People living with obesity have multiple impairments in the host immune response, which is associated with a higher risk for severe infectious diseases and reduced efficacy of vaccines. To date, it remains unclear to what degree variation in diet directly affects the host defence in people with obesity and whether specific dietary interventions may improve immune responses and vaccine efficacy. In TransInf, we will deepen and apply our recent findings in the diet-microbiome-immune axis in healthy, non-obese individuals living in a rapidly urbanizing environment in Tanzania. Transitioning populations in sub-Saharan Africa offer unique opportunities to study the immuno-modulatory effects of diets at the extreme ends of the spectrum ('traditional' versus 'Western') and of specific food components that have largely been eliminated from diets in the industrialized world. In TransInf we will enrol a new cohort of people living with overweight/obesity and non-obese controls in Tanzania (WP1). In-depth immune profiling and omics measurements will address how diet and obesity influence immune responses to SARS-Cov-2, influenza and other pathogens. Next, a randomized, open-label, proof-of-principle dietary intervention study is performed to investigate the effects of a traditional plant-based fibre and polyphenol-rich diet and a fermented banana beverage on obesity-related immune dysregulation and the immune response to pathogens and vaccines (WP1). We will obtain mechanistic insights how diet influences the immune system and vaccinations responses by assessing (i) epigenetic modifications in immune cells and long non-coding RNAs (WP1), (ii) intestinal B-cell homeostasis and immunoglobulin responses to the microbiome and the mycobiome (WP2), (iii) telomere length of immune cells (WP3) and (iv) whole blood transcriptome (WP4). Data generated in the new cohorts will be integrated and compared with data available from existing cohorts of the Human Functional Genomics Projects (including an obesity cohort form the Netherlands). Multi-omics analysis and data integration will be performed and a 'metabolic-related chronic inflammatory burden model' will be constructed to predict immune responses to microbes and pathogens (WP4). As such, TransInf will establish the cause-and-effect relationship between diet and immune function in people with obesity and contribute to the identification of specific foods and food-derived metabolites with beneficial immuno-modulatory effects.