Influence of obesity on susceptibility to systemic symptoms and host responses to orthoflaviviral infection: a prospective observational study using yellow fever vaccine to simulate acute infection

BACKGROUND: Orthoflaviviruses, as exemplified by the prototypic yellow fever virus (YFV), have been recently identified by the World Health Organisation as major pandemic threats. Although factors such as globalisation and climate change have been identified to increase the prevalence of orthoflaviviral diseases, the ongoing obesity pandemic is a neglected but important contributory factor to exacerbating the risk of severe orthoflaviviral diseases. Indeed, how obesity affects the outcome of orthoflaviviral infection remains undefined. METHODS: ) to receive YF17D subcutaneously. We subsequently assessed and compared the clinical and molecular outcomes of vaccination between the two groups. FINDINGS: We found increased prevalence of systemic symptoms; myalgia and axillary soreness from lymphadenopathy were more common in participants with obesity compared to those without despite comparable YF17D RNAaemia levels. Moreover, transcriptomic and cytokine profiling revealed BMI-dependent differences in pro-inflammatory states at both pre- and post-infection. INTERPRETATION: Our findings indicate obesity as a susceptibility factor of symptomatic orthoflaviviral infection and suggest anti-inflammatory approaches to mitigate risks of severe orthoflaviviral diseases. FUNDING: National Medical Research Council of Singapore.