Title:
Protein nanoparticle vaccines
Protein nanoparticle vaccines
Author(s)
Chang, Timothy Z.
Advisor(s)
Champion, Julie A.
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Abstract
Highly conserved pathogen proteins are essential for broadly cross-protective vaccines, but tend to be poorly immunogenic. Protein nanoparticle vaccines made from conserved influenza matrix protein 2 (M2e) trigger specific, adaptive immune responses that soluble protein cannot. Without excipients or adjuvants, protein nanoparticles eliminate the possibility of off-target immune responses, and their abiotic nature makes them amenable to cold chain-independent storage and use. The work described herein (1) tests an expanded range of recombinant influenza proteins as viable components of influenza protein nanoparticle vaccines, (2) establishes the immunological basis behind protein nanoparticle adjuvancy in vitro and in vivo, (3) examines long-term, cold-chain-independent storage of protein nanoparticle vaccines, and (4) explores using molecular adjuvants as nanoparticle coatings for enhancing vaccine efficacy. Nanoparticle size and coating were found to be important design criteria for immunogenic protein nanoparticles, and in vivo biodistribution and in vitro dendritic cell processing of nanoparticles yielded insights into mechanisms of protein nanoparticle adjuvancy. Extended room-temperature wet storage of nanoparticles for up to 3 months was shown to yield no loss in immunogenicity, and the molecular adjuvants flagellin and immunoglobulin were shown to enhance various aspects of the immune response in a mouse immunization model. As cold chain-independent storage is an important goal for disseminating new types of vaccines to the developing world, protein nanoparticles have proven to be an attractive and stable platform technology for the co-delivery of antigen and immunostimulatory adjuvant. Furthermore, the ability of immunoglobulin (Ig) to enhance immune responses to protein nanoparticles yields fundamental insights into the innate immunofeedback mechanisms mediated by this protein. In addition to providing a host-derived means of enhancing adjuvancy, Ig-opsonized protein nanoparticles could serve as a tool for further investigations in the broader field of immunoengineering.
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Date Issued
2017-04-06
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Text
Resource Subtype
Dissertation