Green and blue coronavirus cells under magnification intertwined with DNA cell structure
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T cell populations can change significantly after each COVID mRNA vaccine or booster, a new study from Japan demonstrates. The study, which included about 40 patients and used TCR sequencing, shows certain spike epitopes can become immunodominant. In addition, the team found intra-epitope shifts of vaccine-responding immune cell clonotypes.

The authors say this work provides insights that could be crucial for developing next-generation vaccines for more effective and broad protection against viruses.

The group’s report appeared in Cell Reports on March 7. Hiroyasu Aoki from the University of Tokyo is the lead author.

The COVID mRNA vaccines elicit  both cellular and humoral immune responses against the spike protein of the SARS-CoV-2 virus that causes the disease. They contain hundreds of epitopes recognized by CD4+ or CD8+ T cells, and the strength and the kinetics of the T cell response differ between epitopes.  A single spike epitope is recognized by multiple T-cell clones. 

“Our analysis suggests T cells can “re-write” themselves and reshape their memory populations after successive vaccinations. This re-writability not only maintains the number of memory T cells but also maintains diversity that can respond to different variants of pathogens,” said senior author Satoshi Ueha, from the Tokyo University of Science.

“By tuning the replacement of memory cells, more effective vaccines can be developed that can also be tailored to an individual’s unique immune response,” he added.

Studies show that the number of spike-reactive T cells increases in the peripheral blood after the first vaccine and is further boosted after the second shot. Also, the third mRNA vaccination rapidly re-expands spike-reactive T cells that have waned after the second shot.

This team aimed to develop a kinetic profile of spike-reactive T-cell clones during repetitive mRNA vaccination. They performed a longitudinal TCR sequencing on peripheral T cells of 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 clonotypes.

Their findings revealed that while the primary T-cell response of naïve T cells generally peaked 10-18 days after the first shot, expansion of “early responders” was detected on day seven after the first shot, suggesting that these early responders contain memory T cells against common cold coronaviruses. They also found a “main responder” that expanded after the second shot and did not expand early after the first shot and a “third responder” that appeared and expanded only after the third shot. 

By longitudinally tracking the total frequency of each response pattern, it was observed that, after the second shot, a shift among the clonotypes occurred, wherein the major population changed from early responders to main responders, suggestive of a shift in clonal dominance. A similar shift of responding clones was also observed in CD4+ T cells.

Expanding upon the research process, said Ueha, “We next analyzed the phenotype of main responders after the second and the third vaccination. The results showed that the main responders after the second and third shots mostly consist of effector-memory T cells (TEM), with more terminally differentiated effector memory-like phenotype after the third shot.”

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