A prevaccination validated network that drives the breadth of the protective neutralizing antibody response following Dengue Vaccine TV003 immunization

Abstract

Development of fully protective dengue virus (DV) vaccines has been problematic as infection with DV requires a broad antibody immune response that targets all 4 possible serotypes. Herein, we used an integrated systems vaccinology approach to identify prevaccination features that allow the development of fully protective DV-specific antibody responses. This approach allowed us to identify a transcription network in a subset of monocytes defined by the expression of CD68 and downstream of specific pro- and anti-inflammatory cytokines. Moreover, we identified metabolites as drivers of an immune response that induced neutralizing antibodies to the 4 DV serotypes. Specifically, PC/PE drove the production of TGF-B in CD68 low monocytes, which was a positive correlate of the protective antibody response. In contrast, primary and secondary bile acids triggered a proinflammatory response downstream of TGR5 signaling and inflammasome activation in CD68 high monocytes, which was associated to a non-protective antibody response. These features were validated in vitro in primary myeloid cells. Our results highlight the role of cell and systemic metabolism as regulators of protective immune responses to vaccination, and that systems vaccinology is a key tool to identify such mechanisms.

Pan-vaccine analysis reveals innate immune endotypes predictive of antibody responses to vaccination

“…Indeed, both interferons, TNF and the inflammasome are potent inducers of adaptive immune responses and are triggered by alum and MF59, two adjuvants that are widely used in vaccines. Of note, presence of the interferon signature before vaccination was negatively associated with the antibody responses in live viral vaccines in some populations (yellow fever, smallpox and dengue vaccine 32 ). This inhibitory effect of interferons is most likely due to their antiviral…”

Innate antiviral immunity: how prior exposures can guide future responses

“…By contrast, we recently preliminarily reported (in preprint) that BA-induced IFN exerted a negative impact on the vaccine response to Dengue virus in humans by suppressing the replication of the attenuated virus in the vaccine, and inducing an inflammatory state in monocytes, both of which led to reduced antibody breadth against the four antigen serotypes found in the vaccine [2]. In vitro validation experiments performed on purified human monocytes confirmed induction of type I IFN after stimulation with primary (glycocholic acid) and secondary (lithocholic acid) BAs [2]. However, further testing will be required to follow this line of investigation.…”

“…Multiple reports have shown that the presence of BAs during an immune response can induce IFN expression, which can have disparate outcomes; for instance, induction of IFNs by BAs in mice has been deemed to exert a protective role by limiting Chikungunya viral infection and dissemination, leading to viral clearance [38]. By contrast, we recently preliminarily reported (in preprint) that BA-induced IFN exerted a negative impact on the vaccine response to Dengue virus in humans by suppressing the replication of the attenuated virus in the vaccine, and inducing an inflammatory state in monocytes, both of which led to reduced antibody breadth against the four antigen serotypes found in the vaccine [2]. In vitro validation experiments performed on purified human monocytes confirmed induction of type I IFN after stimulation with primary (glycocholic acid) and secondary (lithocholic acid) BAs [2].…”

“…These cells directly sense and kill microbes, produce cytokines/chemokines which enhance migration/function, and/or process and present antigens to T cells in lymphoid tissues, including lymph nodes [1]. Specific innate immune cells (i.e., monocytes and macrophages), defined by their functional and transcriptomic profiles, can regulate vaccine responsesfor example, by promoting immune protection following simian immunodeficiency virus (SIV) vaccination in monkeysor have a deleterious impact on antibody titers in humans (in response to dengue virus vaccination) [2,3]; however, some of these studies will require further validation. Early pioneering work demonstrated that innate immune cells express germline-encoded patternrecognition receptors (PRRs) (see Glossary) [4,5] which, along with cytokine/chemokine receptors, activate intracellular signaling cascades that modulate the pro-and anti-inflammatory phenotype of innate immune cells.…”

Fighting the SARS-CoV-2 pandemic requires a global approach to understanding the heterogeneity of vaccine responses

“…The composition of mucosal and circulating metabolites is also influenced by nutrition and diet. Notably, this is true for SCFAs/ butyrates 88,89 and bile acids [90][91][92] , which have been shown to impede the response to vaccines 80,93 , presumably by triggering T reg cell differentiation and the production of the anti-inflammatory cytokines IL-10 94-96 and TGF-β [97][98][99] . High glucose levels provide another source of immune modulation.…”