A pre-vaccination immune metabolic interplay determines the protective antibody response to a dengue virus vaccine

Protective immunity to dengue virus (DENV) requires antibody response to all four serotypes. Systems vaccinology identifies a multi-OMICs pre-vaccination signature and mechanisms predictive of broad antibody responses after immunization with a tetravalent live attenuated DENV vaccine candidate (Butantan-DV/ TV003). Anti-inflammatory pathways, including TGF-b signaling expressed by CD68low low monocytes, and the metabolites phosphatidylcholine (PC) and phosphatidylethanolamine (PE) positively correlate with broadly neutralizing antibody responses against DENV. In contrast, expression of pro-inflammatory pathways and cytokines (IFN and IL-1) in CD68hi hi monocytes and primary and secondary bile acids negatively correlates with broad DENV-specific antibody responses. Induction of TGF-b and IFNs is done respectively by PC/ PE and bile acids in CD68low low and CD68hi hi monocytes. The inhibition of viral sensing by PC/PE-induced TGF-b is confirmed in vitro. . Our studies show that the balance between metabolites and the pro- or anti-inflammatory state of innate immune cells drives broad and protective B cell response to a live attenuated dengue vaccine.