibiotic resistance.
A vaccine against H. pylori has the potential to significantly reduce the
morbidity and mortality associated with chronic H. pylori infection. A
vaccine with both prophylactic and therapeutic potential would be enormously
valuable. However, the specific immune responses that mediate either
protection or cure in humans are incompletely characterized and thus whether a
single vaccine could deliver both prophylactic and therapeutic protection is
still in question. In addition, no investigational vaccine has yet achieved
sterilizing immunity in humans. Bacterial colonization has been reduced but
it is not known whether that end point will be sufficient to have a
significant impact on the clinical course of infection. The high incidence of
H. pylori infection in the developing world and the eventual adoption of a
protective vaccine suggests the need for a low cost product that will meet the
demands of use in developing countries.

D. Development of point of care diagnostics for GAS

Many point of care diagnostics for detection of GAS have been commercialized
over the years. Experience in the medical community demonstrates variability
in the sensitivity and specificity of currently used methodologies . As GAS
vaccines are being developed, it is important to have burden of disease data
at a field site to determine the sample size for clinical trials. Point of
care diagnostics would be helpful in obtaining these data in field sites where
bacterial culture is not routinely performed. Additionally, the public health
community would benefit from improved, accurate, and rapid tests for GAS
diagnostics.

E. Development of point of care diagnostics for GBS

Although there is a need for point of care diagnostics for detection of GBS,
development has been affected by Center for Disease Control and Prevention
guidelines for prenatal GBS disease prevention. These guidelines demonstrated
the need to test both vaginal and rectal specimens and use selective growth
media for optimal detection of GBS. Most of the commercially available direct
antigen tests were not validated using selective media and none were validated
using rectal specimens. A Safety Alert was issued in 1997 by the FDA for use
of direct antigen tests. The impact on point of care diagnostics was that
some products were discontinued, effectively removing them from the
marketplace. Only one new product has been commercialized that meets the CDC
guidelines for sensitivity. This diagnostic product was only recently
approved and its performance in the community over time will need to be
assessed.

Research Goals and Objectives

Applications should address research that will advance the development
vaccines against GAS, GBS or H. pylori or development of point of care
diagnostics for GAS or GBS. Research is not required to result in a "final"
product but must advance the development of a candidate product.

One objective of this RFA is to stimulate scientifically sound, original, and
innovative research requiring comprehensive team and multidisciplinary effort
that is likely to advance promising candidate products through the product
development pathway. All applications should define the proposed project
goal, interim objectives (development milestones), a general description of
the potential ultimate product (a specific product profile that is defined by
licensing indication is not requested), and provide a schedule or timeline for
milestone and goal attainment. When appropriate, research plans should
include an awareness of guidelines that govern GLP (as defined by 21 CFR(58))
and GMP (as defined by 21 CFR(211)) manufacturing and/or IND enabling studies
that will be performed with this award as they would be applicable to eventual
product licensure in the U.S.

VACCINES

It is the purpose of this RFA to fund research that addresses key issues
related to the development of vaccines against GAS, GBS or H. pylori. These
issues may include, but are not limited to, research focused on:

o The identification and validation of protective immune responses, including
antigen and/or epitope
identification and characterization of the immune effector cells;
o Delivery systems that target appropriate immune responses and stimulate
active immunity without
inducing undesirable inflammatory responses;
o Evaluation of the safety, toxicity, immunogenicity and protective immunity
in animal models;
o Process development for the production of specified vaccine components,
including QA/QC methods
for product recovery, characterization, purification, identity, stability i.e.
all the benchmarks required for successful submission and review of an
Investigational New Drug application by the Food and Drug Administration (FDA)
(http://www.fda.gov/cber/vaccine/vacappr.htm);
o Optimization of dose and route of delivery in preclinical evaluation;
o Optimization of formulation with adjuvant (and justification for use of
adjuvant) or specific delivery system;
o Manufacture of pilot lots (GLP or cGMP) for preclinical and early clinical
evaluation;
o Optimization of safety and immunogenicity in Phase I clinical trials;
o Evaluation of dose-ranging and dosing intervals in Phase II clinical
trials; and
o For vaccines against H. pylori, both prophylactic and/or therapeutic
applications are acceptable.
o A research and development plan that defines the proposed project goal,
interim objectives (development milestones) and potential ultimate product,
and provides a schedule or timeline for milestone and goal attainment.

