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

Bruce L Innis,David Kinzler,Nicolas Lecrenier,Florian Krammer,Ariana Hirsh,Corey P Mallett,Raffael Nachbagauer,Peter Palese,Angela Choi,Edith Beaulieu

doi:10.1038/npjvaccines.2016.15

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.

Highlights

Current seasonal influenza virus vaccines show high vaccine efficacy when they are well matched with circulating virus strains.[1]
The prime was given to induce a low level of haemagglutinin molecule (HA) stalk-reactive antibodies that could be boosted with the chimeric vaccines
The mice were bled on the days of vaccination (0, 28, 70) as well as on day 112, 133, 154, 195 and 296 (Figure 1c) and the serum was analysed for reactivity to the HA stalk

Summary

Introduction

Current seasonal influenza virus vaccines show high vaccine efficacy when they are well matched with circulating virus strains.[1]. Several strategies have been developed, which induce broad protection against influenza viruses, overcoming the limitations of currently licensed seasonal vaccines.[8,9,10,11,12,13,14,15,16,17,18] One of these approaches aims at redirecting the immune response away from the immuno-dominant head domain of the viral HA and towards the more conserved and immuno-subdominant stalk domain using chimeric HAs (cHAs).[8,19,20] The cHAs are combinations of 'exotic' head domains, mostly from avian influenza virus subtypes to which humans are naive, paired with a conserved stalk domain (e.g., from H1 or H3 HAs).[21,22] Sequential immunization with cHAs that have different head domains but the same stalk domain can break the immunodominance of the head and re-direct the immune response towards the conserved stalk domain (Figures 1a and b). This work is a necessary precursor to evaluation of the same vaccine strategy in human subjects

Methods

Results

Conclusion