Sinai-Emory Multi-Institutional CIVIC

The Sinai-Emory Multi-Institutional CIVIC (SEM CIVIC) aims to develop improved seasonal and universal influenza virus vaccines that induce long lasting protection against drifted seasonal, zoonotic and future pandemic influenza viruses. This will be achieved through an iterative process of vaccine design, preclinical testing of candidates in animal models, clinical trials in collaboration with other CIVIC components and detailed assessment of immune responses (humoral and cellular) in animals and humans. SEM CIVIC combines expertise in vaccinology and translational vaccine development, molecular virology, immunology including B- and T-cell immunity, antibody function and innate immunity, structural biology, epidemiology and computational biology. Our team is comprised of investigators with a strong background in influenza virus research as well as investigators who are new to the field.

Principal Investigator

Krammer

FLORIAN KRAMMER, PhD
Professor, Microbiology
Icahn School of Medicine at Mount Sinai

 

 

 

 

 

 

Co-Principal Investigator

Ahmed

RAFI AHMED, PhD
Professor, Microbiology and Immunology
Director, Emory Vaccine Center
Emory University

Icahn School of Medicine at Mount Sinai

Palese

Peter Palese, PhD, Professor and Chair, Department of Microbiology

 

 

 

 

 

 

 

GarciaSastre

Adolfo García-Sastre, PhD, Professor, Department of Microbiology

 

 

 

 

 

 

 

Nachbagauer

Raffael Nachbagauer, MD, PhD, Assistant Professor, Department of Microbiology

 

 

 

 

 

 

Emory University

Amara

Rama Rao Amara, PhD, Professor, Department of Microbiology and Immunology

 

 

 

 

 

 

La Jolla Institute for Immunology

Crotty

Shane Crotty, PhD, Professor, Division of Vaccine Discovery

 

 

 

 

 

 

 

PATH Center for Vaccine Innovation and Access

Innis

Bruce Innis, MD, Leader, Respiratory Infections and Maternal Immunization

 

 

 

 

 

 

 

The Rockefeller University

Ravetch

Jeffrey V. Ravetch, MD, PhD, Professor and Head, Laboratory of Molecular Genetics and Immunology

 

 

 

 

 

 

The Scripps Research Institute

Wilson

Ian Wilson, PhD, Professor and Chair, Department of Integrative Structural and Computational Biology

 

 

 

 

 

 

Ward

Andrew B. Ward, PhD, Professor, Department of Integrative Structural and Computational Biology

 

 

 

 

 

 

Stanford University

Wang

Taia T. Wang, MD, PhD, Assistant Professor, Departments of Medicine and Microbiology and Immunology

 

 

 

 

 

 

University of Chicago

PWilson

Patrick C. Wilson, PhD, Professor, Department of Medicine

 

 

 

 

 

 

 

Cobey

Sarah Cobey, PhD, Associate Professor, Department of Ecology and Evolution

 

 

 

 

 

 

University of Michigan

Gordon

Aubree Gordon, PhD, Associate Professor, Department of Epidemiology

 

 

 

 

 

 

 

University of Minnesota

Masopust

David Masopust, PhD, Professor, Department of Microbiology and Immunology

 

 

 

 

 

 

Langlois

Ryan A. Langlois, PhD, Assistant Professor, Department of Microbiology and Immunology

 

 

 

 

 

 

University of Wisconsin-Madison

Kawaoka

Yoshihiro Kawaoka, DVM, PhD, Professor, Department of Pathobiological Sciences

 

 

 

 

 

 

Washington University School of Medicine 

Ellebedy

Ali Ellebedy, PhD, Professor, Department of Pathology and Immunology

 

 

 

 

 

 

 

The Wistar Institute

Weiner

David B. Weiner, PhD, Professor and Director, Vaccine and Immunotherapy Center

 

 

 

 

 

 

Kulp

Daniel Kulp, PhD, Associate Professor, Vaccine and Immunotherapy Center

 

 

 

 

 

 

 

Yale University

Iwasaki

Akiko Iwasaki, PhD, Professor, Departments of Immunology and Molecular, Cellular, and Developmental Biology

Program Manager

Center Coordinator

Data Manager

PI location 1 (PI: Dr. Florian Krammer and admin core):
Icahn School of Medicine at Mount Sinai
Department of Microbiology
One Gustav L. Levy Place
New York
NY 10029

