Boston Children’s Hospital and Harvard Medical School
NATIONAL INSTITUTES OF HEALTH P01AI089618
INVESTIGATORS & CORES
This project brings together collaborating groups at Boston Children's Hospital and Harvard Medical School (Harrison), the Duke Human Vaccine Institute (DHVI)(Moody, Sempowski), the Duke University School of Medicine Department of Immunology (Kelsoe, Kuraoka), the Ragon Institute of MGH, MIT and Harvard (Schmidt), and Dartmouth College (Lee). It capitalizes on the powerful technologies they together command, to probe B-cell dynamics and antibody output in the response to influenza vaccination and infection.
Stephen C. Harrison, PI of the P01, PD of Project 4 (Structural biology of influenza Ab-antigen interactions) and Core A (Administration).
Giovanni Armenise-Harvard Professor in Basic Biomedical Sciences, Harvard Medical School and Boston Children's Hospital, and Investigator in the Howard Hughes Medical Institute. He is also Head of the Laboratory of Molecular Medicine at Children's Hospital and Faculty Director of the Harvard cryo-EM Center for Structural Biology. A leading expert on the structure of viruses and viral proteins, as studied at high resolution by x-ray crystallography and by cryo-EM, Harrison has worked on both non-enveloped and enveloped viruses, including the surface glycoproteins of flaviviruses, herpesviruses, coronaviruses, and HIV/SIV, and on the mechanisms of viral fusion. He has contributed to influenza virus immunology, as head of this project for the past ten years.
M. ANTHONY MOODY
M. Anthony Moody, MD, PD of Project 1 (Human and non-human primate B-cell and antibody repertoires).
Professor of Pediatrics and Immunology, Duke University School of Medicine. An experienced clinician in Pediatric Infectious Diseases, he is the P.I. of the Duke CIVIC Vaccine Center (DCVC) at the Duke Human Vaccine Institute (DHVI), one of three vaccine discovery centers in the NIH-funded Collaborative Influenza Vaccine Innovation Centers program, working to develop the next generation of influenza vaccines. Moody's primary basic research interest is the B cell response to vaccination, infection, and autoimmune disease. His current research is on influenza, syphilis, and HIV.
PD of Project 2 (Affinity maturation of the B-cell repertoire)
James B. Duke Professor of Immunology, Duke University School of Medicine, and Member of DHVI. An expert in the biology and somatic genetics of B lymphocytes, who pioneered our current understanding of B-cell hypermutation and affinity-driven selection in germinal centers, Kelsoe has long-standing collaborations with B.F. Haynes to study the role of immunological tolerance in preventing robust humoral immunity to HIV-1. Collaborations with T. Nojima, A.G. Schmidt, and S.C. Harrison have focused on the population genetics of humoral responses to influenza HA. His laboratory developed novel cloning methods central to the research strategy in this proposal.
AARON G. SCHMIDT
PD of Project 3 (Influenza virus HA and NA immunogen design)
Assistant Professor of Microbiology in the Department of Microbiology at Harvard Medical School and of Immunology at Massachusetts General Hospital, and Group Leader at the Ragon Institute of MGH, MIT and Harvard. Schmidt will use structure-guided protein engineering for immunogen design and contemporary methods for in vitro directed evolution to ask basic questions about the humoral immune response. His postdoctoral work led to key papers for this Program Project characterizing structurally and biochemically the humoral response to influenza HA, particularly the RBS.
PD of Core B (Virology)
Professor of Medicine and Pathology, Duke University School of Medicine and primary faculty in DHVI. Sempowski is Director of the Duke RBL and Scientific Director for all DHVI Core Facilities and lead of the Duke CIVICS Vaccine Center Immunological Analyses Unit, which provides pre-clinical cellular, humoral and molecular characterization of influenza immune responses (human, mouse, ferret, NHP), and lab oversight and harmonization lead for the Coordinating Center in the newly created Centers for Research in Emerging Infectious Diseases Network (CREID; NIAID-DMID).
