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. Here, we developed a holistic approach to study immune function, generating >3,100 readouts across 16 cell types, 18 pattern recognition receptors, and 11 produced cytokines using spectral flow cytometry. To explore geographical variation, we compared Europeans and urban and rural Indonesians. We observed different immune responses, such as increased interleukin (IL)-1β production in rural Indonesians and impaired interferon (IFN) γ production by innate lymphocytes after Toll-like receptor (TLR) 8 stimulation. In Europeans vaccinated with mRNA-1273, baseline IFNγ production by innate lymphocytes correlated with SARS-CoV-2 spike-specific immune responses. <i>In vitro</i> mRNA vaccine stimulation also induced IFNγ production, which was TLR8 dependent and reduced in rural Indonesians. This study highlights functional immune diversity and TLR8's potential role in mRNA vaccine responses.