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Vaccine Research Center
Research Areas
Laboratory of Virology—Gary
J. Nabel, M.D., Ph.D.
The mission of the Laboratory
of Virology is to achieve a clear understanding of immune
correlates and mechanisms of protection against primary HIV
infection. Our efforts focus on understanding the cellular
and molecular regulation of viral gene expression, entry into
the cell, and correlates of immune protection. Our primary
objective, in collaboration with the structural biology and
virology laboratories, is to utilize genetic mutations and
immunologic assessment in order to develop immunogens that
elicit broadly neutralizing antibodies to HIV with the goal
of developing safe and effective AIDS vaccines. Our major
areas of investigation involve the human immunodeficiency
virus (HIV) and emerging viruses such as Ebola. Other areas
of study address mechanisms of viral gene regulation and provide
insight into the regulation of eukaryotic gene expression.
Vector Core Laboratory—Gary
J. Nabel, M.D., Ph.D.
The mission of the Vector
Core Laboratory is to design CTL-based HIV vaccine candidates
by preparing gene-based immunogens. HIV cDNAs are inserted
into relevant plasmids in order to produce effective immunogens
that induce CTL. Various cDNAs have been tested using plasmid-based
gene delivery and selected candidates that express either
Gag, Pol, various Gag-Pol fusion proteins and mutants, as
well as Env and Nef cDNAs, have also been inserted into viral
vectors. These vectors include replication-defective forms
of adenoviruses and poxviruses. The viral genes include both
clade B and non-clade B viruses. Gene-based immunogens are
modified to improve protein expression and immunogenicity.
These approaches provide great flexibility in identifying
immunogens that can induce broad and potent CTL immune responses.
BSL3 Core Virology Laboratory—John
Mascola, M.D.
The BSL3 Core
Virology Laboratory will accommodate VRC laboratory work
requiring level 3 biosafety containment. The laboratory will
produce and characterize viral stocks of SIV and HIV, including
diverse viral strains representing multiple genetic subtypes.
The laboratory also performs studies of antibody-mediated
neutralization of HIV and SIV, with a focus on primary virus
strains and physiologically relevant target cells. As accurate
measurement of neutralization of primary HIV-1 strains is
important for the evaluation of immune responses to candidate
vaccines, high throughput assays will evaluate neutralizing
antibody levels in serum from preclinical and clinical vaccine
studies.
Cellular Immunology Section—Robert
Seder, M.D.
The goal of the Cellular
Immunology Section is to develop vaccines for infectious
diseases in which the cellular immune response is required
to mediate protection (eg Leishmania major, Mycobacterium
tuberculosis, HIV). In this regard, the major focus of the
laboratory is to understand the cellular and molecular mechanisms
by which various cytokines and costimulatory molecules regulate
cellular immunity in vivo. Moreover, a particular emphasis
is directed toward how memory Th 1 responses are regulated.
Clinical Trials Core—Barney
Graham, M.D., Ph.D.
The Clinical
Trials Core will perform Phase I trials of candidate HIV
vaccines developed by the VRC. This will involve community
education on HIV prevention, recruitment of healthy adults
into clinical trials, study design and analysis, and maintenance
of regulatory standards. The Clinical Studies Core will also
conduct studies of the natural history of HIV infection and
evaluate basic aspects of pathogenesis, antigen presentation,
and immune response. In addition, other vaccine candidates
developed by VRC investigators for agents other than HIV will
be evaluated in clinical trials.
Flow Cytometry Core Laboratory—Mario
Roederer, Ph.D.
The mission of the Flow
Cytometry Core Laboratory is to support the flow cytometry
needs of the VRC research laboratories and the VRC clinical
trials, as well as to bring in or develop new Flow-based assays
and technologies to support these efforts. The Flow Cytometry
Core Laboratory maintains and operates a range of instruments
from basic benchtop analyzers to the most sophisticated sorter
extant. In addition, the Core will manage all Flow Cytometric
data collected by researchers and clinical trials, and assist
in the analysis and presentation of Flow Cytometric experiments.
Human Immunology Section—Daniel
Douek, M.D., MRCP, Ph.D.
The mission of the Human
Immunology Section is to understand the induction, maintenance
and reconstitution of immunity in humans. We approach this
from the point of view of T cell clonotype—their specificity
and frequency. By studying HIV disease and vaccination against
HIV, we aim to establish correlates of effective and protective
immunity. By studying immune reconstitution, we aim to understand
the mechanisms by which recovery from HIV disease can be enhanced.
Together, these approaches address both prevention and effective
treatment of HIV disease.
Immunology Core Laboratory—Rick
Koup, M.D.
