Dissecting Sex Differences in the Immune Response to Vaccines

剖析疫苗免疫反应的性别差异

• 批准号: 454008211
• 负责人: Professorin Dr. Marylyn Martina Addo
• 金额: --
• 依托单位: Sektion Infektiologie
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/454008211?language=en
• 关键词: Dissecting; Sex; Differences; Immune; Response

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.

疫苗是最有效的公共卫生干预措施之一，每年可预防全世界数百万人感染和死亡。正如最近埃博拉病毒、中东呼吸综合征冠状病毒和最近的SARS-CoV-2等新病毒引起的流行病或大流行疫情所表明的那样，快速和战略性疫苗开发的必要性仍然是最重要的。越来越多的数据表明，接种疫苗后的免疫反应存在性别差异。男性和女性对疫苗的免疫反应不同，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经历更多的不良反应。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，这表明除了激素影响之外的因素，如染色体因素和表观遗传学可能导致了这种现象。然而，两性之间疫苗结果差异所涉及的确切机制和信号通路仍然不完全清楚。我们假设：a)性激素调节关键的先天信号通路，导致疫苗反应性和免疫原性的不同结果；b)逃避X染色体失活(XCI)导致的基因剂量效应导致疫苗应答的性别差异。将使用研究新型紧急疫苗的两个独特的第一阶段临床试验的数据和生物材料来探索这些假设。我们建议前瞻性地研究和剖析针对两种新发现的新冠状病毒：MERS-CoV和SARS-CoV-2这两种具有大流行潜力和高度全球意义的重要呼吸道病原体的病毒载体疫苗的性别特异性。具体地说，我们建议前瞻性地调查两种新型冠状病毒疫苗MVA-MERS-S-DF1和MVA-SARS-2的总体反应性、抗体和T细胞反应的性别差异(目标1)，用系统疫苗学方法综合分析疫苗接种后先天免疫反应的性别差异(目标2)，并调查树突状细胞和B细胞中X染色体编码基因的表达差异是否与疫苗诱导的抗体反应的大小有关(目标3)。对疫苗诱导的免疫反应中与性别差异相关的分子因素的详细了解可能最终允许对疫苗免疫进行战略性调节，并促进个性化的疫苗设计。