Dissecting Sex Differences in the Immune Response to Vaccines

疫苗是最具影响力的公共卫生干预措施之一，每年可预防全球数百万例感染和死亡。正如最近由埃博拉病毒、中东呼吸综合征冠状病毒和最近的SARS-CoV-2等新出现的病毒引起的流行病或大流行病爆发所表明的那样，对快速和战略性疫苗开发的需求仍然至关重要。越来越多的数据表明，接种疫苗后免疫反应存在性别差异。男性和女性对疫苗接种的免疫反应不同，女性通常会产生更高的抗体反应，但在接种疫苗后也会比男性发生更多的不良反应。这种影响不仅在青春期后观察到，而且在所有年龄段的儿童中也观察到，这表明不仅仅是激素影响的因素，如染色体因素和表观遗传学可能有助于这种现象。然而，性别之间差异疫苗结果所涉及的确切机制和信号通路仍不完全清楚。我们假设：a）性激素调节关键的先天信号传导途径，导致疫苗反应原性和免疫原性的不同结果，和B）X染色体失活（XCI）逃逸导致的基因剂量效应导致疫苗应答的性别特异性差异。这些假设将使用来自两项独特的1期临床试验的数据和生物材料进行探索，这些试验研究了新型应急疫苗。我们建议前瞻性地研究和剖析针对两种重要的新出现的具有大流行潜力和高度全球意义的呼吸道病原体的病毒载体疫苗免疫的性别特异性：MERS-CoV和SARS-CoV-2，两种最近发现的新型冠状病毒。具体而言，我们建议前瞻性研究对两种新型冠状病毒疫苗MVA-MERS-S-DF 1和MVA-SARS-2的总体反应原性、抗体和T细胞应答的性别差异（目标1），使用系统疫苗学方法全面分析接种疫苗后先天免疫应答谱的性别差异（目的2）并研究树突状细胞和B细胞中X染色体编码的基因表达的差异是否与疫苗诱导的抗体应答的幅度相关（目的3）。详细了解与疫苗诱导的免疫应答中的性别差异相关的分子因素可能最终允许疫苗免疫的战略性调节并促进个性化疫苗设计。

Vaccines represent one of the most impactful public health interventions with the prevention of millions of infections and deaths annually worldwide. As illustrated by recent epidemic or pandemic outbreaks caused by emerging viruses such as Ebola Virus, MERS-CoV and more recently SARS-CoV-2, the need for rapid and strategic vaccine development remains paramount. A growing body of data have demonstrated sex differences in immune responses following vaccination. Men and women differ in the immune response to vaccination with females typically developing higher antibody responses, but also experiencing more adverse reactions following vaccination than males. This effect is not only observed post-puberty, but also in children of all ages, suggesting that factors beyond mere hormonal influences, such as chromosomal factors and epigenetics may contribute to this phenomenon. Yet the exact mechanisms and signaling pathways involved in the differential vaccine outcomes between the sexes remain incompletely understood. We hypothesize that: a) sex hormones regulate critical innate signaling pathways resulting in differential outcomes in vaccine reactogenicity and immunogenicity and b) gene-dosage effects resulting from escape from X-chromosome inactivation (XCI) contribute to sex-specific differences in vaccine responses. These hypotheses will be explored using data and biomaterial from two unique Phase 1 clinical trials investigating novel emergency vaccines. We propose to prospectively investigate and dissect sex-specificity in immunity to viral vector vaccines against two important emerging respiratory pathogens with pandemic potential and high global significance: MERS-CoV and SARS-CoV-2, two recently discovered novel coronaviruses. Specifically we propose to prospectively investigate sex-differences in the overall reactogenicity, antibody and T cell response to the two novel coronavirus vaccines, MVA-MERS-S-DF1 and MVA-SARS-2 (Objective 1), to comprehensively analyze sex-differences in innate immune response profiles following vaccination using a systems vaccinology approach (Objective 2) and to investigate whether differences in the expression of genes encoded by the X chromosome in dendritic cells and B cells are associated with the magnitude of vaccine-induced antibody responses (Objective 3). A detailed understanding of the molecular factors associated with sex-differences in vaccine-induced immune responses may ultimately allow for strategic modulation of vaccine immunity and foster individualized vaccine design.