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Observed Structural Heterogeneity of Human Hepatitis B Virus Surface Antigen Particles by Cryo-electron Microscopy

Due to the integrated use of bioinformatics, structural biology, and gene synthesis, the design of vaccine nanoparticles is an area of research that is gaining interest. This is due to the fact that conserved epitopes can be engineered to be displayed on nanoparticles with improved immunogenicity. One example of this antigen design concept is the use of ferritin to display epitopes from the influenza viral glycoprotein, hemagglutinin [1,2]. Ferritin is a particle with octahedral symmetry, and epitopes displayed on ferritin have been shown to elicit protective immune responses [1,2,3]. Interestingly, hepatitis B virus (HBV) surface antigen particles (sAg) isolated from sera were used as the first HBV vaccine and later replaced with recombinant sAg particles [4,5]. Furthermore, the sAg particles had been reported also to have octahedral symmetry by single-particle cryo-electron microscopy (cryo-EM) analysis [6]. To the contrary, tomographic analysis by cryo-EM did not detect octahedral symmetry [7]. Thus, whether nanoparticles that are efficacious in animals and humans must have strict octahedral has not been explored. To address the question of the structural organization of HBV sAg particles, we analyzed sAg particles of the Ad subtype isolated from human sera. We used the methods of single-particle cryo-EM with movie-mode data collection, resolution assessment, 2D classification and 3D reconstruction.