F-101 A hemagglutinin stalk-based universal influenza virus vaccine

Abstract

Influenza virus infections are a significant cause of morbidity and mortality worldwide. Current vaccines show acceptable efficacy against antigenically matched viruses by inducing strain specific antibodies against the membrane-distal globular head domain of the viral hemagglutinin, but fail to protect against drifted and pandemic strains. The membrane-proximal stalk domain of the viral hemagglutinin exhibits a high degree of conservation across influenza virus subtypes, and monoclonal antibodies directed against this region typically show broad neutralizing activity. However, these antibodies are rare and usually not induced/boosted by regular seasonal vaccines. Here, we developed a universal influenza virus vaccination strategy based on the conserved stalk domain of group 1 and group 2 hemagglutinins. By sequential vaccination of mice and ferrets with chimeric hemagglutinin constructs that share the same stalk domain but have divergent head domains we were able to specifically boost broadly neutralizing antibody titers against conserved epitopes in the hemagglutinin stalk. Animals vaccinated with these constructs were protected from morbidity and mortality induced by infection with a panel of heterologous and heterosubtypic influenza A viruses, including avian influenza virus subtypes of concern like H5N1 and H7N9. The induced antibody response was long-lived and also interfered with virus transmission between animals. The present data suggest that this vaccine strategy has the potential to provide broad influenza virus protection in humans and clinical trials are currently ongoing. A universal influenza virus vaccine would represent a major advance towards the control of influenza worldwide and would significantly enhance our pandemic preparedness.