Cabrera-Serrano Antonio José, Ruiz-Durán Lucía, Gutiérrez-Bautista Juan Francisco, Carretero-Fernández María, Ter Horst Rob, Li Yang, Reyes-Zurita Fernando Jesús, García-Verdejo Francisco José, Netea Mihai G, Sánchez-Rovira Pedro, López-Nevot Miguel Ángel, Sampedro Antonio, Sainz Juan
Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, Parque Tecnológico de Ciencias de la Salud (PTS), Granada, Spain.
Instituto de Investigación Biosanitaria IBs.Granada, Granada, Spain.
Front Immunol. 2025 Aug 18;16:1639825. doi: 10.3389/fimmu.2025.1639825. eCollection 2025.
The COVID-19 pandemic had significant global public health consequences, affecting over 200 countries and regions by 2020. The development and efficacy of specific vaccines, such as the mRNA-1273 (Spikevax) vaccine developed by Moderna Inc., have substantially reduced the impact of the pandemic and mitigated its consequences. This study aims to identify novel genetic loci associated with the effectiveness of the mRNA-1273 vaccine, as measured by elevated anti-Spike (anti-S) IgG levels at multiple time points post-vaccination.
We conducted three genome-wide association studies (GWAS) in a cohort of Spanish healthcare workers, analyzing anti-S IgG levels at one-month post-vaccination (n=567), at three months post-vaccination (n=447), and the difference in circulating anti-S IgG levels between these two time points (n=447).
We identified fourteen novel loci associated with increasing concentrations of anti-S IgG post-vaccination (=5.01×10 and =2.81×10). Functional results showed that some of the novel risk alleles influence the absolute counts of specific B cell subsets (=2.57×10-8.82×10), which are involved in immune signaling pathways and metabolic processes. Furthermore, these variants co-localize with multiple QTLs and epigenetic marks, suggesting that the GWAS hits may affect regulatory activity in promoters, enhancers, and transcriptional regions, thereby modulating gene expression relevant to the humoral immune response.
In conclusion, this study highlights the complex interplay of genetic factors influencing the immune response to vaccination, particularly through modulation of B cell activity, immune signaling pathways, and metabolic processes. The identification of genetic variants could inform future strategies to enhance vaccine efficacy and provide a deeper understanding of individual variability in vaccine responses, especially for COVID-19 and other viral infections.
新冠疫情产生了重大的全球公共卫生影响，截至2020年已波及200多个国家和地区。特定疫苗的研发及有效性，如Moderna公司研发的mRNA-1273（Spikevax）疫苗，已大幅降低了疫情的影响并减轻了其后果。本研究旨在确定与mRNA-1273疫苗有效性相关的新基因位点，有效性通过接种疫苗后多个时间点抗刺突蛋白（anti-S）IgG水平升高来衡量。
我们对一组西班牙医护人员进行了三项全基因组关联研究（GWAS），分析接种疫苗后1个月（n = 567）、接种疫苗后3个月（n = 447）的抗S IgG水平，以及这两个时间点循环抗S IgG水平的差异（n = 447）。
我们确定了14个与接种疫苗后抗S IgG浓度增加相关的新基因位点（P = 5.01×10⁻⁸和P = 2.81×10⁻⁸）。功能研究结果表明，一些新的风险等位基因影响特定B细胞亚群的绝对计数（P = 2.57×10⁻⁸ - 8.82×10⁻⁸），这些B细胞亚群参与免疫信号通路和代谢过程。此外，这些变异与多个数量性状位点（QTL）和表观遗传标记共定位，表明GWAS检测到的位点可能影响启动子、增强子和转录区域的调控活性，从而调节与体液免疫反应相关的基因表达。
总之，本研究突出了影响疫苗免疫反应的遗传因素之间复杂的相互作用，特别是通过调节B细胞活性、免疫信号通路和代谢过程。基因变异的鉴定可为未来提高疫苗效力的策略提供信息，并更深入地了解疫苗反应中的个体差异，尤其是针对新冠病毒及其他病毒感染。