PI location 2 (coPI: Dr. Rafi Ahmed):
Emory University, School of Medicine
1510 Clifton Rd. NE
Rollins Research Center-Rm. G211
Atlanta
GA 30322

Dr. Peter Palese, Dr. Adolfo García-Sastre and Dr. Raffael Nachbagauer
Icahn School of Medicine at Mount Sinai
Department of Microbiology
One Gustav L. Levy Place
New York
NY 10029 

Dr. Ian Wilson and Dr. Andrew Ward:
The Scripps Research Institute
10550 North Torrey Pines Road 
La Jolla, CA 92037

Dr. Masopust and Dr. Ryan A. Langlois:
University of Minnesota
3 Morrill Hall
100 Church St. S.E.
Minneapolis MN 55455 

Dr. Shane Crotty
La Jolla Institute for Immunology
9420 Athena Circle La Jolla, CA 92037 

Dr. Ali Ellebedy
Washington University School of Medicine
660 S. Euclid Ave., St. Louis, MO 63110

Dr. David B. Weiner and Dr. Daniel Kulp
The Wistar Institute
3601 Spruce Street Philadelphia, PA 19104 

Dr. Yoshihiro Kawaoka
University of Wisconsin-Madison School of Veterinary Medicine
2015 Linden Dr.
Madison, WI 53706 

Dr. Patrick Wilson and Dr. Sarah Cobey
University of Chicago
Edward H. Levi Hall
5801 South Ellis Avenue
Chicago, Illinois 60637 

Dr. Akiko Iwasaki
Yale School of Medicine
333 Cedar Street
New Haven, CT 06510 

Dr. Jeffrey V. Ravetch
The Rockefeller University
1230 York Avenue
New York, NY 10065 

Dr. Taia T. Wang
Standford University
450 Serra Mall, Stanford, CA 94305

Dr. Aubree Gordon
University of Michigan
500 S State St, Ann Arbor, MI 48109 

Dr. Rama Rao Amara
Emory University
201 Dowman Dr, Atlanta, GA 30322 

Dr. Bruce Innis
PATH Center for Vaccine Innovation and Access
2201 Westlake Avenue, Suite 200
Seattle, WA 98121, USA
Mailing address
PO Box 900922
Seattle, WA 98109

Adolfo García-Sastre
Adolfo García-Sastre’s team evaluates preclinical vaccine efficacy in animal models, takes the measurements of host response in vaccinated/infected individuals to identify early correlates of long-lasting immune protection and investigates how innate immune responses regulate adaptive immunity in the context of influenza virus infection or vaccination.

Sarah Cobey
Sarah Cobey’s group will perform computational modeling of the immune responses to influenza vaccines to understand factors affecting the durability and magnitude of responses.

Bruce Innis
The PATH team will provide expertise and help in influenza vaccine design, discovery, and development, adjuvant development, and their knowledge of regulatory guidelines and submission processes for clinical testing of candidate vaccines. 

Taia T. Wang

Dr. Wang’s team will be characterizing functional antibody responses elicited by experimental vaccines and adjuvants.

Akiko Iwasaki

Dr. Iwasaki’s  contribution to CIVIC is to examine the ability of various adjuvants to induce systemic and mucosal antibody and T cell immunity by vaccine antigens identified by CIVIC against influenza virus challenge in mice, and to dissect the innate immune signaling pathways that leads to protective immunity by the candidate vaccines.

Raffael Nachbagauer
With the focus on immune responses to infection and vaccination, as well as vaccine development, the Nachbagauer laboratory is currently involved in the clinical development of novel universal influenza virus vaccine candidates based on chimeric hemagglutinins. The Nachbagauer laboratory is also working on mRNA-based vaccination approaches against influenza viruses.

Ian Wilson & Andrew Ward
The structural biology component of this project comprises of two interrelated components, X-ray crystallography in the Wilson laboratory and electron microscopy (EM) in the Ward laboratory, coupled with other biophysical analyses. Together, we perform all structural biology studies in the CIVIC project to determine the binding and three-dimensional structure of influenza HA and NA antigens (from influenza A and B viruses) in complex with neutralizing antibodies whether elicited through natural infection or vaccine-induced, and also designed immunogens also in complex with antibodies. That information will be used to help design and characterize immunogens as universal vaccine candidates. These immunogens will then be tested in vivo and in vitro in the other components of the CIVIC in iterative cycles of structure, design and functional studies. The structural methods include X-ray crystallography, negative-stain electron microscopy, cryo-electron microscopy and cryo-electron tomography (if necessary) as well as electron microscopy polyclonal epitope mapping (EMPEM) on serum samples from patients enrolled in vaccine trials. Other biophysical methods, including Bio-Layer Interferometry (BLI), Isothermal Titration Calorimetry (ITC), Differential Scanning Calorimetry (DSC), and Surface Plasmon Resonance (SPR), will also be used to characterize influenza HA and NA antigens (from influenza A and B viruses), vaccine candidates, and their complexes with neutralizing antibodies.