DIAGNOSTICS

There is need for point-of-care rapid diagnostics for detection of GAS and
GBS.

All applications should include:

o Preliminary data to support the basis of the diagnostic method;
o Description of the capabilities of the method, technology, or assay, and
advantages over currently
available diagnostics;
o Plans for determining performance characteristics including
- sensitivity
- false positive and false negative rates in the population of
diagnostic interest
- specificity
- reproducibility
- minimum turnaround time for results
- validation of the technology, assay, and diagnostic;
o Methods for rapid sample preparation and processing;
o Feasibility of specimen collection and detecting organism in that specimen;
o Process development for the manufacturing of diagnostic components,
including QA/QC methods for reagent production, characterization,
purification, identity, stability etc.;
o Appropriateness of release criteria;
o Appropriateness of internal controls;
o Applicability in a clinical setting, and evaluation in human clinical
studies; and
o A research and development plan that defines the proposed project goal,
interim objectives (development milestones) and potential ultimate product,
and provides a schedule or timeline for milestone and goal attainment.

Tests for use on human samples may consider benchmarks required for FDA
approval (http://www.fda.gov/cdrh).

MECHANISM OF SUPPORT

This RFA will use NIH U01 award mechanism(s). As an applicant you will be
solely responsible for planning, directing, and executing the proposed
project. This RFA is a one-time solicitation. Future unsolicited, competing-
continuation applications based on this project will compete with all
investigator-initiated applications and will be reviewed according to the
customary peer review procedures. Applications that are not funded in the
competition described in this RFA may be resubmitted as NEW investigator-
initiated applications using the standard receipt dates for NEW applications
described in the instructions to the PHS 398 application.

This RFA uses just-in-time concepts. It also uses the modular budgeting
format. (see http://grants.nih.gov/grants/funding/modular/modular.htm).
Specifically, if you are submitting an application with direct costs in each
year of $250,000 or less, use the modular format. This program does not
require cost sharing as defined in the current NIH Grants Policy Statement at
http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm.

The NIH (U01) is a cooperative agreement award mechanism in which the
Principal Investigator retains the primary responsibility and dominant role
for planning, directing, and executing the proposed project, with NIH staff
being substantially involved as a partner with the Principal Investigator, as
described under the section "Cooperative Agreement Terms and Conditions of
Award"

The total project period for applications submitted in response to this RFA
may not exceed five years.

FUNDS AVAILABLE

The NIAID intends to commit approximately $4 million in FY 2004 to fund
approximately 6 to 10 new grants in response to this RFA. An applicant may
request a project period of up to 5 years and a budget for direct costs must
be less than $ 500,000 per year. Applications greater than $500,000 in direct
costs per year will not be accepted. Because the nature and scope of the
proposed research will vary from application to application, it is anticipated
that the size and duration of each award will also vary. Although the
financial plans of the NIAID provide support for this program, awards pursuant
to this RFA are contingent upon the availability of funds and the receipt of a
sufficient number of meritorious applications.

ELIGIBLE INSTITUTIONS

The applicant may submit (an) application(s) if the institution has any of the
following characteristics:

o For-profit or non-profit organizations
o Public or private institutions, such as universities, colleges, hospitals,
and laboratories
o Units of State and local governments
o Eligible agencies of the Federal government

Both domestic and foreign organizations are eligible. Institutions must be in
compliance with U.S. laws and regulations and DHHS and NIH policies in effect
at the time of grant award and during the period of performance of the
research.

