Reading of Human Acute Immune Dynamics in Omicron SARS-CoV-2 Breakthrough Infection

The dynamics of the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infections remain unclear, particularly when compared to responses in naive individuals. In this longitudinal prospective cohort study, 13 participants were recruited. Peripheral blood samples were collected every other day until day 7 after symptom onset. Transcriptome sequencing, single-cell sequencing, T-cell receptor (TCR) sequencing, B-cell receptor (BCR) sequencing, Olink proteomics, and antigen-antibody binding experiments were then performed. During the incubation periods of breakthrough infections, peripheral blood exhibited type 2 cytokine response, which shifted to type 1 cytokine response upon symptom onset. Plasma cytokine levels of C-X-C motif chemokine ligand 10, monocyte chemoattractant protein-1, interferon-γ, and interleukin-6 show larger changes in breakthrough infections than naïve infections. The inflammatory response in breakthrough infections rapidly subsided, returning to homeostasis by day 5 after symptom onset. Notably, the levels of monocyte-derived S100A8/A9, previously considered a marker of severe disease, physiologically significantly increased in the early stages of mild cases and persisted until day 7, suggesting a specific biological function. Longitudinal tracking also revealed that antibodies anti-Receptor Binding Domain (anti-RBD) in breakthrough infections significantly increased by day 7 after symptom onset, whereas cytotoxic T lymphocytes appeared by day 5. This study presents a reference for interpreting the immunological response to breakthrough infectious disease in humans.