A chimeric haemagglutinin-based influenza split virion vaccine adjuvanted with AS03 induces protective stalk-reactive antibodies in mice

Abstract

Seasonal influenza virus vaccines are generally effective at preventing disease, but need to be well matched to circulating virus strains for maximum benefit. Influenza viruses constantly undergo antigenic changes because of their high mutation rate in the immunodominant haemagglutinin (HA) head domain, which necessitates annual re-formulation and re-vaccination for continuing protection. In case of pandemic influenza virus outbreaks, new vaccines need to be produced and quickly distributed. Novel influenza virus vaccines that redirect the immune response towards more conserved epitopes located in the HA stalk domain may remove the need for annual vaccine re-formulation and could also protect against emergent pandemic strains to which the human population is immunologically naive. One approach to create such universal influenza virus vaccines is the use of constructs expressing chimeric HAs. By sequential immunization with vaccine strains expressing the same conserved HA stalk domain and exotic HA heads to which the host is naive, antibodies against the stalk can be boosted to high titres. Here we tested a monovalent chimeric HA-based prototype universal influenza virus split virion vaccine candidate with and without AS03 adjuvant in primed mice. We found that the chimeric HA-based vaccination regimen induced higher stalk antibody titres than the seasonal vaccine. The stalk antibody responses were long lasting, cross-reactive to distantly related HAs and provided protection in vivo in a serum transfer challenge model. The results of this study are promising and support further development of a universal influenza vaccine candidate built on the chimeric HA technology platform.

Influenza: Developing an effective vaccine for an unstable virus

A genetically engineered vaccine candidate against influenza provides protection irrespective of viral mutation. Florian Krammer of the Icahn School of Medicine at Mount Sinai, New York, Corey Mallett of GlaxoSmithKline, and and colleagues targeted the conserved ‘stalk’ of influenza’s surface protein hemagglutinin, rather than the mutation-prone ‘head’. The team tested sequential dosing of their candidate expressing conserved stalks with differing head sections, with the aim of amplifying immune response against the stalk in a mouse model. Results showed significant induction of stalk-specific antibodies up to day 296 post-vaccination, and also increased levels of antibodies against neuraminidase, another surface protein. As current vaccines target the hemagglutinin head and require annual reformulation due to mutations of the virus, these results warrant further investigation into the ability of these candidates to provide enduring protection against emergent strains of influenza virus.