Correlates of immune mediated protection to most viral and cancer vaccines are still unknown. This impedes the development of novel vaccines to incurable diseases such as HIV and cancer. In this study, we have used functional genomics and polychromatic flow cytometry to define the signature of the immune response to the yellow fever (YF) vaccine 17D (YF17D) in a cohort of forty volunteers followed for up to one year after vaccination. We show that immunization with YF17D leads to an integrated immune response that includes several effector arms of innate immunity including complement, the inflammasome and interferons, as well as adaptive immunity as shown by an early T cell response followed by a brisk and variable B cell response. Development of these responses is preceded, as demonstrated in three independent vaccination trials and in a novel in vitro system of primary immune responses (Modular IMmune In vitro Construct (MIMIC) system), by the coordinated up-regulation of transcripts for specific transcription factors including STAT1, IRF7 and ETS2 that are upstream of the different effector arms of the immune response. These results clearly show that the immune response to a strong vaccine is preceded by coordinated induction of masters transcription factors, that lead to the development of a broad, polyfunctional and persistent immune response that integrates all effector cells of the immune system.
This study has 3 branches, two of which are in vivo vaccination studies in two different Locations (Montreal,Canada and Lausanne, Switzerland). The third branch is an in vitro system mimicing (VaxDesign Mimic experiment) the environment in a lymph node. The Montreal Cohort enrolled 15 donors, and sampled whole blood pre vaccination with the Sanofi-Pasteur YF17D-204 YF-VAX vaccine, and on days 3,7,10,14,28,60,365 post vaccination. In the Lausanne Cohort 11 donors were enrolled vaccinated with Stamail, wohle blood was sampled on days 0,3 and 7. The VaxDesign experiment used purified CD4+ T-cells and autologus DC from 3 different donors, YF17D stimulated and unstimulated control samples were analyzed on day 0,3 and 7 after the start of co culturing of T-Cells and DC.