Biomaterials for nanoparticle vaccine delivery systems

Abstract

Subunit vaccination benefits from improved safety over attenuated or inactivated vaccines, but their limited capability to elicit long-lasting, concerted cellular and humoral immune responses is a major challenge. Recent studies have demonstrated that antigen delivery via nanoparticle formulations can significantly improve immunogenicity of vaccines due to either intrinsic immunostimulatory properties of the materials or by co-entrapment of molecular adjuvants such as Toll-like receptor agonists. These studies have collectively shown that nanoparticles designed to mimic biophysical and biochemical cues of pathogens offer new exciting opportunities to enhance activation of innate immunity and elicit potent cellular and humoral immune responses with minimal cytotoxicity. In this review, we present key research advances that were made within the last 5 years in the field of nanoparticle vaccine delivery systems. In particular, we focus on the impact of biomaterials composition, size, and surface charge of nanoparticles on modulation of particle biodistribution, delivery of antigens and immunostimulatory molecules, trafficking and targeting of antigen presenting cells, and overall immune responses in systemic and mucosal tissues. This review describes recent progresses in the design of nanoparticle vaccine delivery carriers, including liposomes, lipid-based particles, micelles and nanostructures composed of natural or synthetic polymers, and lipid-polymer hybrid nanoparticles.

Figure 1. Fusogenic polymer-modified liposomes for cytosolic delivery of antigens

(A) Liposomes were incorporated with pH-responsive, fusogenic poly(glycidol) derivatives in either a linear (MGlu-LPG) or hyperbranched structure (MGlu-HPG). (B) Confocal images of BMDCs treated with liposomes containing rhodamine-labeled phospholipid (Rh-PE) and FITC-OVA. MGlu-LPG induced more pronounced cytosolic delivery of antigens, compared with MGlu-HPG. (C) Mice were inoculated with E.G7-OVA cells on day 0, and vaccinated with 50 g of OVA either in unmodified liposomes (open triangles), MGlu-LPG-liposomes (open squares), or MGlu-HPG-liposomes (closed squares) on days 7 and 14. MGlu-LPG-liposomes reduced tumor volume more effectively compared with other formulations. Reproduced with permission (46). Copyright 2013, Elsevier.

Figure 2. Elicitation of potent mucosal CD8+ T cell responses with pulmonary nanoparticle vaccination

(A) Intratracheal administration of ICMVs loaded with fluorescent OVA (red) resulted in efficient antigen delivery to mediastinal lymph nodes draining lungs by day 4. (B) Expansion and migration of OVA-specific OT-I CD8+ T cells expressing luciferase was monitored after vaccination. Pulmonary administration of ICMVs led to robust expansion of OT-I CD8+ T cells in the lungs by day 3, and their dissemination to the lungs (L), gastrointestinal tracts (G), Peyer’s patches (PP), and vaginal tract (V) by day 5. Mice immunized via pulmonary route with soluble antigen or subcutaneous route with particles had significantly reduced signals from OT-I T cells in mucosal tissues. (C) Pulmonary vaccination with ICMVs loaded with SIV gag antigen, AL11, and PADRE peptide on days 0 and 28 protected mice against challenge by intratracheal administration of AL11-expressing vaccinia virus, whereas pulmonary vaccination with soluble antigens or subcutaneous vaccination with particles failed to protect the animals. Reproduced with permission (52). Copyright 2013, The American Association for Advancement of Science.

Figure 3. PLGA vaccine particles for co-delivery of antigens and adjuvant molecules

(A) PLGA nanoparticles were coated with a chitosan derivative and co-loaded with bovine serum albumin and TLR7 agonist, imiquimod. Humoral immune responses were evaluated after three immunizations with the particles via either subcutaneous or intranasal route of administration. Local administration of PLGA particles via intranasal route induced higher IgA titers in mucosal surfaces. (B) PLGA microparticles were designed to undergo degradation in the terminal ileum, allowing uptake of particles co-loaded with antigens and TLR agonists in the large intestine. Oral administration of the particles coated with FS30D, a biodegradable polymer at pH > 7.0, led to elicitation of antigen-specific CD8+ T cells in the colorectum. However, particles coated with L100-55, which undergoes degradation at pH > 5.5 and allows particle uptake in small intestine, promoted significantly reduced frequency of tetramer+ CD8+ T cells. Orally delivered FS30D-coated PLGA particles conferred T cell-mediated resistance and reduced viral load following an intra-colorectal viral challenge. Panels (A) reproduced with permission (102). Copyright 2013, American Chemical Society. Panels (B) reproduced with permission (90). Copyright 2012, Nature Publishing Group.

Figure 4. Nanoparticle vaccine based on pH-responsive copolymers for cytosolic delivery of antigen and immunostimulatory molecules

(A) Schematic for the amphiphilic diblock copolymers with (i) hydrophilic and cationic block for conjugation of antigen and electrostatic complexation with CpG and (ii) hydrophobic and endosomolytic block for micelle assembly and cytosolic delivery of antigens. (B) Mice were immunized with conjugates (ova-pol), ova mixed with free CpG (ova+CpG), dual-delivery vehicles (ova-pol/CpG), and free ova mixed with CpG/micelle complexes (ova+pol/CpG). Splenocytes were restimulated ex vivo with free OVA_257-264 for IFN-γ production among CD8+ T cells detected via intracellular cytokine staining (left panel) and ELISPOT (middle panel). ELISPOT quantification of IFN-γ production among CD4+ T cells after splenocytes restimulation with OVA_323-339 (right panel). Reproduced with permission (115). Copyright 2013, American Chemical Society.

Figure 5. Nanoparticle vaccine based on pH-responsive copolymers for cytosolic delivery of antigen and immunostimulatory molecules

(A) Solid-core nanoparticles and aqueous core polymersomes were compared for induction of immune responses. Solid-core nanoparticles had antigens conjugated on their surface via a reduction-sensitive disulfide bond. Polymersomes loaded with antigens in the aqueous core were synthesized by self-assembly of a block copolymer, consisted of hydrophilic poly(ethylene glycol) in the outer and inner core and hydrophobic poly(propylene sulfide) in the center of the lamella. (B) Mice immunized with polymersomes (PS-OVA+CpG) or nanoparticles (NP-OVA+CpG) were analyzed for OVA-specific CD4+ and CD8+ T cell responses with intracellular cytokine staining and tetramer staining. Polymersomes were more effective than nanoparticles at induction of IFN-γ producing CD4+ T cells. In contrast, nanoparticles elicited higher frequency of OVA-specific CD8+ T cells than polymersomes. Reproduced with permission (120). Copyright 2013, Elsevier.