The immune mechanisms mediating COVID-19 vaccine attenuation of COVID-19 remain undescribed. We conducted comprehensive analyses detailing immune responses to SARS-CoV-2 virus in blood post-vaccination with ChAdOx1 nCoV-19 or a placebo. Samples from randomised placebo-controlled trials (NCT04324606 and NCT04400838) were taken at baseline, onset of COVID-19-like symptoms, and 7 days later, confirming COVID-19 using nucleic amplification test (NAAT test) via real-time PCR (RT-PCR). Serum cytokines were measured with multiplexed immunoassays. The transcriptome was analysed with long, short and small RNA sequencing. We found attenuation of RNA inflammatory signatures in ChAdOx1 nCoV-19 compared with placebo vaccinees and reduced levels of serum proteins associated with COVID-19 severity. KREMEN1, a putative alternative SARS-CoV-2 receptor, was downregulated in placebo compared with ChAdOx1 nCoV-19 vaccinees. Vaccination ameliorates reductions in cell counts across leukocyte populations and platelets noted at COVID-19 onset, without inducing potentially deleterious Th2-skewed immune responses. Multi-omics integration links a global reduction in miRNA expression at COVID-19 onset to increased pro-inflammatory responses at the mRNA level. This study reveals insights into the role of COVID-19 vaccines in mitigating disease severity by abrogating pro-inflammatory responses associated with severe COVID-19, affirming vaccine-mediated benefit in breakthrough infection, and highlighting the importance of clinically relevant endpoints in vaccine evaluation.

介导 COVID-19 疫苗减毒的免疫机制尚未被描述。我们进行了全面分析，详细分析了 ChAdOx1 nCoV-19 或安慰剂疫苗接种后血液中对 SARS-CoV-2 病毒的免疫反应。随机安慰剂对照试验（NCT04324606 和 NCT04400838）的样本是在基线、出现 COVID-19 样症状时以及 7 天后采集的，通过实时 PCR（RT）使用核酸扩增测试（NAAT 测试）确认了 COVID-19 -PCR）。用多重免疫测定法测量血清细胞因子。通过长、短和小RNA测序对转录组进行分析。我们发现，与安慰剂疫苗接种者相比，ChAdOx1 nCoV-19 中的 RNA 炎症特征减弱，并且与 COVID-19 严重程度相关的血清蛋白水平降低。KREMEN1是一种假定的 SARS-CoV-2 替代受体，与 ChAdOx1 nCoV-19 疫苗接种者相比，安慰剂在安慰剂中表达下调。疫苗接种可改善 COVID-19 发病时白细胞群和血小板的细胞计数减少，而不会诱导潜在有害的 Th2 偏向免疫反应。多组学整合将 COVID-19 发病时 miRNA 表达的整体减少与 mRNA 水平的促炎症反应增加联系起来。这项研究揭示了 COVID-19 疫苗通过消除与严重 COVID-19 相关的促炎症反应来减轻疾病严重程度的作用，肯定了疫苗介导的突破性感染的益处，并强调了疫苗评估中临床相关终点的重要性。