Full Text AI-93-017

MULTICOMPONENT VACCINE DEVELOPMENT

NIH GUIDE, Volume 22, Number 28, August 6, 1993

RFA:  AI-93-017

P.T. 34

Keywords: 
  Vaccine 
  Viral Studies (Virology) 
  Immunology 


National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  October 1, 1993
Application Receipt Date:  November 24, 1993

PURPOSE

The National Institute of Allergy and Infectious Diseases (NIAID)
invites applications to conduct basic research leading to the design
of new innovative approaches for the synthesis and development of
combination vaccines.  Multicomponent (multivalent) combination
vaccines containing antigens to viral and/or bacterial components
provide many distinct advantages over conventional vaccines and allow
for the introduction of "disease-specific", "age-specific" and
"duration-specific" designer vaccines.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This Request
for Applications (RFA), Multicomponent Vaccine Development, is
related to the priority area of immunization and infectious diseases.
Potential applicants may obtain a copy of "Healthy People 2000" (Full
Report:  Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary
Report:  Stock No. 017-001-00473-1) through the Superintendent of
Documents, Government Printing Office, Washington DC 20402-9325
(telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State or local
governments, and eligible agencies of the Federal Government.
Applications from minority individuals and women are encouraged.

MECHANISM OF SUPPORT

Awards made under this RFA will use the National Institutes of Health
(NIH) individual research project grant (R01).  Responsibility for
the planning, direction, and execution of the proposed project will
be solely that of the applicant.  The total project period for
applications submitted by domestic institutions in response to the
present RFA may not exceed four years; the total project period for
applications submitted by foreign institutions may not exceed three
years.  The earliest possible award date is July 1, 1994.

Applicants are encouraged to coordinate, through the use of
consortium arrangements or subcontracts, integrated approaches with
individuals or institutions having relevant reagents and expertise in
their use, demonstrated ability in a particular area of relevant
research, or access to relevant patient populations so as to
accelerate technical progress and clinical development of promising
therapies.  Because the nature and scope of the research proposed in
response to this RFA may vary, it is anticipated that the amounts of
the awards will vary also.

This RFA is a one-time solicitation.  Future competing continuation
applications will compete with all unsolicited investigator-initiated
applications and be reviewed by an appropriate Study Section
according to the customary NIH referral and peer review procedures.

FUNDS AVAILABLE

The estimated level of support (total direct and indirect costs) for
the entire program for the first year is $1.5 million.  Foreign
applications that may be funded under this RFA are not eligible for
indirect costs.  The NIAID anticipates making a minimum of four new
awards.

RESEARCH OBJECTIVES

Background

Immunization is a principal feature of the health care of infants and
young children throughout the world.  Universal immunization
programs, those that deliver vaccines to all children, are
responsible for much of the increase in life expectancy in the last
half-century.  Although most infants receive their first dose of
vaccine at an appropriate age, by the third dose of DTP vaccines,
immunization of inner city and minority children in the U.S. is
significantly delayed and they are, therefore, at risk of disease.
Vaccines that would require fewer doses and could be administered
orally would facilitate the immunization of all infants.

The future impact of combination vaccines on immunization programs
must be considered in the context of the Children's Vaccine
Initiative (CVI).  The ability to selectively eradicate various
childhood diseases through the development of immunization programs
that incorporate new emerging technologies for the creation of
improved, safe and efficacious vaccines is the primary aim of the
NIAID and of the CVI program.  A major concept advanced by the CVI
program is the idea of providing fewer doses of vaccine to help
facilitate delivery and broaden the coverage of immunization.

The Division of Microbiology and Infectious Diseases (DMID), NIAID
has a long standing commitment to study and support the development
and evaluation of new generation vaccines against the major childhood
infectious diseases.  For example, the DMID effort to evaluate new
acellular pertussis vaccines for licensure in the United States is an
essential component of the development of new multicomponent
vaccines, as the success of the latter will depend on incorporation
of an acellular pertussis vaccine for infants.

