Detailed delineation of the immune response to COVID-19 mRNA vaccination via high-temporal frequency blood transcriptomics [third]

mRNA vaccines have played a crucial role in combating the COVID-19 pandemic, but the long-term dynamics of immune responses to repeated vaccination remain poorly understood. In this study, we extend our previous work on first and second dose responses by characterizing the immune signatures elicited by a third dose of COVID-19 mRNA vaccines. Using high-resolution temporal profiling of blood transcriptomes, we analyzed samples collected daily for 9 days post-vaccination across all three doses. We observed distinct patterns of gene expression related to interferon responses, inflammation, erythroid cell signatures, and plasmablast activity. While the first dose elicited a modest response primarily characterized by interferon signaling, the second dose induced a robust, polyfunctional response. Surprisingly, the third dose, administered months later, showed a response pattern that shared similarities with both previous doses but also exhibited unique features. The interferon response following the third dose mirrored the timing of the first dose, peaking on day 2, but matched the amplitude of the second dose. Notably, we observed a progressive amplification of the plasmablast response across the three doses, with an earlier peak (day 4) compared to other vaccines, potentially a unique feature of mRNA vaccines. These findings provide crucial insights into how the immune system adapts to repeated mRNA vaccination over extended periods. They demonstrate that the heightened responsiveness induced by initial doses is maintained months later, suggesting effective immune memory. Our results contribute to a more comprehensive understanding of mRNA vaccine-induced immunity, with implications for optimizing booster strategies and developing next-generation vaccines.