Immuno-functionomics reveals geographical variation and a role for TLR8 in mRNA vaccine responses

The innate immune system plays a pivotal role in pathogen defense via pattern recognition receptor sensing, initiating responses upon infection or vaccination. Understanding its functional capacity is crucial for deciphering correlates of vaccine efficacy and understanding responses to infection. In this study, we developed a holistic approach to study immune function, generating >3100 readouts across 16 cell types, 18 pattern recognition receptors and 11 produced cytokines using spectral flow cytometry. To explore geographical variation, we studied the immune system of Europeans, urban, and rural Indonesians. We found differences in immune responses, such as increased IL1β production in rural Indonesians and impaired IFNγ production by innate lymphocytes after TLR8 stimulation. In Europeans vaccinated with mRNA-1273, baseline IFNy production by innate lymphocytes correlated with SARS-CoV-2 Spike-specific immune responses. In vitro mRNA vaccine stimulation also induced IFNy production, which was TLR8-dependent and reduced in rural Indonesians. This study highlights functional immune diversity and the potential role for TLR8 in mRNA vaccine responses.