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

项目摘要 COVID-19病例和儿童住院治疗在全球范围内急剧增加。虽然大多数COVID- 19是轻症儿童，严重的疾病和感染后并发症可以发生。我们和其他人发现， 儿童是家庭和社区传播的重要来源。接种疫苗最有效 预防严重感染和减少传播的方法。6个月以下的婴儿有很高的风险， 危及生命的并发症，但该年龄组的疫苗尚未进入临床试验;因此，产妇 接种疫苗和母乳喂养可能是保护感染的重要策略。SARS-CoV-2感染和 疫苗免疫研究主要集中在成人身上，但儿童的免疫力正在发展， 系统，并可能对新的mRNA疫苗接种平台的反应与成人不同。这项建议 解决了研究COVID-19 mRNA疫苗接种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。我们有一个成功的持续纵向COVID-19 疫苗接种队列于2020年12月开始，我们收集了368份生物样本 个体，包括成人、儿童和哺乳期母婴对。我们将招募总共560人 在mRNA疫苗获得紧急使用许可（EUA）后， 年龄段参与者每3个月进行一次鼻，唾液，乳汁（如果哺乳期）和血液样本的随访。我们 将在整个研究期间对所有有COVID-19症状或暴露的参与者进行突破性感染检测 期我们的核心假设是，COVID-19疫苗的种类、规模和寿命- 诱导的免疫反应将取决于年龄和先前的SARS-CoV-2经验 感染重要的是，我们的研究还将超越全身免疫反应， 呼吸道和母乳中的粘膜免疫。为了验证假设，我们将描述 疫苗诱导的血清、鼻腔和唾液SARS-CoV-2特异性抗体应答（Aim 1）和细胞免疫应答（Aim 1）。 (CD4+/CD 8+）反应（目标2），并确定关键的免疫相关性， 防止突破性感染。我们还将确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中的表达，并评估疫苗诱导的差异基因 在牛奶中的表达，指导免疫应答（目标3）。我们的合作团队拥有疫苗学方面的专业知识， 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， 这些免疫学和转录组学数据的解释。研究完成后， 跨年龄纵向COVID-19 mRNA疫苗诱导免疫的综合表征 通过对不同群体和母乳中的疫苗接种情况进行分析，为疫苗接种战略提供信息，以优化对儿童和婴儿的保护。

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.