Synthetic mRNA Vaccines and Transcriptomic Dysregulation: Evidence from New-Onset Adverse Events and Cancers Post-Vaccination

Background/Objectives: Synthetic mRNA vaccines have raised concerns regarding prolonged spike protein expression, immune activation, and potential off-target effects. This study investigates transcriptomic alterations in individuals with new-onset adverse events or cancer following mRNA COVID-19 vaccination. Methods: Bulk RNA sequencing was performed on peripheral blood from two patient groups: individuals with new-onset nonmalignant adverse events and individuals newly diagnosed with cancer post-vaccination. A control group of healthy individuals was used for comparison. Differential gene expression was analyzed using DESeq2, and Gene Set Enrichment Analysis (GSEA) was conducted using the MSigDB database and custom gene sets. Results: Both vaccine patient groups displayed widespread transcriptional dysregulation. In the nonmalignant adverse event group, hallmark enrichments included mitochondrial dysfunction, proteasome-mediated stress, transcriptomic instability, and systemic inflammation. The cancer group exhibited additional hallmarks of genomic instability, and epigenetic reprogramming. Nonsense-mediated decay (NMD), ribosomal stress, and MYC activation were prominent in both groups, while immune signaling via TLRs and type I interferons was particularly elevated in cancer patients. Overall design: We enrolled adult participants (ages 18–70) who developed either new-onset symptoms following administration of mRNA-based COVID-19 vaccines (BNT162b2 [Pfizer] or mRNA-1273 [Moderna]). Total RNA was extracted using the Quick-DNA/RNA Viral Kit (Zymo Research), following the manufacturer's protocol for whole blood RNA extraction. RNA libraries were prepared using the Illumina TruSeq Stranded Total RNA Kit, incorporating ribosomal RNA depletion and strand-specific cDNA synthesis. RNA-seg profiling of whole blood cells were conducted.