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

The COVID-19 pandemic has prompted vaccine development efforts on an unprecedented scale. Vaccines based on mRNA technology have emerged as particularly attractive due to their high efficacy and short development timelines. However, relatively little is known about the factors contributing to the development of protective immunity by this new class of vaccines. We employed a high-temporal-resolution transcriptome profiling approach to investigate responses to COVID-19 mRNA vaccination. A cohort of 23 subjects was recruited and changes in blood transcript abundance were measured daily for 9 days post-priming and post-booster vaccination via RNA sequencing. Antibody responses were measured on days 7 and 14 post-vaccination using a custom multiplex assay. Marked differences were observed between responses to the priming and booster doses, with the latter inducing widespread changes in blood transcript abundance consistent with those found in patients with acute viral respiratory infections. The delineation of interferon responses at a high-temporal frequency also suggested that the priming and booster doses elicited distinct types of responses that peaked on day 2 post-priming dose and day 1 post-booster dose. The booster dose also induced inflammation on day 1 and erythroid cell signatures as well as an atypical plasmablast signature on day 4. Notably, this plasmablast signature, together with the post-booster interferon response signature, correlated with the antibody response levels induced on day 14 after the booster dose. Taken together, this work provides a detailed map of the antibody and transcriptional responses to the first and second doses of a new class of vaccine and yields important insights into the mechanisms underlying their immunogenicity. Furthermore, our results suggest that implementing high-temporal-frequency immune profiling protocols may provide an opportunity to better resolve the immune responses elicited by the growing number of available COVID-19 vaccines. After puncturing the skin with a finger stick, 50 µl of blood was collected in a capillary/microfuge tube assembly supplied by KABE Labortechnik (Numbrecht, Germany) containing 100 µl of tempus RNA-stabilizing solution aliquoted from a regular-sized tempus tube (designed for the collection of 3 ml of blood and containing 6 ml of solution; ThermoFisher, Waltham, MA, USA). Blood was collected prior to the vaccine being administered (day 0), on the same day, and daily thereafter over the next 10 days. This protocol was followed for both the priming and booster doses.