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Cryo-electron microscopy and image analyses of influenza vaccine nanoparticles suggest conformational and orientational design constraints correlated with multivalent binding and increased vaccine response

Friday, September 18, 2015 — Poster Session IV

12:00 p.m. – 1:30 p.m.
FAES Terrace
NIAID
STRUCTBIO-4

* FARE Award Winner

Authors

  • JR Gallagher
  • M Kanekiyo
  • HM Yassine
  • JC Boyington
  • BS Graham
  • AK Harris

Abstract

Vaccines based upon recombinantly engineered proteins are revolutionizing the process of vaccine design. Presentation of multiple copies of antigens on nanoparticles substantially increases the immune response to vaccination when compared to unitary monovalent counterparts, in part due to multivalent binding sites on immunogens facilitating B-cell receptor activation. To determine structural and geometrical parameters for multivalent nanoparticle design, we determined the structure of a ferritin-based nanoparticle designed to present a conserved influenza hemaglutinnin (HA) stem epitope on its surface. Using cryo-electron microscopy, image processing and molecular modeling, we found that ferritin-HA was rigid and homogeneous, which facilitated presentation of the conserved antigen. Twenty-four HA protomers associated via octahedral symmetry to form the ferritin particle surface. Using the cryo-EM density map, we resolved the angular orientation of protruding HA trimers relative to the threefold symmetry axis of HA. The angular orientation of the HA trimers were offset from each other, permitting us to model Fab fragments binding to all 24 epitopes on the ferritin-HA particle. Fabs passed next to each without overlap, while protruding outward from the particle where sufficient space existed to accommodate a full antibody. Thus, the structure indicated that a full complement of 24 antibodies may bind to the ferritin-HA nanoparticle. Guidelines for nanoparticle based vaccine design based upon validated structural data such as ferritin-HA promise to lead to improved immune responses to nanoparticle based vaccine candidates and a rapid development process for more efficacious influenza vaccines.

Category: Structural Biology