| Much of the successful early vaccines were developed based on a process of trial and error where the infectious microorganism was manipulated through attenuation, inactivation, or insertion of antigens in viral vectors. In that earlier era the details of why these vaccines worked was not important; what was important was that the vaccines protected an individual from disease without inducing disease themselves. However modern attempts to use the growing number of adjuvants to rationally design synthetic vaccines have met with little success partly because of inattention to what makes our historical vaccines effective. By returning to study one of the early effective attenuated viral vaccines, we hope to reveal insights that will aid in the targeted development of highly effective synthetic vaccines, and, in the process, develop systems biology research approaches that can be used for deeper understanding of the mechanisms of effective vaccines and improve development of future vaccine candidates.; The live attenuated yellow fever vaccine 17D (YF-17D) is one of these early empirically derived highly effective vaccines. Here we present data that suggests that YF-17D stimulates multiple pathogen recognition methods on distinct subsets of antigen presenting cells (APCs) to elicit a broad spectrum of innate and adaptive immune responses. Specifically, YF-17D activates APCs via toll-like receptors (TLRs) 2, 7, 8 and 9, to elicit potent pro-inflammatory cytokines, as well as IFNalpha. Furthermore, distinct TLRs appear to differentially control the Th1/Th2 balance. Our systems biology human study revealed the induction of a strong anti-viral gene network. Activation of the complement cascade suggests that the complement pathways may be important targets of this effective vaccine. Computational modeling identified gene signatures, which correlated with the magnitude of the antigen-specific CD8+ T-cell response, and which were capable of predicting the magnitude of the CD8+ T-cell responses in an independent, blinded trial with 90% accuracy. This study enhances our understanding of the molecular mechanism of action of YF-17D, highlights the potential of vaccination strategies that use combinations of adjuvants to stimulate polyvalent immune responses and demonstrates that systems biology is an effective tool for developmental insights to vaccines. |
