Seasonal influenza imposes a significant socio-economic burden on humanity. Vaccination, the best hope for reducing the impact of influenza, is even under optimal circumstance effective in only 60% of individuals. The difficulty, of course, stems from the protean ability of influenza A virus (IAV) to rapidly escape existing immunity. IAV evolved an error prone polymerase that drives the rapid antigenic evolution of the two virion surface glycoproteins, neuraminidase (NA) and hemagglutinin (HA). Since the most potent antibodies (Abs) at neutralizing viral infectivity (neutralizing Abs, NAbs) are directed the head of the HA, amino acid substitutions in this region enable IAV to evade antibody (Ab)-based immunity. We are studying how IAV evolves under antibody pressure in vitro and in vivo, using ultra deep sequencing to detect mutations that reduce antibody affinity for IAV antigens and as well as epistatic alterations that mitigate fitness costs incurred by escape mutations. We are also studying the B cell response to IAV antigens, and have devised a novel approach that has enabled us for the first time to characterized the immunodominance hierarchy of antibody responses for distinct antigenic sites on the hemagglutinin glycoprotein.

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2016
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Kosik, Ivan; Ince, William L; Gentles, Lauren E et al. (2018) Correction: Influenza A virus hemagglutinin glycosylation compensates for antibody escape fitness costs. PLoS Pathog 14:e1007141
Altman, Meghan O; Angeletti, Davide; Yewdell, Jonathan W (2018) Antibody Immunodominance: The Key to Understanding Influenza Virus Antigenic Drift. Viral Immunol 31:142-149
Kosik, Ivan; Ince, William L; Gentles, Lauren E et al. (2018) Influenza A virus hemagglutinin glycosylation compensates for antibody escape fitness costs. PLoS Pathog 14:e1006796
Angeletti, Davide; Yewdell, Jonathan W (2018) Understanding and Manipulating Viral Immunity: Antibody Immunodominance Enters Center Stage. Trends Immunol 39:549-561
Jegaskanda, Sinthujan; Mason, Rosemarie D; Andrews, Sarah F et al. (2018) Intranasal Live Influenza Vaccine Priming Elicits Localized B Cell Responses in Mediastinal Lymph Nodes. J Virol 92:
Yewdell, Jonathan W (2018) What's Fair Is Fair: Leveling the Playing Field for Young Scientists. Vaccines (Basel) 6:
Kosik, Ivan; Yewdell, Jonathan W (2017) Influenza A virus hemagglutinin specific antibodies interfere with virion neuraminidase activity via two distinct mechanisms. Virology 500:178-183
Angeletti, Davide; Frank, Gregory M; Yewdell, Jonathan W (2017) Flow-Cytometric Method Measuring B Cell Surface Immunoglobulin Avidity. Methods Mol Biol 1623:181-189
Angeletti, Davide; Yewdell, Jonathan W (2017) Is It Possible to Develop a ""Universal"" Influenza Virus Vaccine? Outflanking Antibody Immunodominance on the Road to Universal Influenza Vaccination. Cold Spring Harb Perspect Biol :
Rosshart, Stephan P; Vassallo, Brian G; Angeletti, Davide et al. (2017) Wild Mouse Gut Microbiota Promotes Host Fitness and Improves Disease Resistance. Cell 171:1015-1028.e13

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