Structural characterization of influenza virus-like particles displaying hemagglutinin have structural variances from native virus with potential for immunological impact

Authors

• DM McCraw
• JR Gallagher
• UM Torian
• AK Harris

Abstract

Despite the availability of seasonal vaccines, influenza virus continues to be a major health concern due to the continually changing surface antigen, hemagglutinin (HA). Highly conserved epitopes reside within the less-accessible stem domain of HA and are the targets of broadly neutralizing antibodies, thereby holding promise for the design of a universal influenza vaccine. Virus-like particles (VLPs) containing HA are a promising vaccine platform that have been shown to protect mice against heterosubtypic challenge in animal models. However, the structure of influenza VLPs is not fully understood. Here we used cryo-electron microscopy, immunoassays, image analysis to characterize the structure and morphology of influenza VLPs that display HA from the 1918 H1N1 pandemic. We found that the VLPs were predominantly spherical in shape and HA was uniformly distributed on the VLP, but exhibited a tighter packing than influenza virus. However, heterosubtypic antibodies still bound to conserved epitopes on the HA stem domain. Cryo-EM segmentation identified HA displayed on the surface and HA contained within the VLP—which we termed ‘molecular cargo’. Our observations suggest that influenza VLPs share a similar morphology to H1N1 viruses and that the tightly packed arrangement of HA molecules on the VLP does not ablate binding by broadly neutralizing antibodies. HA was confirmed to be both externally exposed and internally contained as ‘molecular cargo’, which may suggest the promotion of multiple immunological pathways. Further studies of additional influenza VLP subtypes would aid in optimizing the display of conserved epitopes for designed immunogens—including a universal influenza vaccine.

Scientific Focus Area: Virology

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