Ensemble modeling of SARS-CoV-2 immune dynamics in immunologically naïve rhesus macaques predicts that potent, early innate immune responses drive viral elimination.

Introduction: An unprecedented breadth of longitudinal viral and multi-scale immunological data has been gathered during SARS-CoV-2 infection. However, due to the high complexity, non-linearity, multi-dimensionality, mixed anatomic sampling, and possible autocorrelation of available immune data, it is challenging to identify the components of the innate and adaptive immune response that drive viral elimination. Novel mathematical models and analytical approaches are required to synthesize contemporaneously gathered cytokine, transcriptomic, flow cytometry, antibody response, and viral load data into a coherent story of viral control, and ultimately to discriminate drivers of mild versus severe infection. Methods: We investigated a dataset describing innate, SARS-CoV-2 specific T cell, and antibody responses in the lung during early and late stages of infection in immunologically naïve rhesus macaques. We used multi-model inference and ensemble modeling approaches from ecology and weather forecasting to compare and combine various competing models. Results and discussion: Model outputs suggest that the innate immune response plays a crucial role in controlling early infection, while SARS-CoV-2 specific CD4+ T cells correspond to later viral elimination, and anti-spike IgG antibodies do not impact viral dynamics. Among the numerous genes potentially contributing to the innate response, we identified IFI27 as most closely linked to viral load decline. A 90% knockdown of the innate response from our validated model resulted in a ~10-fold increase in peak viral load during infection. Our approach provides a novel methodological framework for future analyses of similar complex, non-linear multi-component immunologic data sets.