Poster Presentation Lorne Infection and Immunity 2018

Subunit vaccines based on stabilisation of trimeric, pre-fusion influenza HA elicits cross-protection between highly divergent influenza A viruses (#150)

Christopher McMillan 1 , Keith Chappell 1 , Daniel Watterson 1 , Kirsty Short 1 , Paul Young 1
  1. Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD, Australia

Influenza viruses remain a major cause of morbidity and mortality worldwide despite the availability of vaccines. Constant antigenic drift in circulating virus populations means current vaccines must be updated and re-administered annually. This approach is time-consuming and expensive and hindered by occasional mismatches between circulating and vaccine strains. Strain mismatch can contribute to poor vaccine efficacy, which has ranged from 10-60% over the last decade. In 2017 Australia experienced its largest epidemic for many decades with an estimated protective efficacy for that year’s vaccine of 10%. This poor efficacy has been attributed to a sequence mismatch in vaccine and circulating strains. Furthermore, recent sporadic zoonotic outbreaks of highly pathogenic avian viruses, to which current vaccines provide no immunity, have been observed, with fatality rates around 40%. This raises serious concerns of a global pandemic with the potential to spread rapidly before vaccines can be manufactured. Novel approaches to influenza vaccination are clearly needed in order to overcome these limitations. We have developed a method to stabilize recombinant influenza haemagglutinin (rHA) in its native, pre-fusion conformation by the addition of a novel “clamp” stabilization motif to enhance vaccine potency and breadth of protection. Immunisation of mice with clamp-stabilized prefusion rHA elicits a potent neutralizing antibody response (~4-fold improvement over current vaccines). Furthermore, antibodies elicited upon immunisation with clamp-stabilised prefusion rHA (HA1 or HA3) showed up to an 80-fold increase in cross-reactivity to rHA (HA5) derived from a divergent, highly pathogenic avian virus when compared to the current influenza vaccines. We have now shown that clamp-stabilised prefusion rHA (based on H3 – Group 2) elicits cross-protection in a mouse model to challenge with a highly divergent influenza virus (H1N1) belonging to a different phylogenetic clade (Group 1). Ultimately, this approach could represent a form of universal influenza vaccine, providing enhanced cross-protection against seasonal influenza viruses while simultaneously providing an increased cross-reactive humoral immune response to potential zoonotic pandemic strains.