MI2025 – Youjia Zhong

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

Abstract:
Vaccines have greatly reduced the burden of childhood infections; however, developing better vaccines for childhood infections remains a major challenge because of incomplete knowledge about the mechanisms underlying protective immunity. While systems vaccinology methods have been used to identify early molecular determinants of antibody responses to vaccinations against a variety of infections, the innate determinants of T cell responses are poorly understood. However, we have recently identified T cell responses to be the most important correlate of protection against symptomatic SARS-CoV-2 infection in vaccinated children1. We were thus interested in the post-vaccination molecular determinants of protective T cell immunity in children.

In this study, using 37 children aged 5 to 12 years with no clinical or immunologic evidence of SARS-CoV-2 infection up to 3 months post-vaccination, we performed bulk RNA sequencing on whole blood pre- and day 1 post-vaccination, in order to identify early host responses to mRNA vaccination. Children were split into low (n = 16) and high (n = 21) responders based on month 3 Spike (S)-reactive T cell responses.

Differentially expressed genes (DEGs) were identified by comparing the fold changes in gene expression with vaccination between the two groups, and confirmed by unsupervised hierarchical clustering. DEGs with greatest predictive capabilities for T cell response were identified, and pathway enrichment analysis was performed for co- expressed genes in order to identify biological processes in the early post-vaccination host response which determine cellular immune response.

LEP, PLCE1 and PLPP2 were significantly downregulated in low responders; combining these three biomarkers had a strong predictive capacity for month 3 T cell responses with area under receiver operating curve (AUROC) of 0.890 (95% CI 0.783, 0.996). Pathway enrichment analysis of co-expressed pathways identified negatively enriched innate immune response pathways, such as interferon, antiviral, myeloid cell and inflammation signatures. Critically, the expression of transcription factors ATF3, STAT1 and IRF7 was negatively correlated with LEP, PLCE1 and PLPP2. Taken together, our results suggest that a reduced innate immune response promotes S- reactive T cell responses after mRNA SARS-CoV-2 vaccination.

While the innate immune response is important for the initiation of adaptive immune responses post vaccination, over-induction of innate immune responses may be counterproductive for optimal cellular immunity.

Biography:
Youjia is an Assistant Professor in the National University Hospital Department of Paediatrics, and runs a research programme in Paediatric Translational Vaccinology. She is also an Associate Consultant in the Division of Allergy, Immunology and Rheumatology in Paediatrics, National University Hospital, with a special clinical interest in inborn errors of immunity. She is the Principal Investigator of the MARkers of Vaccine Efficacy and Longevity in SARS-CoV-2 (MARVELS) cohort study, which investigates correlates of protection and innate determinants of adaptive immune responses in healthy and immunocompromised children undergoing SARS-CoV-2 mRNA vaccination.