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.

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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