PD of Core C (Ig-seq and BCR-seq)
Ralph and Marjorie Crump Assistant Professor of Engineering at Dartmouth College. Lee is an expert in immune profiling of Ab repertoire in humans using cutting-edge technologies involving high-throughput sequencing of B cells (BCR-Seq) and proteomic deconvolution of serum Abs (Ig-Seq). His research concerns development of the infectious pathogen-specific Ab repertoire in circulation and at mucosal sites and how it biases humoral immune responses to repeated exposures. He has collaborated with the investigators of the Program Project since 2014.
PI of Core D (Bmem analysis)
Assistant Research Professor in the Department of Immunology at Duke University. Kuraoka will be responsible for use of feeder-layers cultures ("Nojima cultures") to analyze memory B cells of mice, macaques and humans. He established (with collaborators) the Nojima culture method for mouse B cells and adapted it to human B cells. He will provide supervision, direction and oversight for Core D personnel and carry out the analysis and interpretation data and their transfer to P01 investigators.
Other key personnel of Projects and Cores:
Robert Wes Rountree, Director of the Biostatistics Center at DHVI, will assist with statistical analyses. He provides statistical oversight and management of the various programs and studies at DHVI. He has been the lead statistician on Phase II clinical trials and large multi-site Phase III randomized controlled clinical trials, assisted with study design, data capture methods and data analysis, and provided statistical analysis for researchers, DSMBs, and the FDA.
Kevin Wiehe, Associate Director of Research, Director of Computational Biology and Co-director of the Quantitative Research Division at DHVI, has been a regular collaborator with this P01. His expertise includes computational structural biology, computational genomics, computational immunology and genetic sequence-based bioinformatics. For the past two decades, he has developed computational approaches for vaccine development and modeled and characterized Ab recognition of antigens. He assists Project 1 and advises Core C.
Thomas Oguin III, Virology Unit Manager, will coordinate Core B technical staff and consult with the RBL Animal Models team. Oguin worked at St. Jude Children’s Research Hospital from 2008-2015 on immune signaling during influenza infection. His expertise in virology enable him to provide optimized virology assays and challenge models.
Akiko Watanabe, Research Scientist, is Manager of Core D. She works closely with Project 1 for processing human PBMC samples. She developed the culture methods for single B-cell cloning of human and rhesus macaque B cells that will be used in Core D. Application of her expertise in cell cloning techniques and in characterizing clonal IgG and V(D)J rearrangements from single B cells led to identification of H1-H3 cross-reactive Abs and discovery of a novel HA-head interface epitope.
BARTON F. HAYNES
Frederic M. Hanes Professor of Medicine and Immunology and Director of the Human Vaccine Institute at Duke, as well as Principal Investigator for the Center for HIV/AIDS Immunology -- Immunogen Design (CHAVI-ID) and PI of a Gates Collaboration for AIDS Vaccine Discovery (CAVD) Center grant. Haynes has led the development of much of the technology for analysis of naïve B-cell repertoires in acute HIV infection -- efforts that have in turn led to the strategies adopted in Project 1. The Program Project and its PI benefits from Dr. Haynes expertise in B-cell immunology, from his long experience in vaccine research, and from his outstanding record of organizing and leading large, interdisciplinary research teams.
Dula D. Cockrell Centennial Chair in Engineering at University of Texas, Austin, has developed the elegant mass-spectrometry methods that enable deconvolution of amino-acid sequences in serum Abs (Ig-seq) and the high-throughput, single-cell, paired-chain NGS method, both of which Dr. Lee has implemented in Core C. He collaborated with the Program Project in the previous cycle and in the first two years of the current cycle; he has now transferred that responsibility to Dr. Lee. His deep knowledge of immune repertoires and their analysis is of great value for the project team.
External Scientific Advisory Board:
Sir John J. Skehel, Francis Crick Institute, London, UK
Prof. Eric Meffre, Yale University, New Haven, CT
Dr. Philip R. Dormitzer, Pfizer Vaccines, Pearl River, NY