RNA-based transcriptome analysis to investigate variability in vaccine response in healthy recipients of a booster (third) dose schedule of the mRNA BNT162b2 vaccine against COVID-19.

This study aims to comprehend the Underlying molecular mechanisms that lead to the host responsiveness variability to COVID-19 vaccines in a cohort sampled from Southeast Brazil (Rio de Janeiro state). The cohort was divided into two groups: (1) low-stable individuals, with antibody concentration anti SARS-CoV IgG S1 below 0.4 percentile at 180 days after boosting vaccination; and (2) high-stable individuals, with antibody values greater than 0.6 percentil of the range in the same period (median 9,525 [185-80,000] AU/mL). Differential gene expression, expressed single nucleotide variants and insertions/deletions, differential splicing events, and allelic imbalance were explored to broaden our understanding of the immune response sustenance. Our analysis revealed a differential expression of genes with immunological functions in individuals with low antibody titers, compared to those with a more robust response to vaccination, underscoring the fundamental importance of the innate immune response for boosting immunity. Our findings also provide new insights into the determinants of the immune response variability to the SARS-CoV-2 mRNA vaccine booster, highlighting the significance of differential splicing regulatory mechanisms, mainly concerning HLA alleles, in delineating vaccine immunogenicity.

本研究旨在解析巴西东南部（里约热内卢州）采集队列中，宿主对COVID-19疫苗应答存在个体差异的潜在分子机制。该队列被划分为两组：(1) 低稳定性个体：加强接种后180天，抗SARS-CoV IgG S1抗体浓度低于0.4百分位；(2) 高稳定性个体：同期抗体值高于该区间的0.6百分位（中位数9525 [185~80000] AU/mL）。本研究通过分析差异基因表达、表达型单核苷酸变异与插入/缺失、差异剪接事件以及等位基因失衡，以深化对免疫应答维持机制的认知。分析结果显示，与疫苗应答更为强劲的个体相比，低抗体滴度个体的免疫功能基因存在差异表达，凸显了固有免疫应答对于强化免疫的核心重要性。本研究成果还为SARS-CoV-2 mRNA疫苗加强针的免疫应答差异决定因素提供了全新视角，强调了差异剪接调控机制（尤其是与HLA等位基因相关的调控机制）在明确疫苗免疫原性中的关键意义。