This project is focused on the development of a unique GMP-compliant particle molding technology that we have pioneered called PRINT? (Particle Replication in non-wetting templates) as a delivery platform for particulate multivalent vaccines targeting influenza and Dengue viruses. PRINT provides complete control over particle size, shape and chemical composition, and enables the systematic tailoring of antigen proximity to the particle, antigen density and particle size and shape to screen and identify the optimal particle parameters to elicit enhanced immunological responses. The down-selected particle parameters will provide design rules to manufacture influenza and dengue particulate multivalent vaccines to investigate the ability to generate a complete and robust neutralizing antibody response to each antigen. Also, additional Projects within our Program will utilize these multivalent particulate vaccines to address the use of novel adjuvants to modulate the immune response. These particulate vaccines will be evaluated in a humanized mouse model to determine how to prevent infection of homotypic or all 4 dengue virus serotypes. We will combine the learning from each Project to scale-up the most promising multivalent particulate vaccines and advance these to large animal challenge studies for both influenza and dengue. Due to the immediate medical need for multivalent vaccines for influenza and dengue and the cGMP-compliant nature of our particle molding technology, the formulations can be advanced into product development for human trials.
This project will employ a novel, cGMP-compliant nanoparticle molding technology that we have pioneered to develop multivalent vaccines against influenza and dengue virus. Utilizing the unique plug and play capabilities of our process to incorporate and mix and match known anitgens, we will be able to adapt our findings to tailor particulate vaccines to protect against emerging or re-emerging infectious disease.
|Metz, Stefan W; Gallichotte, Emily N; Brackbill, Alex et al. (2017) In Vitro Assembly and Stabilization of Dengue and Zika Virus Envelope Protein Homo-Dimers. Sci Rep 7:4524|
|Junkins, Robert D; Gallovic, Matthew D; Johnson, Brandon M et al. (2017) A robust microparticle platform for a STING-targeted adjuvant that enhances both humoral and cellular immunity during vaccination. J Control Release 270:1-13|
|Cheng, Liang; Zhang, Zheng; Li, Guangming et al. (2017) Human innate responses and adjuvant activity of TLR ligands in vivo in mice reconstituted with a human immune system. Vaccine 35:6143-6153|
|Kai, Marc P; Brighton, Hailey E; Fromen, Catherine A et al. (2016) Tumor Presence Induces Global Immune Changes and Enhances Nanoparticle Clearance. ACS Nano 10:861-70|
|DeSimone, Joseph M (2016) Co-opting Moore's law: Therapeutics, vaccines and interfacially active particles manufactured via PRINT®. J Control Release 240:541-543|
|Metz, Stefan W; Tian, Shaomin; Hoekstra, Gabriel et al. (2016) Precisely Molded Nanoparticle Displaying DENV-E Proteins Induces Robust Serotype-Specific Neutralizing Antibody Responses. PLoS Negl Trop Dis 10:e0005071|
|Fromen, Catherine A; Rahhal, Tojan B; Robbins, Gregory R et al. (2016) Nanoparticle surface charge impacts distribution, uptake and lymph node trafficking by pulmonary antigen-presenting cells. Nanomedicine 12:677-687|
|Callaway, Justin B; Smith, Scott A; Widman, Douglas G et al. (2015) Source and Purity of Dengue-Viral Preparations Impact Requirement for Enhancing Antibody to Induce Elevated IL-1? Secretion: A Primary Human Monocyte Model. PLoS One 10:e0136708|
|Callaway, Justin B; Smith, Scott A; McKinnon, Karen P et al. (2015) Spleen Tyrosine Kinase (Syk) Mediates IL-1? Induction by Primary Human Monocytes during Antibody-enhanced Dengue Virus Infection. J Biol Chem 290:17306-20|
|Robbins, Gregory R; Roberts, Reid A; Guo, Haitao et al. (2015) Analysis of human innate immune responses to PRINT fabricated nanoparticles with cross validation using a humanized mouse model. Nanomedicine 11:589-99|
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