We have added Core E, to support a new joint Aim of the POI, described in both in the plans for the coming year in Project 3 and more briefly in Project 1. Dr. Kelsoe, the Pi of this Core, has been working closely with Haynes, Liao, and Harrison, and he is a coauthor (with Haynes, Harrison, and Kepler) ofthe review that describes (and names) B-cell lineage based immunogen design (Haynes, B.F., Kelsoe, G., Harrison, S.C, Kepler, T.B. B-cell-lineage immunogen design in vaccine development with HlV-1 as a case study. Nature Biotechnology 10: 423 (2012), PMC3512202). The novel, single-cell, B-cell culture system will allow us to test this notion on a feasible timescale in a tractable mouse model, and it will yield data that should facilitate more realistic models of the germinal center reaction and antibody affinity maturation (in humans as well as in mice) in the context of an influenza virus immunogen.
Human pathogens can escape or mitigate host immunity by variation of surface epitopes. Neutral mutations in the influenza virus hemagglutinin accumulate during transmission such that humoral responses to infection are literally seasonal: immunity against this season's flu does not reliably protect against virus circulating in the next year. Nonetheless, influenza viruses do express conserved structures/epitopes (e.g., the stem of influenza virus hemagglutinin) recognized by neutralizing antibodies that could serve, in principle, as targets for protection against all influenza types. This conserved stem region is weakly immunogenic, however, and the central problem for the development of such universal influenza vaccines is whether vaccines can be designed that reliably elicit such responses.
|Kuraoka, Masayuki; Schmidt, Aaron G; Nojima, Takuya et al. (2016) Complex Antigens Drive Permissive Clonal Selection in Germinal Centers. Immunity 44:542-52|
|Xu, Huafeng; Schmidt, Aaron G; O'Donnell, Timothy et al. (2015) Key mutations stabilize antigen-binding conformation during affinity maturation of a broadly neutralizing influenza antibody lineage. Proteins 83:771-80|
|Schmidt, Aaron G; Do, Khoi T; McCarthy, Kevin R et al. (2015) Immunogenic Stimulus for Germline Precursors of Antibodies that Engage the Influenza Hemagglutinin Receptor-Binding Site. Cell Rep 13:2842-50|
|Harrison, Stephen C (2015) Viral membrane fusion. Virology 479-480:498-507|
|Schmidt, Aaron G; Therkelsen, Matthew D; Stewart, Shaun et al. (2015) Viral receptor-binding site antibodies with diverse germline origins. Cell 161:1026-34|
|Jackson, Katherine J L; Liu, Yi; Roskin, Krishna M et al. (2014) Human responses to influenza vaccination show seroconversion signatures and convergent antibody rearrangements. Cell Host Microbe 16:105-14|
|Schmidt, Aaron G; Xu, Huafeng; Khan, Amir R et al. (2013) Preconfiguration of the antigen-binding site during affinity maturation of a broadly neutralizing influenza virus antibody. Proc Natl Acad Sci U S A 110:264-9|
|Dormitzer, Philip R; Grandi, Guido; Rappuoli, Rino (2012) Structural vaccinology starts to deliver. Nat Rev Microbiol 10:807-13|
|Whittle, James R R; Zhang, Ruijun; Khurana, Surender et al. (2011) Broadly neutralizing human antibody that recognizes the receptor-binding pocket of influenza virus hemagglutinin. Proc Natl Acad Sci U S A 108:14216-21|