The proposed work is to generate broadly-protective influenza virus vaccines. The basic experimental approach that we will use to accomplish the goal of vaccine generation is divided into two phases.
Aim 1 involves characterization of human and murine monoclonal antibodies with broad protective activity against hemagglutinins of distinct influenza virus strains. Efforts will be made to determine the precise region of binding of these broadly-protective antibodies on the hemagglutinin molecule.
Aim 2 of this work will involve the design and production of novel vaccine constructs that focus immunity towards those epitopes determined to mediate broad protection. We will construct a set of novel immunogens: several will be based on conserved, continuous, polypeptidic regions of the hemagglutinin, others are based on conformational, discontinuous moieties or on chimeric hemagglutinins. The vaccination strategies will involve the use of DNA, recombinantly purified protein or purified (chimeric) virus. In collaboration with Projects 2 and 3, the vaccine constructs will be optimized by use of complementary adjuvant preparations and will be evaluated for efficacy in both mouse and in ferret models of disease.

Public Health Relevance

Present influenza virus vaccines have to be newly manufactured every year because the circulating influenza virus strains are continuously changing. We are attempting to design novel universal influenza virus vaccines which would be cross-protective against different strains and thus last longer, avoiding the necessity of annual revaccinations;this will be done by first identifying cross-protective monoclonal antibodies (directed against the viral hemagglutinin) and the precise epitopes/sequences they recognize. These epitopes will then be used to guide the design of vaccine constructs which induce cross-protective immune responses against many different influenza virus variants.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI097092-02
Application #
8528831
Study Section
Special Emphasis Panel (ZAI1-RB-M)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$299,093
Indirect Cost
$68,848
Name
Icahn School of Medicine at Mount Sinai
Department
Type
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Mullarkey, Caitlin E; Bailey, Mark J; Golubeva, Diana A et al. (2016) Broadly Neutralizing Hemagglutinin Stalk-Specific Antibodies Induce Potent Phagocytosis of Immune Complexes by Neutrophils in an Fc-Dependent Manner. MBio 7:
Ryder, Alex B; Nachbagauer, Raffael; Buonocore, Linda et al. (2016) Vaccination with Vesicular Stomatitis Virus-Vectored Chimeric Hemagglutinins Protects Mice against Divergent Influenza Virus Challenge Strains. J Virol 90:2544-50
Tran, Erin E H; Podolsky, Kira A; Bartesaghi, Alberto et al. (2016) Cryo-electron Microscopy Structures of Chimeric Hemagglutinin Displayed on a Universal Influenza Vaccine Candidate. MBio 7:e00257
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
Leon, Paul E; He, Wenqian; Mullarkey, Caitlin E et al. (2016) Optimal activation of Fc-mediated effector functions by influenza virus hemagglutinin antibodies requires two points of contact. Proc Natl Acad Sci U S A 113:E5944-E5951
Ho, Irvin Y; Bunker, Jeffrey J; Erickson, Steven A et al. (2016) Refined protocol for generating monoclonal antibodies from single human and murine B cells. J Immunol Methods 438:67-70
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
Neu, Karlynn E; Wilson, Patrick C (2016) Taking the Broad View on B Cell Affinity Maturation. Immunity 44:518-20
Thornburg, Natalie J; Zhang, Heng; Bangaru, Sandhya et al. (2016) H7N9 influenza virus neutralizing antibodies that possess few somatic mutations. J Clin Invest 126:1482-94
Tan, Gene S; Leon, Paul E; Albrecht, Randy A et al. (2016) Broadly-Reactive Neutralizing and Non-neutralizing Antibodies Directed against the H7 Influenza Virus Hemagglutinin Reveal Divergent Mechanisms of Protection. PLoS Pathog 12:e1005578

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