Characterization of Alphavirus Replicon Based Vaccines and Adjuvants in a Neonatal Murine Model

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  • March 19, 2019
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  • Khalil, Syed Muaz
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Infectious diseases are the leading cause of childhood morbidity and mortality worldwide. Not only is there a lack of vaccines for many deadly diseases, early life immunization with the available vaccines is frequently ineffective and requires multiple doses to induce protective immune response. Additionally, the neonatal immune responses to infection and vaccination are biased towards TH2 at the cost of pro-inflammatory TH1 responses needed to combat intracellular pathogens. However, upon appropriate stimulation, the neonatal immune system can induce adult-like TH1 responses. We hypothesized that non-propagating Venezuelan equine encephalitis virus replicon (VEE)-based vaccine platforms (VRP) are good candidates for safe early life immunization, based on their ability to (1) target dendritic cells (DC) in the draining lymph node and (2) induction of robust innate immune response through intracellular amplification of replicon RNA. In the VRP expression vector, the same replicon particle functions to deliver the antigen and to serve as innate immune-stimulant. On the other hand, in the VRP as adjuvant (GVI3000), the replicon particle only provides the danger signal function, while the antigen is not expressed from the replicon particle, but co-delivered as purified protein or inactivated virions. By separating the antigen delivery function from the adjuvant function in the GVI3000, we were able to demonstrate the role of the adjuvant function in the VRP, and to start to understand how it mediates the changes in the quality and magnitude of the immune response in the neonate. In this thesis, using a neonatal mouse model, we showed that both platforms induced effective and protective immunity against two different infectious agents, influenza virus and dengue virus. Furthermore, VRP replicon particles served as useful tools to better understand the induction of the neonatal immune response. In summary, the VRP expression vector vaccines and adjuvants induced an adult-like adjuvant effect against dengue influenza antigens, and have the potential to improve the immunogenicity and protective efficacy of new and existing neonatal vaccines.
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  • In Copyright
Advisor
  • Heise, Mark
  • Abel, Kristina
  • White, Laura
  • Swanstrom, Ronald
  • Damania, Blossom
  • Whitmire, Jason
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2014
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  • Chapel Hill, NC
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  • There are no restrictions to this item.
Date uploaded
  • April 22, 2015

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