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Over-induction of innate immune responses suppresses T cell response to mRNA SARS-CoV-2 vaccination
Carina J X Tay1, Clara W T Koh2, Justin S G Ooi2
1Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Insights
SARS-CoV-2 mRNA vaccines protect children, but molecular mechanisms are unclear. Modulating innate immune responses may enhance T cell immunity for better vaccine efficacy.
Area of Science:
- Immunology
- Vaccinology
- Molecular Biology
Background:
- SARS-CoV-2 mRNA vaccines induce strong T cell responses in children, offering protection against severe disease.
- The molecular mechanisms behind this robust cellular immunogenicity in pediatric populations remain largely unknown.
Purpose of the Study:
- To investigate the molecular mechanisms underlying T cell responses to SARS-CoV-2 mRNA vaccination in children.
- To identify potential biomarkers and therapeutic targets for improving mRNA vaccine efficacy in pediatric populations.
Main Methods:
- Bulk RNA sequencing was performed on immunological naïve children (age 6-10) at baseline and 1 day post-vaccination.
- Spike-reactive T cell responses were measured at 3 months post-vaccination.
- Children were categorized into high and low responders based on established T cell response thresholds.
Main Results:
- Low responders exhibited greater induction of innate immune responses, including heightened expression of STAT1, ATF3, and IRF7, compared to high responders.
- LEP, PLCE1, and PLPP2 gene expression was significantly downregulated in low responders.
- Gene expression signatures at day 1 post-vaccination showed strong predictive value for T cell responses at 3 months (AUROC 0.89).
Conclusions:
- Excessive innate immune responses may impair T cell responses to mRNA vaccines in some children.
- Modulating innate immunity could be a strategy to enhance T cell responses and improve mRNA vaccine efficacy.
- Findings suggest future mRNA vaccine design and vaccination regimens should aim to optimize the balance between innate and adaptive immunity.
Abstract:
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.
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