The generation of an effective pan-influenza vaccine should induce the following immune memory responses: 1) protective titers of serum antibody that potently neutralizes a wide variety of influenza strains; 2) a robust memory B cell pool that can be rapidly adapted by somatic mutation to neutralize varying influenza strains that evolve in the future;and 3) the requisite T cell mediated memory response to support this adaptation within germinal center reactions. The three projects in this program will work towards these goals using the mAb technology core as a central resource in order to inform antigen and vaccine design. These antibodies will be used to quantify the efficiency of broadly-neutralizing antibodies elicited in mice and to evaluate the ability of human B cell responses to target candidate epitope specificities such as those induced by the long alpha helix of the HA2 molecule and the headless HA construct from Peter Palese's group. The studies proposed will generate large panels of both mouse and human mAbs that may themselves be valuable as therapeutic reagents to treat severe cases of influenza infection. The relative efficacy of these antibodies and thus the epitopes that elicit them will be evaluated in vivo by the Garcia-Sastre project. The requisite T cell epitopes required to elicit broadly protective antibodies will be evaluated by the Ahmed project, using the core to evaluate the spectrum of B cell epitopes supported by T cell epitopes during influenza responses in both mice and humans. The mAb core will be responsible generating both classic mouse hybridomas and recombinant monoclonal antibodies for use by the three projects. The Core will also be responsible for the initial biochemical characterization of both human and mouse monoclonals. Specifically, Project 1 will use the core to generate mAbs against broadly neutralizing epitopes. This project will utilize the core extensively for production of mouse antibodies. Further, the core will provide broadly protective human antibodies to template novel vaccine candidate constructs. Project 2 will explore coordinate epitope specificities in mice lymphoid tissues and human tonsils. The B cell epitopes will be identified through the generation of mouse and human antibodies from the same tissues that TFH cells are isolated. Project 3 will examine the efficacy of mAbs generated by the core for prophylaxis against various influenza virus strains in mice and ferrets. These mAbs will help in evaluating candidate vaccine efficacy and identify mechanisms of neutralization.

Public Health Relevance

The goal of generating a broadly protective vaccine effective against most influenza strains is centered on the specificity of antibodies that can be induced. This core will utilize our specialized approaches to generate and study antibody responses to assist the program projects to both template and evaluate candidate pan-influenza vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI097092-03
Application #
8711243
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
García-Sastre, Adolfo (2017) Ten Strategies of Interferon Evasion by Viruses. Cell Host Microbe 22:176-184
He, Wenqian; Chen, Chi-Jene; Mullarkey, Caitlin E et al. (2017) Alveolar macrophages are critical for broadly-reactive antibody-mediated protection against influenza A virus in mice. Nat Commun 8:846
Martín-Vicente, María; Medrano, Luz M; Resino, Salvador et al. (2017) TRIM25 in the Regulation of the Antiviral Innate Immunity. Front Immunol 8:1187
Jacobsen, Henning; Rajendran, Madhusudan; Choi, Angela et al. (2017) Influenza Virus Hemagglutinin Stalk-Specific Antibodies in Human Serum are a Surrogate Marker for In Vivo Protection in a Serum Transfer Mouse Challenge Model. MBio 8:
Wohlbold, Teddy John; Podolsky, Kira A; Chromikova, Veronika et al. (2017) Broadly protective murine monoclonal antibodies against influenza B virus target highly conserved neuraminidase epitopes. Nat Microbiol 2:1415-1424
Ermler, Megan E; Kirkpatrick, Ericka; Sun, Weina et al. (2017) Chimeric Hemagglutinin Constructs Induce Broad Protection against Influenza B Virus Challenge in the Mouse Model. J Virol 91:
Schotsaert, Michael; García-Sastre, Adolfo (2017) Inactivated influenza virus vaccines: the future of TIV and QIV. Curr Opin Virol 23:102-106
Klausberger, Miriam; Tscheliessnig, Rupert; Neff, Silke et al. (2016) Globular Head-Displayed Conserved Influenza H1 Hemagglutinin Stalk Epitopes Confer Protection against Heterologous H1N1 Virus. PLoS One 11:e0153579
Chen, Chi-Jene; Ermler, Megan E; Tan, Gene S et al. (2016) Influenza A Viruses Expressing Intra- or Intergroup Chimeric Hemagglutinins. J Virol 90:3789-93
Ajmani, Gaurav S; Suh, Helen H; Pinto, Jayant M (2016) Effects of Ambient Air Pollution Exposure on Olfaction: A Review. Environ Health Perspect 124:1683-1693

Showing the most recent 10 out of 76 publications