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Barney S. Graham, M.D., Ph.D.
Vaccine Research Center
Building 40, Room 2502
40 Convent Drive
Bethesda, MD 20892-3017
Phone: 301-594-8468
Fax: 301-480-2771
bgraham@mail.nih.gov

Additional Information From NIAID

Vaccine Research Center (VRC)

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Barney Graham, M.D., Ph.D.

Photo of Barney Graham, M.D., Ph.D.

Chief, Viral Pathogenesis Laboratory

Major Areas of Research

  • Respiratory syncytial virus pathogenesis and vaccine development
  • Functional hierarchy and regulation of T-cell responses to vaccination and viral infection in adults and neonates
  • Structural basis of antibody-based virus neutralization
 

Program Description

The goal of the Viral Pathogenesis Laboratory (VPL) is to better understand basic aspects of viral pathogenesis and immunology and apply that knowledge toward vaccine development. Evaluation of viral pathogenesis and viral immunology is conducted by assessing in vitro systems and animal models and by evaluating human immune responses to vaccines and viral pathogens in clinical trials.

Respiratory syncytial virus (RSV) is an important cause of respiratory disease that has received high priority for vaccine development. Previous vaccine candidates have failed in clinical trials, and a formalin-inactivated whole virus preparation (FI-RSV) was associated with vaccine-enhanced illness. Our laboratory has previously contributed original discoveries and observations related to the pathogenesis of the FI-RSV vaccine-enhanced disease that inform current vaccine strategies. Understanding pathogenesis requires information about both the pathogen and the host, so our studies have involved basic aspects of immunology and virology. In prior immunology-oriented work we developed a murine model of RSV infection to define the role of T cells and antibody in viral clearance, the influence of Th2 cytokines on virus-specific immune responses and airway hyperresponsiveness, and methods for controlling immune response patterns by cytokine modulation. Prior virological studies have demonstrated an important role for RhoA activation, cytoskeleton rearrangement, and cholesterol-rich lipid raft microdomains during RSV infection and their influence virus budding and morphology. In addition, we have explored the immunomodulatory effects of the RSV G glycoprotein.

Current work on T-cell immunobiology is focused on mechanisms underlying the hierarchical response patterns to epitopes presented by virus infection or vaccination. These studies utilize a murine model of RSV for which MHC class I and MHC class II tetramers are available. In addition, we have recently characterized three new strains of T-cell receptor transgenic mice restricted by H-2Kd and H-2Db that allow detailed evaluation of functional hierarchies and antigen presentation by selected dendritic cell subpopulations. Another major project has been to characterize the regulatory T-cell response to RSV exploiting one of the I-Ab tetramers that selects a large proportion of FoxP3-expressing CD4 T cells. These studies explore the mechanisms by which Tregs control CD8-mediated immunopathology and how Tregs are selectively induced and maintained.

The F glycoprotein is a class I fusion protein and is essential for viral entry. Because it is a major target for vaccine-induced antibodies, we have concentrated on defining the structure of F-specific neutralizing antibodies interacting with F epitopes. In collaboration with the Structural Biology Section, we have solved the structure of the pre- and post-fusion conformation of RSV and defined the interactions of antibodies to antigenic sites II and IV and a recently described antigenic site 0 that is present only in the pre-fusion state. These studies have created a platform for structure-based vaccine design to create new RSV immunogens based on stabilized pre-fusion F antigens.

Biography

Dr. Graham is an immunologist, virologist, and clinical trials physician whose primary interests are viral pathogenesis, immunity, and vaccine development. His work is focused on HIV, respiratory syncytial virus (RSV), and emerging viral diseases. He has been involved in the clinical evaluation of candidate HIV vaccines for more than 25 years and has an ongoing interest in science education and expanding research opportunities for African-Americans and other under-represented minorities. After graduating magna cum laude from Rice University, he obtained his M.D. from the University of Kansas School of Medicine in 1979. He then completed residency and two chief residencies in internal medicine, a fellowship in infectious diseases, and a Ph.D. in microbiology and immunology at Vanderbilt University School of Medicine, where he rose to the rank of professor of medicine with a joint appointment in the department of microbiology and immunology. In 2000, he became one of the founding investigators for the NIAID Vaccine Research Center, where he is chief of the Viral Pathogenesis Laboratory and Clinical Trials Core. He is a member of the American Society for Clinical Investigation and the American Association of Physicians and a fellow of the Infectious Disease Society of America and the American Academy of Microbiology. He has served on editorial boards for the Journal of Biological Chemistry, Journal of Virology, Journal of Infectious Diseases, and Journal of AIDS and is a member of scientific advisory boards for organizations involved in HIV, RSV, malaria, and TB vaccine development.

Selected Publications

McLellan JS, Chen M, Leung S, Graepel KW, Du X, Yang Y, Zhou T, Baxa U, Yasuda E, Beaumont T, Kumar A, Modjarrad K, Zheng Z, Zhao M, Xia N, Kwong PD, Graham BS. Structure of RSV fusion glycoprotein trimer bound to a prefusion-specific neutralizing antibody. Science. 2013 May 31;340(6136):1113-7.

Johnson TR, McLellan JS, Graham BS. Respiratory syncytial virus glycoprotein G interacts with DC-SIGN and L-SIGN to activate ERK1 and ERK2. J Virol. 2012 Feb;86(3):1339-47.

Ruckwardt TJ, Malloy AM, Gostick E, Price DA, Dash P, McClaren JL, Thomas PG, Graham BS. Neonatal CD8 T-cell hierarchy is distinct from adults and is influenced by intrinsic T cell properties in respiratory syncytial virus infected mice. PLoS Pathog. 2011 Dec;7(12):e1002377.

McLellan JS, Yang Y, Graham BS, Kwong PD. Structure of respiratory syncytial virus fusion glycoprotein in the postfusion conformation reveals preservation of neutralizing epitopes. J Virol. 2011 Aug;85(15):7788-96.

Billam P, Bonaparte KL, Liu J, Ruckwardt TJ, Chen M, Ryder AB, Wang R, Dash P, Thomas PG, Graham BS. T-cell receptor clonotype influences epitope hierarchy in the CD8+ T cell response to respiratory syncytial virus infection. J Biol Chem. 2011 Feb 11;286(6):4829-41.

Graham BS. Biological challenges and technological opportunities for respiratory syncytial virus vaccine development. Immunol Rev. 2011 Jan;239(1):149-66.

Visit PubMed for a complete publication listing.

Last Updated July 17, 2013