Peter Palese
The Palese laboratory focuses on generating mosaic HA vaccine constructs, including H1, H3 and B HAs, as well as characterizing their immunogenicity in mice. The immunodominant, sequence-variable antigenic sites of the mosaic HAs (mHA) are silenced by mutating them to corresponding sequences of avian HA proteins to yield the “mosaic” phenotype. These constructs will be used in sequential vaccination regimes with constructs having a conserved “framework” and different grafted antigenic sites at each immunization. We hypothesize that this vaccination approach will focus antibody responses to the subdominant, conserved epitopes in both the head and stalk domains, thereby generating broad and long-lasting immunity.

Jeffrey V. Ravetch
Dr. Jeffrey V. Ravetch is the Theresa and Eugene M. Lang Professor at the Rockefeller University and Head of the Leonard Wagner Laboratory of Molecular Genetics and Immunology. Dr. Ravetch has made ground-breaking discoveries on the mechanisms by which antibodies mediate protective responses in vivo. These studies have established the general foundation of antibody-mediated therapy by demonstrating the essential role of Fc interactions with distinct Fc receptors, resulting in the development and approval of novel antibody therapeutics. In recent studies, Dr. Ravetch has demonstrated a critical role for Fc receptor pathways in modulating vaccine efficacy, as well as in contributing to the in vivo protective activity of antibodies against infectious pathogens, including influenza virus, anthrax, Ebola virus, and HIV-1. As part of the CIVIC consortium, Dr. Ravetch aims to study the Fc effector function of vaccine-elicited IgG responses, determining the role of Fc-FcγR interactions in the in vivo activity of protective anti-influenza antibodies. These studies will be performed in novel mouse strains, previously developed and characterized by the Ravetch laboratory. Such strains faithfully recapitulate the unique complexity of human FcγR biology, serving as a robust platform for the evaluation of human antibody function in vivo.

Aubree Gordon
Aubree Gordon’s group will work on correlates of protection as well as correlates of long-lived immunity. This work will include examining correlates in observational epidemiological studies of natural infections in humans, in animal studies, and in next-generation and universal influenza virus vaccine trials.

Ali Ellebedy
The Ellebedy lab interrogates the dynamics and specificity of germinal center and memory B cell responses to universal influenza vaccine candidates in both pre-clinical models and clinical specimens.

Patrick C. Wilson
The ultimate goal of most – if not all – human vaccines currently in use is to generate antigen-specific memory B cells (MBCs) and long-lived plasma cells (LLPCs). Both of these subsets provide the host with a persistent source of protective antibodies and are therefore needed to maintain durable immune protection following vaccination. Thus, understanding how B cells are initially recruited and stimulated by vaccines and the specificity and functional capacity of antibodies encoded by these cells is a central component to the candidate vaccines’ development and evaluation. The laboratory of Patrick Wilson will work in the characterization of B cell and monoclonal antibody responses in detail. Also the Wilson laboratory has accumulated an extensive collection of monoclonal antibody reagents against influenza virus produced in similar studies that will be of value in templating and evaluating novel vaccine candidates and for iterative vaccine design.

Yoshihiro Kawaoka
Together with the García-Sastre group at the Icahn School of Medicine at Mount Sinai, the Kawaoka group at the University of Wisconsin-Madison will assess influenza vaccine candidates in different animal models. Specifically, the Kawaoka group will test the immunogenicity, virulence, transmissibility, and/or protective efficacy of vaccine candidates in mice, guinea pigs, and/or ferrets. Moreover, the Kawaoka group will establish pre-immunization animal models to test vaccine efficacy in animals with prior exposure to influenza viruses, similar to the situation in humans (with the exception of infants).

