mRNA vaccines developed against the spike glycoprotein of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) showed remarkable efficacy in fighting coronavirus 19 (COVID-19). These vaccines work by triggering both cellular and humoral immune responses against the virus’s spike protein. Cellular immunity may play a more protective role than humoral immunity to variants of concern (VOCs) against SARS-CoV-2, as it targets conserved regions of the spike protein and possibly cross-reacts with other variants.
Since multiple T cell clones recognize a single spike epitope, the T cell response induced by mRNA vaccination may consist of multiple spike-reactive clones. Therefore, it is important to understand the mechanism of the cellular immune response induced by mRNA vaccination. However, a clonally resolved analysis of T cell responses to mRNA vaccination has not yet been performed to address this analysis.
To close this gap, a team of researchers, led by Associate Professor Satoshi Ueha, including Professor Kouji Matsushima from the Tokyo University of Sciences (TUS), Japan, Mr Hiroyasu Aoki from the University of Tokyo and Professor Toshihiro Ito of Nara Medical University, aimed to develop a kinetic profile of spike-reactive T cell clones during repetitive mRNA vaccination. To do this, they performed longitudinal TCR sequencing on peripheral T cells from 38 participants who had received the Pfizer vaccine from before the vaccine to after the third vaccination and then analyzed the single-cell gene expression and epitope specificity of the clones.
Their findings, published in Cellular reports on March 7, 2024, revealed that while the primary response of naïve T cells generally peaked between 10 and 18 days after the first injection, the expansion of “early responders” was detected on day 7 after of the first injection, suggesting that these early responders contain memory T cells against common cold coronaviruses. They also found a “primary responder” that expanded after the second shot and did not expand shortly after the first shot and a “third responder” that appeared and expanded only after the third shot.
By longitudinally tracing the total frequency of each response pattern, it was observed that, after the second shot, a shift occurred between clones, in which the main population changed from early responders to main responders, suggesting a change in the clonal dominance. A similar change of responding clones was also observed in CD4+ T cells.
Expanding on the research process, Professor Ueha says: “We next analyzed the phenotype of the main responders after the second and third vaccination. The results showed that the main responders after the second and third injection mainly consist of effector memory T cells (TEM), with more Terminally differentiated effector memory-like phenotype after the third shot.“.
The researchers then examined the repertoire changes of the top responders, revealing that the expansion of top responders, which occurred after the second shot, decreased after the third shot, and clonal diversity decreased and was partially replaced by third responders. . Potentially, this may mean that the third vaccination selected clones that responded better.
Due to the vaccination-induced change in the immunodominance of spike epitopes, the study supports the epitope-switching model. Additionally, there were intraepitope changes of vaccine-responsive clonotypes within the spike epitopes.
Professor Ueha explains the importance of these results: “Our analysis suggests that T cells can “rewrite” themselves and remodel their memory populations after successive vaccinations. This rewritability not only maintains the number of memory T cells but also maintains the diversity that can respond to different pathogen variants. Additionally, by fine-tuning the replacement of memory cells, more effective vaccines can be developed that can also be tailored to each individual’s unique immune response.“.
Overall, this study provides important information on the T cell responses induced by the mRNA vaccine, which will be crucial for developing next-generation vaccines for more effective and broad protection against viruses.