Longitudinal SARS-CoV-2 mRNA vaccine-induced mucosal, serological, and cellular immunity in children and human milk

项目总结 全球范围内，儿童新冠肺炎病例和住院人数大幅增加。尽管大多数COVID- 19岁对儿童来说是轻微的，严重的疾病和感染后的并发症都可能发生。我们和其他人发现 儿童是家庭和社区传播的重要来源。接种疫苗是最有效的 预防严重感染和减少传播的方法。6个月以下的婴儿患糖尿病的风险很高。 危及生命的并发症，但针对这一年龄段的疫苗尚未进入临床试验；因此，母婴 接种疫苗和母乳喂养可能是保护感染者的重要策略。SARS-CoV-2感染和 疫苗免疫研究主要集中在成人身上，但儿童有逐渐形成的免疫力。 新的信使核糖核酸疫苗接种平台的反应可能与成人不同。这项建议 解决了研究新冠肺炎基因疫苗的短期和长期免疫反应的迫切需要 在儿童、母乳和母乳喂养的婴儿中。我们有一个成功的正在进行的纵向新冠肺炎 从2020年12月开始的疫苗接种队列，在这个队列中，我们收集了368个生物样本 包括成人、儿童和哺乳期母婴配对在内的个人。我们将招收560名个人 在信使核糖核酸疫苗获得年轻儿童紧急使用授权(EUA)后6个月内 年龄段。每3个月对参与者进行一次鼻腔、唾液、牛奶(如果是哺乳期)和血液样本的跟踪调查。我们 将在整个研究过程中测试所有有新冠肺炎症状或接触过新冠肺炎的参与者是否有突破性感染 句号。我们的中心假设是新冠肺炎疫苗的配方、数量和寿命- 诱导的免疫反应将取决于年龄和既往感染SARS-CoV-2的经验 感染。重要的是，我们的研究还将超越系统免疫反应，以检查 呼吸道和人类乳汁中的粘膜免疫。为了检验这一假设，我们将描述 疫苗诱导血清、鼻腔和唾液SARS-CoV-2特异性抗体反应(AIM 1)和细胞 儿童和成人的(CD4/CD8)应答(目标2)的比较，并确定关键的免疫学相关因素 防止突破性感染。我们还将测定母乳中的体液和细胞反应。 和分泌型IgA在母乳喂养婴儿上呼吸道的表达及疫苗诱导差异基因的评价 在牛奶中引导免疫反应的表达(目标3)。我们在疫苗方面拥有专业知识的合作团队， 免疫学、病毒学、流行病学和生物信息学将确保成功的综合分析和 这些免疫学和转录学数据的解释。研究完成后，将会提供一个 新冠肺炎基因纵向免疫诱导跨年龄免疫的综合特征 为儿童和婴儿提供最佳保护的疫苗接种战略。

PROJECT SUMMARY COVID-19 cases and hospitalizations in children have increased dramatically worldwide. Although most COVID- 19 is mild in children, severe illness and post-infectious complications can occur. We and others have found that children are an important source of household and community transmission. Vaccination is the most effective way to prevent severe infection and decrease transmission. Infants under 6 months of age are at high risk for life-threatening complications, but a vaccine for this age group is not yet in clinical trials; thus, maternal vaccination and breastfeeding may be an important strategy to protect infects. SARS-CoV-2 infection and vaccine immunity studies have focused predominantly on adults, but children have developing immune systems and may respond to the new mRNA vaccination platform differently from adults. This proposal addresses the critical need to study the short- and long-term immune responses to COVID-19 mRNA vaccination in children, human milk, and breastfeeding infants. We have a successful ongoing longitudinal COVID-19 vaccination cohort that began in December 2020, in which we have collected biologic specimens from 368 individuals including adults, children, and lactating mother-infant pairs. We will enroll a total of 560 individuals down to 6 months of age after the mRNA vaccine receives Emergency Use Authorization (EUA) for the younger age group. Participants are followed every 3 months for nasal, saliva, milk (if lactating), and blood samples. We will test all COVID-19 symptomatic or exposed participants for breakthrough infection throughout the study period. Our central hypothesis is that the repertoire, magnitude, and longevity of COVID-19 vaccine- induced immune responses will be dependent on age and previous experience with SARS-CoV-2 infection. Importantly, our study will also move beyond the systemic immune responses to examine mucosal immunity in the respiratory tract and in human milk. To test the hypothesis, we will characterize vaccine induced serum, nasal, and saliva SARS-CoV-2-specific antibody response (Aim 1) and cellular (CD4+/CD8+) response (Aim 2) in children compared with adults and identify key immunologic correlates of protection against breakthrough infection. We will also determine humoral and cellular responses in human milk and secretory IgA in the breastfed infants’ upper respiratory tract and evaluate vaccine-induced differential gene expression in milk that direct the immune response (Aim 3). Our collaborative team with expertise in vaccinology, immunology, virology, epidemiology, and bioinformatics will ensure successful integrative analyses and interpretation of these immunologic and transcriptomic data. Completion of the study will provide a comprehensive characterization of longitudinal COVID-19 mRNA vaccination-induced immunity across age groups and in human milk to inform vaccination strategies to optimize the protection of children and infants.