UC San Diego

Influenza virus is a constant threat to international public health. The current, seasonal vaccine generates a response to epitopes of influenza virus that have a high rate of mutation leading to antigenic drift and antigenic shift leaving current memory responses useless and potentially resulting in a pandemic. The need for a universal influenza vaccine is evident. High affinity, broadly neutralizing antibodies (bnAbs) against a conserved epitope of the influenza virion, such as the stem of hemagglutinin, show potential to protect against a wide breadth, if not all influenza viruses. Identifying germline precursors of these bnAbs and generating immunogens that drive the maturation of a heterosubtypic response could provide a universal answer to influenza. In this thesis, I show the development and characterization of a mouse model consisting of B cells containing the germline heavy chain of the influenza bnAb CR9114. Furthermore, I outline the responses of two germline targeting immunogens to influenza: an anti-idiotypic antibody known as K1-18 and an engineered variant of an H1-hemagglutinin protein known as 587H1-X. Both K1-18 and 587H1-X are shown via calcium flux and activation markers to simulate B cells of our 9114 gH mouse model. Immunization studies with both immunogens show their ability to generate an IgG response that cross binds to wild type hemagglutinin. 587H1-X in particular shows mutation capabilities that drive these gl9114 antibodies towards their mature stage. This study sheds light on a germline targeting approach to inducing a universal response to influenza.