Other new approaches to the development of vaccines include
attenuated organisms, genetically modified organisms, recombinant
viruses, recombinant DNA-derived subunit vaccines, vectors, and novel
delivery technologies such as microencapsulation.  Progress on the
basic areas of research necessary for targeted development of
vaccines have enhanced the understanding of infectious diseases and
furthered the capability to develop other vaccines.  An example of
the latter is the development of glycoconjugate technology for the
enhancement of infants' immune response, which is now being used in a
number of licensed vaccines.

Based on available recombinant DNA technology and advanced computer
modeling techniques, many new possibilities exist for engineering
live attenuated vaccines and developing viral peptides for the
construction of vaccines against medically important pathogens.  One
such example is the development of genetically defined mutations that
can be engineered into the genomes of both RNA and DNA viruses to
produce safe and effective vaccines for viral diseases.

Such an initiative could also result in the acquisition of important
information on the mechanisms of pathogenesis.  Other long term
strategies might include the development of viral peptides containing
several viral specific epitopes, that could be used as carriers for
capsular polysaccharide bacterial antigens.

The use of genetic engineering and protein modeling can maximize the
immunogenicity and range of the protective epitopes of the viruses
and bacteria under consideration.  The construction of bacterial
vector systems (e.g., BCG, Salmonella) expressing genes from a number
of pathogenic organisms, could provide a model system in which a
single injection could provide multiple immunizations at a reduced
cost.  The insertion of multiple epitopes into a single vector may
also help to minimize reactogenicity and may avoid the reduced
immunogenicity that can occur when multiple antigens are delivered as
mixtures on the same or similar carrier proteins.  In the latter
situation, the immune system can become overloaded, resulting in an
impaired response to any vaccine component.  The combination of
vaccines or vaccine components into one vector should effectively
retain each components optimum performance, stability, and reasonable
cost.

Scope of Research

The objective of this RFA is to evaluate new approaches/concepts for
the development of multivalent vaccines to provide safe and long
lasting immunity to multiple agents while providing equivalent
immunogenicity and efficacy of a single component.  Such an approach
will greatly facilitate the implementation of the universal
vaccination programs required to bring under control serious
infectious diseases worldwide.

Barriers to the development of multicomponent vaccines are not merely
technological, but will require scientific advances in a number of
areas in basic science and infectious diseases.  One of the most
complex, but basic issues that needs to be resolved is the problem of
incorporating fundamentally different products or antigens into a
single matrix.  For example, at this time we are not able to mix
attenuated live agents with killed agents such as oral polio vaccine
and Haemophilus influenzae type b conjugate vaccines.  The current
available approach for making combination vaccines is restricted to
mixing either a series of antigens or other "like" immunogens in a
single dose.  Additional research is, therefore, needed to better
understand the immunologic basis for incompatibility/compatibility
among disparate antigens.  Furthermore, it is assumed that the
development of vaccines to diseases that produce systemic infection
will differ significantly from those in which infection occurs at
mucosal or other epithelial surfaces.  This area also needs to be
addressed.

Possible candidates to consider for development into combination
vaccines include the following:

o  Vaccines currently available and licensed (e.g., DTP, hepatitis B,
H. influenzae type b, inactivated and oral polio vaccine, and MMR).

o  Vaccines in Phase III trials, but not yet licensed (e.g.,
hepatitis A, acellular pertussis, live varicella, live attenuated
bivalent influenza).

o  Vaccines undergoing early Phase I/II trials (e.g., respiratory
syncytial virus, herpes virus glycoproteins, Group B streptococcal
conjugates, meningococcal A and C conjugates, and pneumococcal
conjugates).

o  Vaccines in the preclinical evaluation or early developmental
stage (e.g., cytomegalovirus subunit, malarial merozoite and
circumsporozoite antigens, pneumococcal surface proteins).

o  Vaccines that are still in the conceptual stages of development.

