Abstract
Influenza viruses affect millions of people worldwide on an annual basis. Although vaccines are available, influenza still causes significant human mortality and morbidity. Vaccines target the major influenza surface glycoprotein hemagglutinin (HA). However, circulating HA subtypes undergo continual variation in their dominant epitopes, requiring vaccines to be updated annually. A goal of next-generation influenza vaccine research is to produce broader protective immunity against the different types, subtypes, and strains of influenza viruses. One emerging strategy is to focus the immune response away from variable epitopes, and instead target the conserved stem region of HA. To increase the display and immunogenicity of the HA stem, nanoparticles are being developed to display epitopes in a controlled spatial arrangement to improve immunogenicity and elicit protective immune responses. Engineering of these nanoparticles requires structure-guided design to optimize the fidelity and valency of antigen presentation. Here, we review electron microscopy applied to study the 3D structures of influenza viruses and different vaccine antigens. Structure-guided information from electron microscopy should be integrated into pipelines for the development of both more efficacious seasonal and universal influenza vaccine antigens. The lessons learned from influenza vaccine electron microscopic research could aid in the development of novel vaccines for other pathogens.
Highlights
Influenza virus is an enveloped virus composed of several structural layers that lack defined radial symmetry (Figure 1A)
Because electron microscopy has shown to be uniquely suited to study the morphologies of influenza viruses and how adaption and mutations might change the morphology and the nature of transmission, more of this type of research is likely to continue in the future
We focus primarily on the pre-fusion HA structure because it is the relevant species for vaccine design
Summary
Influenza virus is an enveloped virus composed of several structural layers that lack defined radial symmetry (Figure 1A). The viral envelope that surrounds the RNPs consists of an inner layer of matrix, formed by the M1 protein. Viral surface glycoproteins hemagglutinin (HA), neuraminidase (NA) and matrix. Scale individual glycoprotein spikes on the virion surface are indicated with arrows. 25 nm;bar, 50 nm; (C,(D)inset) individual glycoprotein spikes on the virion surface are indicated with arrows. 25ectodomains nm; (D) A/Victoria/3/75 virions with sphericalHA1 morphologies. HA1 is shown in red and HA2 is blue with receptor binding site (PDBID 5UGY); and (H) H1 HA in complex with Fab CR6261 bound to the. Bound to receptor binding site (PDBID 5UGY); and (H) H1 HA in complex with Fab CR6261 bound to the stem region (PDB 3GBN).
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