Advances in structure-based vaccine design

Abstract

Despite the tremendous successes of current vaccines, infectious diseases still take a heavy toll on the global population, and that provides strong rationale for broadening our vaccine development repertoire. Structural vaccinology, in which protein structure information is utilized to design immunogens, has promise to provide new vaccines against traditionally difficult targets. Crystal structures of antigens containing one or more protection epitopes, especially when in complex with a protective antibody, are the launching point for immunogen design. Integrating structure and sequence information for families of broadly neutralizing antibodies (bNAbs) has recently enabled the creation of germline-targeting immunogens that bind and activate germline B-cells in order to initiate the elicitation of such antibodies. The contacts between antigen and neutralizing antibody define a structural epitope, and methods have been developed to transplant epitopes to scaffold proteins for structural stabilization, and to design minimized antigens that retain one or more key epitopes while eliminating other potentially distracting or unnecessary features. To develop vaccines that protect against antigenically variable pathogens, pioneering structure-based work demonstrated that multiple strain-specific epitopes could be engineered onto a single immunogen. We review these recent structural vaccinology efforts to engineer germline-targeting, epitope-specific, and/or broad coverage immunogens.

Figure 1

Structures related to recent germline-targeting work in the field of HIV vaccine design. (a) The crystal structure of anti-HIV bNAb VRC01 bound to gp120 shows how VRC01 binding utilizes the heavy chain (PDBID: 3NGB [38]). Key heavy chain framework positions, most of which are germline-encoded, are indicated with spheres. Coloring: VRC01 heavy chain, blue but with heavy chain CDR3 loop in wheat; VRC01 light chain, pink; gp120, green. (b) The crystal structure of germline VRC01 bound to germline-targeting eOD-GT6 shows that germline VRC01 binds with a similar angle of approach as VRC01 (PDBID: 4JPK [44^••]). Coloring as in (a). (c) The newly discovered bNAb CH103 engages the CD4 binding site of gp120 like VRC01, but approaches with a different angle and relies on variable regions for binding, especially HCDR3 and LCDR3 loops (PDBID: 4JAN [47^••]). Liao et al. monitored viral evolution during the development of CH103 and found that mutations in or near the CH103 epitope occurred first in loop D (yellow), later in the region of β23-V5 loop-β24 (orange), and still later in the CD4-binding loop (red). Other mutations occurred in the V1 loop (not shown). (d) The eOD-GT6 immunogen was genetically fused to a self-assembling protein, to create a virus-like nanoparticle (d). (a)–(c) are shown with the gp120 CD4-binding site in the same orientation.

Figure 2

Immunogen minimization and chimerization strategies employed in structural vaccinology for Group B Streptococcus (GBS). (Left) The crystal structure of GBS protein BP-2a is depicted in cartoon representation for the three structurally defined domains (D2, red; D3, yellow; D4, blue) (PDBID: 2XTL [69^••]) and a green shape represents the one domain (D1) that was cleaved during crystallization. (Middle left) Mice immunized with single D3 or D4 domains, or with full length BP-2a, were protected against strain 515. (Middle right) A chimeric immunogen, 6xD3, was created by linking together D3 domains from six different GBS strains. (Right) Mice immunized with 6xD3 were protected against all six strains.

Figure 3

Examples of epitope-scaffold design for continuous and discontinuous epitopes. The crystal structure of the anti-HIV bNAb 2F5 (heavy chain Fv, red; light chain Fv, purple) in complex with its epitope (yellow) is shown on the top left panel (PDBID: 1TJI [73]). The crystal structure of 2F5 in complex with an epitope-scaffold (blue) is shown on the top-right (PDBID: 3LEV [70]), with the epitope structural mimicry illustrated by aligning the starting epitope (yellow) onto the epitope-scaffold. In the bottom-left panel, the crystal structure of the anti-HIV bNAb B12 (heavy chain Fv, red; light chain Fv, purple) in complex with gp120 (green) is shown (PDBID: 2NY7 [83]). Two gp120 loops that are essential portions of the epitope, the CD4-binding loop and the outer-domain exit loop, are colored in yellow. In the bottom-right panel, the crystal structure of the epitope-scaffold (blue) in complex with B12 is shown, with the two transplanted loops in yellow (PDBID: 3RU8 [46^••]).