FOREIGN ORGANIZATIONS

Several special provisions apply to applications submitted by foreign
organizations.
o Funds for alterations or renovations cannot be requested.
o Charge back of customs and import fees is not allowed.
o Format: every effort should be made to comply with the format specifications, which are based upon a standard US paper size of 8.5" x 11."
o Funds for up to 8% administrative costs can now be requested,
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-028.html)
o Organizations must comply with federal/NIH policies on human subjects,
animals, and biohazards.
o Organizations must comply with federal/NIH biosafety and biosecurity
regulations
o Proposed research should provide a unique research opportunity, not
available in the U.S.

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

Any individual with the skills, knowledge, and resources necessary to carry
out the proposed research is invited to work with their institution to develop
an application for support. Individuals from underrepresented racial and
ethnic groups as well as individuals with disabilities are always encouraged
to apply for NIH programs.

SPECIAL REQUIREMENTS

Depending upon the scientific area, each application must propose a research
and development project whose ultimate goal is to develop a vaccine against
GAS, GBS or H. pylori or to develop a point of care diagnostic for GAS or GBS.
The application must document substantive involvement by the industry partner.

Applications must propose clear project goal(s), including a final product or
stage of development to be completed during the award period. The applicant
must clearly state the interim objectives (developmental milestones) to be
achieved during the project, identify impediments or critical decision points
that could require a revision in the work plan or milestones, and provide a
detailed schedule or timeline for the attainment of each milestone and/or
goal. For applications that contain a clinical study, a mandatory milestone
that must be included is the approval of the final clinical protocol by NIAID.
Applicants must build this milestone into their application.

Intellectual Property

Intellectual property rights are likely to play an important role in achieving
the goals of this program. To this end, the NIAID requires that at the time of
the application all applicants must provide a letter ("Proprietary Rights
Assurance Letter") containing the following assurances, which is signed by a
representative who is duly authorized to provide such assurances on behalf of
the applicant organization:
o Applicant is solely responsible for the timely acquisition of all
proprietary rights, including intellectual property rights, and all materials
needed for applicant to perform the project
o Applicant acknowledges that prior to, during, and subsequent to the award,
the U.S. Government is not required to obtain for applicant any proprietary
rights, including intellectual property rights, or any materials needed by
applicant to perform the project.
o Applicant acknowledges the requirement to report to the U.S. Government all
inventions made in the performance of the project, as specified at 35 U.S.C.
Sect. 202.

Apart from the Proprietary Rights Assurance Letter, applicants are expected to
exercise their Bayh-Dole rights in a manner that does not conflict with the
goals of this award or the intent of the Bayh-Dole Act to promote the
utilization, commercialization and availability of the U.S. Government-funded
inventions for public benefit. In addition, applicants are expected to make
new information and materials known to the research community in a timely
manner through publications, web announcements, and reports to the NIAID or
other mechanisms.

Mandatory Meetings

The Principal Investigator, one or two key personnel designated by the
Principal Investigator and NIAID program staff will meet once a year to review
progress, aid program development, and foster collaborations among the
programs. This meeting will likely be held at the NIH in Bethesda, MD and
applicants should include requests for travel funds (airfare, and per diem)
specifically for this meeting.

COOPERATIVE AGREEMENT TERMS AND CONDITIONS OF AWARD

The following terms and conditions will be incorporated into the award
statement and provided to the Principal Investigator as well as the
institutional official at the time of award.

These special Terms of Award are in addition to, and not in lieu of, otherwise
applicable OMB administrative guidelines, HHS Grant Administration Regulations
at 45 CFR part 74 and 92, and other HHS, PHS, and NIH Grant Administration
policy statements.

