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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Finney, Joel; Yeh, Chen-Hao; Kelsoe, Garnett et al. (2018) Germinal center responses to complex antigens. Immunol Rev 284:42-50
McCarthy, Kevin R; Watanabe, Akiko; Kuraoka, Masayuki et al. (2018) Memory B Cells that Cross-React with Group 1 and Group 2 Influenza A Viruses Are Abundant in Adult Human Repertoires. Immunity 48:174-184.e9
Raymond, Donald D; Bajic, Goran; Ferdman, Jack et al. (2018) Conserved epitope on influenza-virus hemagglutinin head defined by a vaccine-induced antibody. Proc Natl Acad Sci U S A 115:168-173
Ferdman, Jack; Palladino, Giuseppe; Liao, Hua-Xin et al. (2018) Intra-seasonal antibody repertoire analysis of a subject immunized with an MF59®-adjuvanted pandemic 2009 H1N1 vaccine. Vaccine 36:5325-5332
Finney, Joel; Kelsoe, Garnett (2018) Poly- and autoreactivity of HIV-1 bNAbs: implications for vaccine design. Retrovirology 15:53
Liu, Yuhang; Pan, Junhua; Jenni, Simon et al. (2017) CryoEM Structure of an Influenza Virus Receptor-Binding Site Antibody-Antigen Interface. J Mol Biol 429:1829-1839
Liu, Yuhang; Pan, Junhua; Cai, Yongfei et al. (2017) Conformational States of a Soluble, Uncleaved HIV-1 Envelope Trimer. J Virol 91:
Kuraoka, Masayuki; Schmidt, Aaron G; Nojima, Takuya et al. (2016) Complex Antigens Drive Permissive Clonal Selection in Germinal Centers. Immunity 44:542-552
Raymond, Donald D; Stewart, Shaun M; Lee, Jiwon et al. (2016) Influenza immunization elicits antibodies specific for an egg-adapted vaccine strain. Nat Med 22:1465-1469
Lee, Jiwon; Boutz, Daniel R; Chromikova, Veronika et al. (2016) Molecular-level analysis of the serum antibody repertoire in young adults before and after seasonal influenza vaccination. Nat Med 22:1456-1464

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