3D Tissue Models

Robert Seder

TypeWhite Paper Summary

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.

Name:Robert Seder
Organization:National Institutes of Health

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