The administrative and funding instrument used for this program is cooperative
agreement (U01), an "assistance" mechanism (rather than an "acquisition"
mechanism), in which substantial NIH scientific and/or programmatic
involvement with the awardee is anticipated during the performance of the
activity. Under the cooperative agreement, the NIH purpose is to support
and/or stimulate the recipient's activity by involvement in and otherwise
working jointly with the award recipient in a partner role, but it is not to
assume direction, prime responsibility, or a dominant role in the activity.
Consistent with this concept, the dominant role and prime responsibility for
the activity resides with the awardees for the project as a whole, although
specific tasks and activities in carrying out the research will be shared
among the awardees and the NIAID Scientific Coordinator.

1. Monitoring Clinical Studies

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. AN
UPDATED NIAID policy was published in the NIH Guide on July 8, 2002 and is
available at: http://grants.nih.gov/grants/guide/notice-files/NOT-AI-
02-032.html. The full policy, including terms and conditions of award, is
available at: http://www.niaid.nih.gov/ncn/pdf/clinterm.pdf.

2. Awardee Rights and Responsibilities

Awardees will have primary responsibility for defining the research
objectives, approaches and details of the projects within the guidelines of
the RFA and for performing the scientific activity. Specifically, awardees
have primary responsibility as described below.

The Principal Investigator retains primary responsibility for the performance
of the scientific activity, and agrees to accept close assistance in
coordination, cooperation and participation of NIAID staff in scientific and
technical management of the project in accordance with the terms formally and
mutually agreed upon prior to the award. The responsibility for the planning,
direction, and execution of the proposed project will be solely that of the
Principal Investigator.
o Publications: The Principal Investigator will be responsible for the timely
submission of all abstracts, manuscripts and reviews (co)authored by members
of the grant and supported in part or in total under this Agreement. The
Principal Investigator and Project Leaders are requested to submit manuscripts
to NIAID program staff within two weeks of acceptance for publication so that
an up-to-date summary of program accomplishments can be maintained and joint
press conferences prepared. Publications or oral presentation of work done
under this Agreement is the responsibility of the Principal Investigator and
appropriate Project Leaders and will require appropriate acknowledgement of
NIAID support.

Timely publication of major findings is encouraged.

o Data: While the NIAID Scientific Coordinator and program staff have a right
of access to the data (see NIAID staff responsibilities below) the applicant
will retain custody of and right to the data. The awardee must have an
approved data-sharing plan in place (see
http://grants.nih.gov/grants/policy/data_sharing/index.htm).

3. NIAID Staff Responsibilities

Dr. Fran Rubin will serve as NIAID's Scientific Coordinator and will have
substantial scientific/programmatic involvement during the conduct of awarded
activities through technical assistance, advice and coordination above and
beyond normal program stewardship for this award, as described below. Other
appropriate NIAID program staff assistance will be coordinated by the
Scientific Coordinator.

During performance of the award, the NIAID Scientific Coordinator may provide
appropriate assistance, advice, and guidance by: participating in the design
of the activities; advising in the selection of sources or resources (e.g.,
determining where a particular reagent can be found); coordinating or
participating in the collection and/or analysis of data; advising in
management and technical performance; or participating in the preparation of
publications. The Scientific Coordinator will serve as a liaison/facilitator
between the awardee, pharmaceutical and biotech industries, and other
government agencies (e.g., FDA, USDA, CDC), and will serve as a resource of
scientific and policy information related to the goals of the awardee's
research. However, the role of NIAID will be to facilitate and not to direct
the activities. It is anticipated that decisions in all activities will be
reached by consensus and the NIAID program staff will be given the opportunity
to offer input into this process. The manner of reaching this consensus and
the final decision-making authority will rest with the Principal Investigator.

An NIAID Program Official will be responsible for the normal program
stewardship of this award. For clinical studies, a mandatory milestone is the
approval of the final clinical protocol by NIAID. The Program Official may
also serve as the Scientific Coordinator.