Rama Rao Amara
Dr. Amara’s laboratory at the Yerkes National Primate Research Center of Emory University is developing vaccines for HIV, TB and other infectious diseases using the non-human primate (NHP) model. His laboratory developed the state of the art T cell and B cell assays for NHP experiments. As part of this CIVIC, his laboratory will be responsible for studying the longevity of humoral and cellular immune responses induced by various vaccine delivery systems including proteins, DNA and RNA. Protein vaccinations will also test the influence of different adjuvants. One of the primary goals of these experiments will be to identify molecular and immunological mechanisms that are associated with induction of long-lived immunity against influenza proteins in NHPs that can be tested/compared eventually with vaccinations in humans.

Shane Crotty
The Crotty laboratory has expertise in T follicular helper (Tfh) cells (Immunity 2019), germinal center biology, and human and non-human primate vaccine immunology (Cell 2019, Science 2019). We will apply this expertise in the context of the CIVIC to assess candidate universal influenza vaccine approaches to understand the CD4 T cell and B cell immunological challenges that need to be overcome for the development of effective, broad, protective immunity to influenza.

David Weiner & Daniel Kulp (Wistar)
The overall goal of the CIVIC project at the Wistar Institute is to design and evaluate improved Synthetic DNA (SynDNA)-encoded seasonal influenza vaccines. Two integrative approaches will be employed with a focus first on developing improved seasonal vaccines that generate both humoral protection and drive T cell immunity, an important focus for influenza vaccines in older populations. First, we are studying the design and development of micro consensus antigens based on phylogenetic analyses of past and circulating influenza strains and the study of their immune potency. Second, we are generating in vivo assembled nanoparticulate vaccines through protein engineering to scaffold multiple copies of hemagglutinin antigens. These technologies are designed for use with an enhanced SynDNA/electroporation delivery technology for direct in vivo production of the final vaccines. The goal is to facilitate their potential translation into clinical evaluations.

David Masopust & Ryan A. Langlois
Clinical data, recapitulated in animal models, demonstrate that CD8 T cells are highly cross-reactive between different influenza strains and contribute to heterosubtypic immunity. Vaccine-elicited influenza-specific CD8 T cell responses will be evaluated, with an emphasis on the establishment of mucosal and resident memory that provide the best protection. Moreover, mechanisms and biomarkers will be assessed for the induction of long-lived memory T cells that maintain respiratory immunity via recirculation through the lung or residence in lung draining lymph nodes.

Rafi Ahmed
Dr. Ahmed is co-PI of the CIVIC program, Director of the Emory Vaccine Center, and Professor at Emory’s Department of Microbiology and Immunology. He is also a member of the National Academy of Sciences and the National Academy of Medicine. Dr. Ahmed is an eminent immunologist and has published seminal work on T- and B-cell biology. A main focus of the CIVIC studies undertaken by his group will be to use nonhuman primate (NHP) studies to determine which candidate universal influenza virus vaccines induce long term memory, and to understand the factors controlling the establishment and persistence of long-lived plasma cells in the bone marrow after vaccination. An additional important goal will be to assess the persistence of resident memory T cell populations in respiratory tissues in these animals. The NHP model is the most reliable animal model for determining which candidate vaccines and which adjuvants are most likely to generate long term immunity in humans. In complementary studies the Ahmed group will also evaluate the persistence of influenza-specific B cell lineages in humans enrolled in clinical trials of vaccine candidates using a proteomics-based approach to identify the antibody lineages which persist in the serum one year after vaccination.

Another focus of the Ahmed group will be to use murine models to evaluate influenza-specific CD8 T cell responses to the various DNA and RNA influenza vaccine formulations. Harnessing the immune system early after infection to limit productive viral replication and cell-to-cell spread would decrease morbidity and mortality and also reduce transmission. CD8 T cells have a defined role in heterosubtypic immunity which to date have not been optimally leveraged in influenza vaccines. Unlike neutralizing Abs, which primarily recognize conformational epitopes on the viral surface, CD8 T cell memory is highly cross-reactive between different influenza virus subtypes. A vaccine induced CD8 T cell response targeting conserved antigens, from both influenza A and B viruses, could contribute to universal protection against influenza.

If you are interested in reagents produced by our CIVIC or in collaborating with us on exciting vaccine approaches, please contact Program Manager Chiara Mariottini for more information.

 

Chiara Mariottini: chiara.mariottini@mssm.edu.

Krammer F Li L Wilson PC. Emerging from the Shadow of Hemagglutinin: Neuraminidase Is an Important Target for Influenza Vaccination. Cell Host Microbe. 2019 Dec 11;26(6):712-713. doi: 10.1016/j.chom.2019.11.006.