The major objective of this initiative is to encourage innovative
research on the development of combination vaccines.  Applicants are
encouraged to propose innovative approaches to this concept and to
consider the list that follows as areas of prime, but not exclusive,
concern and importance in the development of combination vaccines:

(1)  antigenic competition;
(2)  stability in required formulation (i.e., lyophilization);
(3)  novel delivery systems (i.e., vectors);
(4)  selection of appropriate serotypes for regional needs;
(5)  immune interference (i.e., TH1 and TH2 interactions);
(6)  technical complexity of the manufacturing process (e.g., use of
adjuvants and preservatives);
(7)  valence limitations (number of serotypes in a single package);
(8)  cost and affordability;
(9)  lack of animal models for preclinical evaluation;
(10) vaccine induced immunosuppression;
(11) role of combination vaccines on immunologic memory and priming;
(12) equivocal immunogenicity between polyvalent and monovalent
vaccines; and
(13) oral vaccine formulation.

Applications are being sought that incorporate novel and creative
ideas and that address many of the perplexing problems now facing
investigators interested in developing combination vaccines.  Inter-
and intra-category mixing of vaccines will also require the
rethinking and reshaping of fundamental vaccine strategies, which is
encouraged.  Furthermore, investigators are encouraged to interact on
all levels, especially academia and industry.

SPECIAL REQUIREMENTS

NIAID program staff will organize annual meetings in Bethesda that
Principal Investigators and other key members (as designated by the
Principal Investigators) of the projects are encouraged to attend to
discuss progress.  Funds for travel to these meetings should be
included in the budget.

STUDY POPULATIONS

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

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

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

The rationale for studies on single minority population groups should
be provided.

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

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

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

If the required information is not contained within the application,
the application will be returned.

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

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

NOTE:  Peer review groups need adequate information about the
composition of proposed study populations in all applications
involving human subjects.  To avoid delays in review of such
applications, the NIAID advises that, as a minimum, the application
should contain demographic data about the clinic and/or in-patient
population from which study subjects will be drawn: average hospital
admission per year; percentage distribution of Black/Hispanic/other
minority/non-minority populations; gender; etc.  Studies using
non-hospital populations, such as community-based studies, should
provide similar data about populations in the area or region from
which the study subjects will be drawn.  In the absence of current
data, historical demographic information and/or previous recruitment
data for similar studies from the proposed study sites should be
provided.

LETTER OF INTENT

Prospective applicants are asked to submit, by October 1, 1993, a
letter of intent that includes a descriptive title of the proposed
research, the names and affiliations of proposed key investigators,
and the number and title of the RFA in response to which the
application may be submitted.  Although a letter of intent is not
required, is not binding, and does not enter into the review of
subsequent applications, the information that it contains allows
NIAID staff to estimate the potential review workload and to avoid
possible conflict of interest in the review.  The letter of intent is
to be sent to Dr. Olivia Preble at the address listed under
INQUIRIES.

APPLICATION PROCEDURES

Applications are to be submitted on form PHS 398 (rev. 9/91), the
standard application form for research grants.  Application kits are
available at most institutional offices of sponsored research and may
be obtained from the Office of Grants Information, Division of
Research Grants, National Institutes of Health, Westwood Building,
Room 449, Bethesda, MD 20892, telephone 301/435-0714.  Applicants
must adhere to the format and requirements specified in the PHS 398
application kit.

For purposes of identification and processing, mark "YES" in item 2a
on the face page of the application and type in the RFA number
AI-93-017 and the title "Multicomponent Vaccine Development."  The
RFA label available in the form PHS 398 must be affixed to the bottom
of the face page of the original application.  Failure to use this
label could result in delayed processing of the application such that
it may not reach the review committee in time for review.