4. Collaborative Responsibilities

The specific timelines, interim objectives and funding levels agreed to by the
Principal Investigator and the NIAID shall be included in the terms and
conditions of award. Given the nature of product development, it is
recognized that timelines and interim objectives may require revision and
renegotiation during the course of the project period. The Principal
Investigator and NIAID must agree to all such revisions. Release of each
funding increment by NIAID will be based on a NIAID review of progress towards
achieving the previously agreed upon interim objective. Where scientifically
appropriate NIAID may ask recipients to collaborate or cooperate with other
NIAID funded projects and/or US government agencies, for example CDC, FDA and
USDA.

5. Arbitration

Any disagreement that may arise on scientific or programmatic matters (within
the scope of the award), between award recipients and the NIAID may be brought
to arbitration. An arbitration panel will be composed of three members - one
selected by the Steering Committee (with the NIAID representation not voting)
or by the individual awardee in the event of an individual disagreement, a
second member selected by NIAID, and the third member selected by the two
prior selected members. This special arbitration procedure in no way affects
the awardee's right to appeal an adverse action that is otherwise appealable
in accordance with the PHS regulations at 42 CFR Part 50, Subpart D and HHS
regulation at 45 CFR Part 16.

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA and welcome the opportunity to
answer questions from potential applicants. Inquiries may fall into three
areas: scientific/research, peer review, and financial or grants management
issues:

o Direct questions about scientific/research issues related to GAS and GBS
vaccines and diagnostics to:

Dr. Fran Rubin
Division of Microbiology & Infectious Diseases
National Institute of Allergy and Infectious Diseases
Room Number 5055, MSC-6603
6610 Rockledge Drive
Bethesda, MD 20892-6603
Telephone: (301) 496-5305
FAX: (301) 496-8030
Email: fr28f@nih.gov

o Direct questions about scientific/research issues related to: Helicobacter
pylori vaccines to:

Dr. Katherine Taylor
Division of Microbiology & Infectious Diseases
National Institute of Allergy and Infectious Diseases
Room Number 4011, MSC-6603
6610 Rockledge Drive
Bethesda, MD 20892-6603
Telephone: (301) 451-5068
FAX: (301) 402-1456
Email: kt148o@nih.gov

o Direct questions about peer review issues to:

Madelon Halula, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 2150, MSC-7614
6700-B Rockledge Drive
Bethesda, MD 20892-7614
Telephone: (301) 496-2550
FAX: (301) 402-2638
Email: mh30x@nih.gov

o Direct questions about financial or grants management matters to:

Ms. Donna M. Scarsciotti
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 3223, MSC-7614
6700-B Rockledge Drive
Bethesda, MD 20892-7614 (20817 for courier)
Telephone: (301) 451-9892
FAX: (301) 493-0597
Email: ds421f@nih.gov

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes
the following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel
o Participating institutions
o Number and title of this RFA

Although a letter of intent is not required, is not binding, and does not
enter into the review of a subsequent application, the information that it
contains allows IC staff to estimate the potential review workload and plan
the review.

The letter of intent is to be sent by the date listed at the beginning of this
document. The letter of intent should be sent to:

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application
instructions and forms (rev. 5/2001). The PHS 398 is available at
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive
format. For further assistance contact GrantsInfo, Telephone (301) 435-0714,
Email: GrantsInfo@nih.gov.

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001)
application form must be affixed to the bottom of the face page of the
application. Type the RFA number on the label. 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 2 of the face page of the application form and the YES
box must be marked. The RFA label is also available at:
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.

SUPPLEMENTAL INSTRUCTIONS: See "Research Goals and Objectives" and "SPECIAL
REQUIREMENTS" sections above for additional application instructions.

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of
the application, including the Checklist, and three signed, photocopies, in
one package by commercial carrier 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)

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

Madelon Halula, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 2150, MSC-7614
6700-B Rockledge Drive
Bethesda, MD 20892-7614 (20817 for express mail or courier service)
Telephone: (301) 496-2550
FAX: (301) 402-263
Email: mh30x@nih.gov

Applications must be received on or before September 24, 2003. Applications
that are not received on the receipt date will be judged non-responsive and
will be returned to the applicant.

