A universal influenza virus vaccine strategy targeting the conserved stalk domain of the hemagglutinin

Abstract

Influenza virus infections remain 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 both sequence and structural 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. We hypothesize that a vaccine strategy that stimulates a robust immune response towards this region of the hemagglutinin could provide universal influenza virus protection. 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 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. Additionally, chimeric hemagglutinin vaccination also impacted on virus transmission in the ferret model. In the light of emerging viruses in Asia it is of note that our vaccination regimen also protected animals from H5N1, H6N1 and H7N9 virus challenges and reduced lung titers upon H10 virus infection. Finally, we showed that stalk-reactive antibodies were boosted in individuals that received an H5N1 vaccine in clinical trials. This supports the hypothesis that exposure to hemagglutinins with divergent heads but conserved stalk induces such antibodies in humans. 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, which requires a single or only a few immunizations, would represent a major advance towards the control of influenza worldwide and would significantly enhance our pandemic preparedness.