Virus-like particles against infectious disease and cancer: guidance for the nano-architect

Abstract

Virus-like particles (VLPs) can play important roles in prevention and therapy for infectious diseases and cancer. Here we describe recent advances in rational construction of VLP assemblies, as well as new approaches to enhance long-lasting antibody and CD8⁺ T cell responses. DNA origami and computational protein design identified optimal spacing of antigens. Chemical biology advances enabled simple and irreversible VLP decoration with protein or polysaccharide antigens. Mosaic VLPs co-displayed antigens to generate cross-reactive antibodies against different influenza strains and coronaviruses. The mode of action of adjuvants inside VLPs was established through knock-outs and repackaging of innate immune stimuli. VLPs themselves showed their power as adjuvants in cancer models. Finally, landmark clinical results were obtained against malaria and the SARS-CoV-2 pandemic.

Graphical abstract

Figure 1

Architectural elements in VLP design. Tuning the surface, underlying scaffold and cargo can all have major effects on VLP biological efficacy.

Figure 2

Advances in antigen display technologies. (a) DNA origami testing of antigen spacing. 6-helix DNA bundles were prepared with two copies of antigen anchored at different spacing, before testing of B cell activation. Also, DNA icosahedra were constructed with 5 copies of antigen at different spacing. Based on Ref. [3^••]. (b) Challenges in matching of symmetry between the nanoparticle and antigen. For modular coupling, display of multimeric antigen (in orange) on the VLP (purple) may lead to different densities of display. There is potential for coupling to destabilize the antigen (misfolding shown in magenta) and for bridging of different VLPs by the antigen. Taken from Ref. [5]. (c) Cobalt porphyrin phospholipid (CoPoP) for anchoring His-tagged antigen to the bilayer of liposomes, taken from Ref. [6]. (d) SnoopLigase (dark gray) directs formation of an isopeptide bond (red) from a lysine of SnoopTagJr peptide (blue) to an asparagine of DogTag peptide (yellow), for linking antigen to nanoparticles. Adapted from Ref. [8].

Figure 3

Changing the environment around the antigen at the VLP surface. (a) Masking of antigen by surface VLP architecture. Epitopes at the base of HIV antigen (BG505 SOSIP) are less exposed when displayed on I53-50 nanoparticles compared to T33_dn2 nanoparticles, based on binding by different monoclonal antibodies (target sites on antigen color-coded), taken from Ref. [13^•]. (b) Protein corona interaction with the viral surface. Transmission electron microscopy of RSV close to the cell surface, incubated in serum-free medium, human plasma (HP) or fetal bovine serum (FBS). Arrows point to protein corona bound at the virus surface. On the right is quantification of RSV infectivity (leading to GFP expression) in serum-free conditions compared to different media (BALF, bronchoalveolar lavage fluid; jHP, juvenile human plasma). Taken from Ref. [27^••].

Figure 4

VLP assemblies against coronavirus and malaria. (a) Mosaic vaccine for broad coronavirus protection. RBD variants from SARS-CoV-2 alone or other sarbecoviruses were expressed bearing SpyTag, allowing covalent coupling onto the SpyCatcher003-mi3 nanoparticle. Display of different RBDs on the same VLP elicited antibodies with broad reactivity to sarbecoviruses. Taken from Ref. [36^••]. (b) Two component SARS-CoV-2 VLP vaccine. Model of the SARS-CoV-2 RBD (light blue) fused to the trimeric I53-50A component (gray) and the pentameric I53-50B component (orange). These components are expressed separately and then mixed, to yield a nanoparticle bearing 60 copies of RBD for immunization, taken from Ref. [47]. (c) Malaria VLP vaccine trials results. Incidence of malaria is plotted over time following the third vaccination. Group 1: 5 μg R21/25 μg Matrix M. Group 2: 5 μg R21/50 μg Matrix M. Group 3, rabies control vaccination. The organization of the R21 fusion protein is indicated. Adapted from Ref. [50^••].