It is highly recommended that the appropriate NIAID program contact be
consulted before submitting the letter of intent and during the early stages
of preparation of the application. (See program contact under INQUIRIES).

APPLICATION PROCESSING: Applications must be received by the application
receipt date listed in the heading of this RFA. If an application is received
after that date, it will be returned to the applicant without review.

The Center for Scientific Review (CSR) will not accept any application in
response to this RFA that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending application.
However, when a previously unfunded application, originally submitted as an
investigator-initiated application, is to be submitted in response to an RFA,
it is to be prepared as a NEW application. That is the application for the RFA
must not include an Introduction describing the changes and improvements made,
and the text must not be marked to indicate the changes. While the
investigator may still benefit from the previous review, the RFA application
is not to state explicitly how.

Although there is no immediate acknowledgement of the receipt of an
application, applicants are generally notified of the review and funding
assignment within 8 weeks.

PEER REVIEW PROCESS

Upon receipt, applications will be reviewed for completeness by the CSR and
responsiveness by the (IC).

Incomplete and/or non-responsive applications will be returned to the
applicant without further consideration. Applications submitted by an
academic institution alone without an industrial partner will be considered
non-responsive and will be returned without review.

Applications that are complete and responsive to the RFA will be evaluated for
scientific and technical merit by an appropriate peer review group convened by
the (IC) in accordance with the review criteria stated below. As part of the
initial merit review, all applications will:

o Receive a written critique
o Undergo a selection process in which only those applications deemed to have
the highest scientific merit, generally the top half of applications under
review, will be discussed and assigned a priority score
o Receive a second level review by the National Advisory Allergy and
Infectious Diseases 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. 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:

o Significance
o Approach
o Innovation
o Investigator
o Environment

The scientific review group will address and consider each of these criteria
in assigning the application's overall score, weighting them as appropriate
for each application. 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.

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?

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?

INNOVATION: Does the project employ novel concepts, approaches or methods? Are
the aims original and innovative? Does the project challenge existing
paradigms or develop new methodologies or technologies?

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)?

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?

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following
items will be considered in the determination of scientific merit and the
priority score:

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human
subjects and protections from research risk relating to their participation in
the proposed research will be assessed. (See criteria included in the section
on Federal Citations, below)

INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans
to include subjects from both genders, all racial and ethnic groups (and
subgroups), and children as appropriate for the scientific goals of the
research. Plans for the recruitment and retention of subjects will also be
evaluated. (See Inclusion Criteria in the sections on Federal Citations,
below).

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to
be used in the project, the five items described under Section f of the PHS
398 research grant application instructions (rev. 5/2001) will be assessed.

INTERIM OBJECTIVES (DEVELOMENTAL MILESTONES): Are the interim objectives
(developmental milestones) appropriate and feasible?

STAFF: Are the scientific and technical staff (other than the principal
investigator) appropriate and qualified?

ORGANIZATIONAL AND MANAGEMENT APPROACH: Are the project management and
administrative staff appropriate and qualified?

ADDITIONAL CONSIDERATIONS

DATA SHARING: The adequacy of the proposed plan to share data.

BUDGET: The reasonableness of the proposed budget and the requested period of
support in relation to the proposed research.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date: August 23, 2003
Application Receipt Date: September 24, 2003
Peer Review Date: February 2, 2004
Council Review: May 2004
Earliest Anticipated Start Date: June 1, 2004

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o Scientific merit of the proposed project as determined by peer review
o Availability of funds
o Programmatic priorities.

