Exposure route drives SARS-CoV-2 infection patterns in non-human primates

Public health policy and clinical interventions against infectious diseases rely on understanding the factors that govern the initiation and progression of infections inside hosts. Animal infection experiments are essential tools to study these complex, multi-scale processes under controlled conditions, and they have shown that the dose and route of exposure can influence within-host disease dynamics. However, observed differences are difficult to quantify and to disentangle from confounding factors because small sample sizes limit the statistical power and scientific scope of individual studies. Here, by compiling and analyzing the largest published database of non-human primate challenge experiments (107 studies; 721 animals; 22,183 observations), we quantify how exposure conditions and demographic factors shape within-host SARS-CoV-2 infection kinetics in the respiratory and gastrointestinal tracts. We show that exposure route has stronger effects on kinetics than dose, age, sex, or species, with directly exposed tissues exhibiting distinct spatiotemporal kinetics from non-exposed tissues. We estimate 50% infectious doses for different tissues and show that they vary greatly (from <10 ^1.2 up to >10 ^7.4 pfu) depending on the exposure route. We find that dose effects on kinetics are also route-and tissue-specific, primarily influencing nasally-inoculated animals. Our results suggest that exposure route drives infection kinetics more strongly than dose in a critical model system for translational medicine, and they demonstrate the untapped potential for meta-analysis to extract additional insights from costly animal experiments.