Over-induction of innate immune responses suppresses T cell response to mRNA SARS-CoV-2 vaccination

SARS-CoV-2 mRNA vaccines elicit robust T cell responses in children, resulting in substantial protection against hospitalisation and severe disease. However, the underlying molecular mechanisms that drive this robust cellular immunogenicity of mRNA vaccines in children remains unknown. Here, 37 immunological naïve children underwent primary vaccination (age 6-10) with the SARS-CoV-2 mRNA vaccine and did not acquire natural infection before month 3; bulk RNA sequencing was performed at pre-vaccination baseline and day 1 post vaccination, and Spike-reactive T cell responses were measured at 3 months. Using previously established threshold of T cell responses for clinical protection against symptomatic SARS-CoV-2, we divided our cohort into high responders (n = 21) and low responders (n = 15). Analyses of day 1 post-vaccination gene expression signatures revealed greater induction of innate immune responses, including heightened expression of transcription factors such as STAT1, ATF3 and IRF7 was observed in low responders compared to high responders. On the other hand, LEP, PLCE1 and PLPP2 expression was significantly downregulated in low responders, with strong predictive value for T cell responses at 3 months post-vaccination (AUROC 0.89, 95% CI 0.78-1.00). Taken together, these findings suggest that future mRNA vaccine design and vaccination regimens should aim to modulate excessive innate immune responses to improve T cell responses to mRNA vaccines.