The signed, typewritten original of the application, including the
Checklist, and three exact single-sided copies must be sent to:

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

At the time of submission, two additional copies must also be sent to
Dr. Olivia Preble at the address listed under INQUIRIES.

To ensure their review, applications must be received by both the
Division of Research Grants (DRG) and Dr. Olivia Preble by November
24, 1993.  Applications not received this receipt date will be
considered non-responsive and will be returned to the applicant
without review.  If the application submitted in response to this RFA
is substantially similar to a grant application already submitted to
the NIH for review, but has not yet been reviewed, the applicant will
be asked to withdraw either the pending application or the new one.
Simultaneous submission of essentially identical applications will
not be allowed, nor will essentially identical applications be
reviewed by different review committees.  Therefore, an application
cannot be submitted in response to this RFA that is essentially
identical to one that has already been reviewed. This does not
preclude the submission of substantial revisions of applications
already reviewed, but such applications must include an introduction
addressing the previous critique.

REVIEW CONSIDERATIONS

Review Procedures

Applications will be reviewed by DRG staff for completeness and by
NIAID staff to determine administrative and programmatic
responsiveness to this RFA.  Those judged to be incomplete or
nonresponsive will be returned to the applicant without review.
Those considered complete and responsive may be subjected to a triage
review by an NIAID peer review group, before or during the initial
review meeting, to determine their scientific merit relative to the
other applications submitted in response to this RFA.  The NIAID will
withdraw from competition those applications judged by the triage
peer review group to be noncompetitive for award and will so notify
the applicant investigator and the institutional business official.
Those applications judged to be competitive for award will be
reviewed for scientific and technical merit by a Review Committee
convened by the Division of Extramural Activities, NIAID.  The second
level of review will be provided by the National Advisory Allergy and
Infectious Diseases Council.

Review Criteria

The factors to be considered in scientific review of the application
are:

1.  Scientific merit of the proposed research approach, design, and
methodology as well as the potential scientific, technical or medical
significance of the proposed research.

2.  Research experience and competence of the Principal
Investigator(s) and other staff to conduct the proposed studies.

3.  Adequacy of the time (effort) which the Principal Investigator(s)
and staff would devote to the proposed studies.

4.  Adequacy of facilities, including, if relevant to the proposed
research, the clinical facilities and patient availability for
clinical studies.

AWARD CRITERIA

In selecting applications for funding, while scientific merit is of
primary consideration, applications will also be evaluated for
programmatic relevance and potential for impact on the clinical
management of infectious diseases.  Particular attention will be paid
to studies that assess the basis for non-responsiveness, interference
between agents and/or reactogenicity, and the potential public health
impact of the proposed multicomponent vaccines.

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Dr. David L. Klein
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
Solar Building, Room 3A-10
Bethesda, MD  20892
Telephone:  (301) 496-5305
FAX:  (301) 496-8030
E-mail:  dlk@exec.niaid.pc.niaid.nih.gov

Address the letter of intent, two copies of the completed
application, and direct any questions regarding review procedures to:

Dr. Olivia Preble
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C-19
Bethesda, MD  20892
Telephone:  (301) 496-8208
FAX:  (301) 402-2638

Direct inquiries regarding fiscal matters to:

Mr. Todd Ball
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B-35
Bethesda, MD  20892
Telephone:  (301) 496-7075
FAX:  (301) 480-3780

Schedule

Letter of Intent Receipt Date:  October 1, 1993
Application Receipt Date:       November 24, 1993
Scientific Review Date:         March 1994
Council Meeting Date:           June 1994
Earliest Award Date:            July 1, 1994

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.856, Microbiology and Infectious Disease Research.
Awards are made under authorization of the Public Health Service Act,
Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158,
42 USC 241 and 285) and administered under PHS grants policies and
Federal Regulations 42 CFR 52 and 45 CFR Part 74.  This program is
not subject to the intergovernmental review requirements of Executive
Order 12372 or Health Systems Agency review.

.

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