The mission of the Immunology
Core Laboratory is to develop, validate, and perform assays
of the immune response to HIV and other pathogens on clinical
samples derived from recipients of candidate vaccines. The
Immunology Core Laboratory seeks to perform the most sensitive
and reliable assays as endpoints of phase one and two clinical
trials carried out through the VRC clinical trials program
or other collaborators. In addition, the laboratory strives
to constantly develop new assays and improve upon existing
assays, that these improvements may allow us to better understand
the nature of the immune responses generated by candidate
vaccines.
Immunology Laboratory—Rick
Koup, M.D.
The mission of the Immunology
Laboratory is to investigate novel aspects of the cellular
immune response to pathogens in support of the rational development
of a vaccine against HIV. It is the goal of the Immunology
Laboratory and its sections to rapidly advance the latest
information on ways of manipulating the immune response to
HIV into practical applications in clinical trials of prophylactic
and therapeutic vaccines. In support of this effort, we emphasize
a detailed analysis of the strength, breadth, plasticity,
phenotype, and functional characteristics of the cellular
immune response to HIV during natural infection, and how it
does or does not differ from the immune response generated
after vaccination.
ImmunoTechnology Section—Mario
Roederer, Ph.D.
The goal of the ImmunoTechnology
Section is to elucidate the complex heterogeneity of the
immune system. In particular, the major focus of the Laboratory
is to define the functional roles of each uniquely identifiable
leukocyte subset in the healthy immune system, and to understand
how perturbations in the balance of these subsets leads to
disease. A fundamental strength of the Laboratory is the development
and application of highly sophisticated technologies required
for this research. The Laboratory participates not only in
the dissemination of these technologies to other researchers,
but in the application of these tools to clinical medicine
and vaccine trials.
Laboratory Animal Medicine—Srinivas
Rao, D.V.M., Ph.D.
The mission of Laboratory
Animal Medicine is to provide research support, information
and services and to assist in the design and conduct of critical
research. We ensure the highest quality animal models are
available through programs of animal husbandry as well as
disease prevention, diagnosis, control and treatment. These
services are provided in the context of ensuring the well
being of our animal subjects and complying with Federal laws,
regulations and standards and industry guidelines.
Structural Biology Section—Peter
Kwong, Ph.D.
The Structural
Biology Section of the Vaccine Research Center will apply
the tools of atomic resolution structural analysis—primarily
X-ray crystallography—to the design
of an effective HIV vaccine. Design will involve several components.
Investigations will occur into the mechanisms by which viruses
evade the humoral immune response; structures of relevant
viral antigens will be determined; structure-based manipulation
of these antigens will produce immunogens with altered immunogenicity.
The goal is to produce altered viral antigens that elicit
a broadly neutralizing immune response. Collaborations with
other sections within the VRC will be integral to deciphering
and exploiting the virological, immunological, and biological
implications of the atomic structures. Intramural interactions
with other structural biology sections will aid in establishing
the infrastructure and in developing the methodology necessary
to attack these technically challenging structural projects.
Structural Virology Laboratory—Richard
Wyatt, Ph.D
The goal of the Structural
Virology Laboratory is to utilize virological, immunological,
structural, and biophysical information on the HIV-1 envelope
glycoproteins to rationally design subunit vaccine candidates.
The envelope glycoprotein vaccines will be tested for their
ability to elicit neutralizing antibodies in animal models.
The characterization and development of such vaccine candidates
is likely to be a critical component to the design of a broadly
effective HIV-1 vaccine.
Vaccine Production Program—Phil
Gomez, Ph.D., M.B.A.
The Vaccine Production
Program (VPP) at the VRC is dedicated to advancing candidate
products from the laboratory to the clinic. The VPP develops
manufacturing processes and release tests that provide material
for Phase I/II clinical trials, with particular emphasis on
techniques suitable for eventual large-scale manufacture of
vaccines. Facilities at the VRC as well as contract agreements
are used for production, and a cGMP pilot plant is currently
under construction in Frederick, MD. In addition to production,
the VPP manages the timelines of vaccine projects selected
for clinical trial evaluation, prepares regulatory submissions
and develops appropriate pre-clinical testing for all vaccine
products.
Viral Pathogenesis Laboratory—Barney
Graham, M.D., Ph.D.
The Viral Pathogenesis
Laboratory studies viral immunity and is developing animal
models of viral immunopathogenesis. The Laboratory’s
work on the biology of respiratory syncytial virus and mechanisms
of immunity serves as one such model applicable to the study
of HIV immunopathogenesis. The projects aim to define the
mechanisms by which: 1) RSV?induced immune responses interact
with allergic inflammation to cause airway hyperresponsiveness,
2) the RSV G glycoprotein induces IL?5 and eosinophilia, 3)
IL?4 and other cytokine influence the mechanism of CD8+ CTL-mediated
target cell killing, and 4) how RhoA activation affects virus
morphogenesis, membrane fusion, and early immune responses.
The murine model of RSV also serves as a tool for evaluating
new HIV vaccine concepts. |