Study finds that mRNA vaccines train T cells in waves

mRNA vaccine developed against spike glycoprotein Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has shown remarkable effectiveness in the fight against coronavirus 19 (COVID-19). These vaccines work by eliciting both cellular and humoral immune responses against the virus's spike protein. Cell-mediated immunity plays a more protective role than humoral immunity against variants of concern (VOC) against SARS-CoV-2, as it targets conserved regions of the spike protein and can cross-react with other variants. There is a possibility that it will be fulfilled.

Because a single spike epitope is recognized by multiple T cell clones, the T cell response induced by mRNA vaccination may be composed of multiple spike-reactive clones. Therefore, it is important to understand the mechanisms of cellular immune responses induced by mRNA vaccination. However, no analysis of T cell responses to mRNA vaccination has yet been performed to address this clonal resolution.

To fill this gap, a team of researchers led by Associate Professor Satoshi Ueba includes Professor Koji Matsushima from Tokyo University of Science (TUS) in Japan, Hiroyasu Aoki from the University of Tokyo, and Professor Toshihiro Ito from Nara Medical University. It is. The university aimed to develop the kinetic profile of spike-reactive T cell clones during repeated mRNA vaccinations. For this, they performed longitudinal TCR sequencing on peripheral tissues. T cells We analyzed single-cell gene expression and clonotype epitope specificity in 38 participants who received the Pfizer vaccine from pre-vaccination to after the third vaccination.

Their findings were; cell report On March 7, 2024, we demonstrated that while primary T cell responses of naïve T cells generally peak 10-18 days after initial vaccination, an expansion of “early responders” was detected as early as 7 days after initial vaccination. I made it clear.Responders include memory T cells against colds coronavirus. They also found a “main responder” that expanded after the second shot but did not initially expand after the first shot, and a “third responder” that appeared and expanded only after the third shot.

By tracking the total frequency of each response pattern longitudinally, we observed that changes occurred between clonotypes after the second vaccination, with the main population changing from early responders to main responders, indicating clonal dominance. suggests a change in Similar changes in responding clones were also observed for CD4.⁺ T cells.

We then analyzed the phenotypes of the main responders after the second and third vaccinations. As a result, the main responders after the second and third shots are mostly effector memory T cells (T_E.M.),moreover Terminal differentiated effector memory-like phenotype after third shot. ”

Satoshi Ueha Tokyo University of Science Associate Professor

The researchers then looked at changes in the repertoire of main responders and found that the expansion of main responders that occurred after the second vaccination decreased after the third vaccination, reduced clonal diversity, and partially It became clear that they were replaced by tertiary reactors. This could potentially mean that clones that responded better at the third vaccination were selected.

This study supports the epitope-to-epitope shift model, as vaccination changes the immunodominance of the spike epitope. Additionally, we observed an intraepitopic shift of vaccine-responsive clonotypes within the spike epitope.

Professor Ueha explains the significance of these results as follows.Our analysis suggests that T cells can “rewrite” themselves and re-form memory populations after successive vaccinations. This rewriteability not only maintains the number of memory T cells, but also maintains their diversity to respond to different variants of pathogens. Furthermore, by tailoring the replacement of memory cells, more effective vaccines can be developed that can also be tailored to an individual's unique immune response.. ”

Overall, this study provides important insights into T cell responses induced by mRNA vaccines. This is important for developing next-generation vaccines for more effective and widespread protection against the virus.