Barouch, Dan HGebre, Makda2022-06-0720222022-05-162022-05Gebre, Makda. 2022. Design Optimization and Immune Kinetics of mRNA Vaccines. Doctoral dissertation, Harvard University Graduate School of Arts and Sciences.29209955https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37372232mRNA vaccines allow for rapid development and large-scale production, making them prime candidates for infectious disease outbreak response. CVnCoV (CureVac) is an mRNA vaccine developed to mitigate the current pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). However, it did not offer optimal protective efficacy when evaluated in a clinical phase 2b/3 trial. In this thesis, we investigate the effect of non-coding region modifications in a second-generation vaccine, CV2CoV, using a non-human primate model. In comparison to CVnCoV, CV2CoV resulted in enhanced antigen expression and innate immune response. This translated to improved humoral and cellular immunogenicity as well as protective efficacy against SARS-CoV-2 challenge. Next, we further examined CV2CoV in mice and identified the unique property of mRNA vaccines to elicit more rapid humoral immunogenicity in contrast to DNA, rhesus adenovirus and protein vaccines of the same antigen. In conclusion, we establish, the critical impact of non-coding region optimization on vaccine efficacy as well as mRNA vaccines’ capability for rapid immune kinetics. These observations highlight critical optimizations and immune properties that can be harnessed to advance mRNA vaccine design for future outbreak response.application/pdfenmRNA OptimizationmRNA Vaccine KineticsmRNA VaccinesPreclinical VaccinologyVirologyThesis or Dissertation2022-06-070000-0001-8520-2178