Journal
ACS NANO
Volume 7, Issue 5, Pages 3912-3925Publisher
AMER CHEMICAL SOC
DOI: 10.1021/nn305466z
Keywords
vaccine; pH-responsive polymer; micelle; CpG adjuvant; endosomal escape; antigen cross-presentation
Categories
Funding
- National Institutes of Health [R01EB002991, R01AI074661]
- Washington State Life Science Discovery Fund [2496490]
- National Science Foundation [DGE-9987620, DGE-0718124, DGE-1256082]
- Department of Defense through the National Defense Science and Engineering Graduate Fellowship Program
- Cancer Research Institute
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Protein subunit vaccines offer important potential advantages over live vaccine vectors but generally elicit weaker and shorter-lived cellular immune responses. Here we investigate the use of pH-responsive, endosomolytic polymer nanoparticles that were originally developed for RNA delivery as vaccine delivery vehicles for enhancing cellular and humoral immune responses. Mice liar nanoparticles were assembled from amphiphilic diblock copolymers composed of an ampholytic core-forming block and a redesigned polycationic corona block doped with thiol-reactive pyridyl disulfide groups to enable dual-delivery of antigens and immunostimulatory CpG oligodeoxynucleotide (CpG ODN) adjuvants. Polymers assembled into 23 nm particles with simultaneous packaging of CpG ODN and a thiolated protein antigen, ovalbumin (ova). Conjugation of ova to nanoparticles significantly enhanced antigen cross-presentation in vitro relative to free ova or an unconjugated, physical mixture of the parent compounds. Subcutaneous vaccination of mice with ova nanoparticle conjugates elicited a significantly higher CD8(+) T cell response (0.5% IFN-gamma(+) of CD8(+)) compared to mice vaccinated with free ova or a physical mixture of the two components. Significantly, immunization with ova-nanoparticle conjugates electrostatically complexed with CpG ODN (dual. delivery) enhanced CD8(+) T cell responses (3.4% IFN-gamma(+) of CDS+) 7-, 18-, and 8-fold relative to immunization with conjugates, ova administered with free CpG, or a formulation containing free ova and CpG complexed to micelles, respectively. Similarly, dual-delivery carriers significantly increased CD4(+)IFN-gamma(+) (Th1) responses and elicited a balanced IgG1/IgG2c antibody response. Intradermal administration further augmented cellular immune responses, with dual-delivery carriers inducing similar to 7% antigen-specific CD8(+) T cells. This work demonstrates the ability of pH-responsive, endosomolytic nanoparticles to actively promote antigen cross-presentation and augment cellular and humoral immune responses via dual-delivery of protein antigens and CpG ODN. Hence, pH-responsive polymeric nanoparticles offer promise as a delivery platform for protein subunit vaccines.
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