Enhancement of immune responses to DNA vaccines
Plasmid DNA vaccines are, conceptually, an attractive approach given their safety profile, ease of design and manufacturing, and stability for distribution in the developing world. In practice, however, they have trailed behind viral vectors in the induction of immune responses in non-human primates and human clinical trials, relegating them to a priming role in heterologous prime/boost strategies. In this thesis we show how strategies that are aimed at optimizing multiple aspects of plasmid delivery, expression, or immune modulation result in more robust immune responses in non-human primate studies. We show that enhancing antigen expression through codon and RNA optimization of the antigenic sequence and the addition of IgE leader sequences together increases the immunogenicity of DNA vaccines. Through the use of enhanced delivery techniques, such as electroporation, we have been able to demonstrate log increases in vaccine-specific cellular responses and the induction of protective neutralizing antibody responses in the monkeypox challenge model. We also demonstrate how plasmid-encoded adjuvants such as IL-12 and RANTES or the targeting of co-stimulatory pathways by monoclonal antibody (mAb) infusions during DNA vaccination can modulate the DNA response in ways that impact the outcome of a high dose SIVmac251 mucosal challenge. Finally, we tested an optimized SIV DNA vaccine in a head to head comparison with the Merck rAd5 SIV vaccine, one of the most developed cellular HIV-1 vaccine candidates. We demonstrate that this optimized SIV DNA vaccine induces cellular responses that are higher in frequency, proliferative capacity, and are qualitatively distinct from immune responses induced by the rAd5 vector. Taken together the data in this thesis illustrate a new level of immune potency for DNA vaccines and support their further study as a vaccine platform for HIV as well as other infectious diseases. ^
Biology, Cell|Biology, Virology|Health Sciences, Immunology
Hirao, Lauren A, "Enhancement of immune responses to DNA vaccines" (2010). Dissertations available from ProQuest. AAI3414202.