BBB Seminar: Florian Krammer
Catching a moving target: broadly neutralizing antibodies and the development of a universal influenza virus vaccine
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Influenza virus infections remain a significant cause of morbidity and mortality worldwide. Current vaccines show good efficacy against antigenically matched viruses, but fail to protect against drifted and pandemic strains since they do not induce broadly neutralizing antibodies. Due to the rapid antigenic drift of influenza viruses, these vaccines have to be re-formulated, generated and administered through a cumbersome and expensive process every year. The membrane-proximal stalk domain of the viral hemagglutinin exhibits a high degree of both, sequence and structural conservation across influenza virus subtypes. Furthermore, antibodies directed against this region typically show broad neutralizing activity. We therefore hypothesize that a vaccine strategy that stimulates a robust immune response towards this region of the hemagglutinin could provide universal influenza virus protection. Such a vaccine would thus abolish the need for annual vaccine reformulation and further enhance our pandemic preparedness. We developed a universal influenza virus vaccine based on the conserved stalk domain of group 1 and group 2 hemagglutinins. By sequential vaccination of mice with these chimeric hemagglutinin constructs we were able to boost broadly neutralizing antibody titers against conserved epitopes in the hemagglutinin stalk domain. Mice vaccinated with our constructs were protected from morbidity and mortality induced by infection with a panel of heterologous and heterosubtypic influenza A viruses. Further, we used passive transfer and CD8+ T-cell depletion experiments to show that the observed protection is solely antibody mediated. It is of note that our vaccination regimen protected animals from a stringent H7N1 challenge and also induced high titers of antibodies that reacted strongly with the H7 HA protein derived from the H7N9 strain A/Shanghai/1/13. These findings are of high importance in the light of the emergence of the novel H7N9 strain in China. The present data suggest that this vaccine strategy could be successfully developed in humans to provide broad influenza virus protection and enhance our pandemic preparedness. A universal influenza virus vaccine, which - similar to the ones developed for polio and measles viruses - requires a single or only a few immunizations, would represent a major advance towards the control of influenza worldwide.
Chair: Rebecca Cox, Department of Clinical Science