Structure-Based Vaccine Antigen Design

Abstract

Enabled by new approaches for rapid identification and selection of human monoclonal antibodies, atomic-level structural information for viral surface proteins, and capacity for precision engineering of protein immunogens and self-assembling nanoparticles, a new era of antigen design and display options has evolved. While HIV-1 vaccine development has been a driving force behind these technologies and concepts, clinical proof-of-concept for structure-based vaccine design may first be achieved for respiratory syncytial virus (RSV), where conformation-dependent access to neutralization-sensitive epitopes on the fusion glycoprotein determines the capacity to induce potent neutralizing activity. Success with RSV has motivated structure-based stabilization of other class I viral fusion proteins for use as immunogens and demonstrated the importance of structural information for developing vaccines against other viral pathogens particularly difficult targets that have resisted prior vaccine development efforts. Solving viral surface structures also supports rapid vaccine antigen design and application of platform manufacturing approaches for emerging pathogens.

Respiratory syncytial virus

“…Antibodies directed to antigenic sites present in the pre-F conformation are more efficient at neutralizing RSV than those directed to antigenic sites present in the more stable post-F confirmation. Although it contains a central conserved domain available for neutralizing antibody binding, the G-protein is not a primary target for vaccine development because it is mostly covered in glycans, and it is not as well conserved within RSV types as the F-protein [39,40]. F -determines viral entry to host cells G -determines binding to host cells F and G proteins have the antigenic determinants that elicit neutralizing antibodies to RSV…”

“…This conformational change exposes various antigenic sites, which each elicit the production of neutralizing antibodies that vary in potency depending on the site. The RSV F-protein has been crystallized and its pre-fusion form stabilized [40,49]. A substantial proportion of the neutralizing antibody response to RSV has been shown to be directed against the pre-fusion conformation of the F protein.…”

“…A substantial proportion of the neutralizing antibody response to RSV has been shown to be directed against the pre-fusion conformation of the F protein. Pre-F antibody has been postulated to serve as a more accurate correlate of protection allowing for the identification of novel antigenic sites that may serve as potential antigens for monoclonal antibody or vaccine development [40,48,50].…”

“…Another important area of research in the field of RSV addresses the need to better understand the mechanisms of protection beyond antibodies, such as innate and cellular immunity. Definitive progress in the design and development of RSV vaccines was driven by a better understanding of the conformation depending immunogenicity of the F-protein and the need to target neutralization sensitive epitopes on the functional forms of F-protein [40,57]. All RSV vaccines for maternal immunization developed to date have been based on the F-protein of RSV.…”

Innovations in HIV-1 Vaccine Design

“…Potent bNAbs that targeted the membrane-proximal external region of gp41 had even greater neutralization breadth than VRC01, 51−55 and in recent years more potent next-generation bNAbs have produced neutralization breadth as high as 96% of viruses tested. 46,56,57 This understanding has allowed researchers to use the structural conformation of antibodies and their target antigens to guide structure-based immunogen design 58 and use lineage-based vaccine design to target the unmutated common ancestor and intermediate antibodies of bNAb lineages. 59 The purpose of this narrative review is to describe some of the most innovative HIV-1 vaccine strategies that have emerged during the last 6 years.…”