The emergency use authorization of two mRNA vaccines in less than a year from the emergence of SARS-CoV-2 represents a landmark in vaccinology^1,2. Yet, how mRNA vaccines stimulate the immune system to elicit protective immune responses is unknown. Here we used a systems vaccinology approach to comprehensively profile the innate and adaptive immune responses of 56 healthy volunteers who were vaccinated with the Pfizer–BioNTech mRNA vaccine (BNT162b2). Vaccination resulted in the robust production of neutralizing antibodies against the wild-type SARS-CoV-2 (derived from 2019-nCOV/USA_WA1/2020) and, to a lesser extent, the B.1.351 strain, as well as significant increases in antigen-specific polyfunctional CD4 and CD8 T cells after the second dose. Booster vaccination stimulated a notably enhanced innate immune response as compared to primary vaccination, evidenced by (1) a greater frequency of CD14⁺CD16⁺ inflammatory monocytes; (2) a higher concentration of plasma IFNγ; and (3) a transcriptional signature of innate antiviral immunity. Consistent with these observations, our single-cell transcriptomics analysis demonstrated an approximately 100-fold increase in the frequency of a myeloid cell cluster enriched in interferon-response transcription factors and reduced in AP-1 transcription factors, after secondary immunization. Finally, we identified distinct innate pathways associated with CD8 T cell and neutralizing antibody responses, and show that a monocyte-related signature correlates with the neutralizing antibody response against the B.1.351 variant. Collectively, these data provide insights into the immune responses induced by mRNA vaccination and demonstrate its capacity to prime the innate immune system to mount a more potent response after booster immunization.

SARS-CoV-2 出现后不到一年的时间里，两种 mRNA 疫苗获得紧急使用授权，这是疫苗学领域的一个里程碑^1,2。然而，mRNA 疫苗如何刺激免疫系统引发保护性免疫反应尚不清楚。在这里，我们使用系统疫苗学方法来全面分析 56 名接种辉瑞 BioNTech mRNA 疫苗 (BNT162b2) 的健康志愿者的先天性和适应性免疫反应。疫苗接种导致针对野生型 SARS-CoV-2（源自 2019-nCOV/USA_WA1/2020）和 B.1.351 毒株的中和抗体的大量产生，以及抗原的显着增加-第二次给药后的特异性多功能CD4和CD8 T细胞。与初次疫苗接种相比，加强疫苗接种刺激了显着增强的先天免疫反应，这通过以下证据证明：(1) CD14 ⁺ CD16 ⁺炎性单核细胞的频率更高；(2)血浆IFNγ浓度较高；(3)先天抗病毒免疫的转录特征。与这些观察结果一致，我们的单细胞转录组学分析表明，二次免疫后，富含干扰素反应转录因子且减少 AP-1 转录因子的骨髓细胞簇的频率增加了约 100 倍。最后，我们确定了与 CD8 T 细胞和中和抗体反应相关的独特先天途径，并表明单核细胞相关特征与针对 B.1.351 变体的中和抗体反应相关。总的来说，这些数据提供了对 mRNA 疫苗接种诱导的免疫反应的深入了解，并证明了其启动先天免疫系统以在加强免疫后产生更有效反应的能力。