REQUIRED FEDERAL CITATIONS

HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that
applications and proposals involving human subjects must be evaluated with
reference to the risks to the subjects, the adequacy of protection against
these risks, the potential benefits of the research to the subjects and
others, and the importance of the knowledge gained or to be gained.
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm

MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components
involving Phase I and II clinical trials must include provisions for
assessment of patient eligibility and status, rigorous data management,
quality assurance, and auditing procedures. In addition, it is NIH policy that
all clinical trials require data and safety monitoring, with the method and
degree of monitoring being commensurate with the risks (NIH Policy for Data
Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998:
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: 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 clinical research projects unless a
clear and compelling justification is provided indicating 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 clinical research should read the AMENDMENT "NIH
Guidelines for Inclusion of Women and Minorities as Subjects in Clinical
Research - Amended, October, 2001," published in the NIH Guide for Grants and
Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-
files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are
available at http://grants.nih.gov/grants/funding/women_min/guidelines_
amended_10_2001.htm.

The amended policy incorporates: the use of an NIH definition of clinical
research; updated racial and ethnic categories in compliance with the new OMB
standards; clarification of language governing NIH-defined Phase III clinical
trials consistent with the new PHS Form 398; and updated roles and
responsibilities of NIH staff and the extramural community. The policy
continues to require for all NIH-defined Phase III clinical trials that: a)
all applications or proposals and/or protocols must 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) investigators must report annual accrual and progress in conducting
analyses, as appropriate, by sex/gender and/or racial/ethnic group
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS:
The NIH maintains a policy 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 is available at
http://grants.nih.gov/grants/funding/children/children.htm.

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH
policy requires education on the protection of human subject participants for
all investigators submitting NIH proposals for research involving human
subjects. This policy announcement is in the NIH Guide for Grants and
Contracts Announcement, dated June 5, 2000, at
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The
Office of Management and Budget (OMB) Circular A-110 has been revised to
provide public access to research data through the Freedom of Information Act
(FOIA) under some circumstances. Data that are (1) first produced in a project
that is supported in whole or in part with Federal funds and (2) cited
publicly and officially by a Federal agency in support of an action that has
the force and effect of law (i.e., a regulation) may be accessed through FOIA.
It is important for applicants to understand the basic scope of this
amendment. NIH has provided guidance at
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this PA in a public archive,
which can provide protections for the data and manage the distribution for an
indefinite period of time. If so, the application should include a description
of the archiving plan in the study design and include information about this
in the budget justification section of the application. In addition,
applicants should think about how to structure informed consent statements and
other human subjects procedures given the potential for wider use of data
collected under this award.

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The
Department of Health and Human Services (DHHS) issued final modification to
the "Standards for Privacy of Individually Identifiable Health Information",
the "Privacy Rule," on August 14, 2002. The Privacy Rule is a federal
regulation under the Health Insurance Portability and Accountability Act
(HIPAA) of 1996 that governs the protection of individually identifiable
health information, and is administered and enforced by the DHHS Office for
Civil Rights (OCR). Those who must comply with the Privacy Rule (classified
under the Rule as "covered entities") must do so by April 14, 2003 (with the
exception of small health plans which have an extra year to comply).

Decisions about applicability and implementation of the Privacy Rule reside
with the researcher and his/her institution. The OCR website
(http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including
a complete Regulation Text and a set of decision tools on "Am I a covered
entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes
involving the review, funding, and progress monitoring of grants, cooperative
agreements, and research contracts can be found at
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

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. Furthermore, we
caution reviewers that their anonymity may be compromised when they directly
access an Internet site.

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 RFA is
related to one or more of the priority areas. Potential applicants may obtain
a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance at
http://www.cfda.gov/ in the following citations: No. 93.855, Immunology,
Allergy, and Transplantation Research and No. 93.856, Microbiology and
Infectious Diseases 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 NIH Grants Policy Statement is available at
http://grants.nih.gov/grants/policy/policy.htm. This document includes general
information about the grant application and review process; information on the
terms and conditions that apply to NIH Grants and cooperative agreements; and
a listing of pertinent offices and officials at the NIH. All awards are
subject to the terms and conditions, cost principles, and other considerations
described in the NIH Grants Policy Statement.

The PHS strongly encourages all grant recipients to provide a smoke-free
workplace and discourage the 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.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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