Surveillance and identification of variants of concern within circulating SARS-CoV-2 across Kentucky

项目摘要 导致COVID-19疾病的SARS-CoV-2病毒的出现和传播已导致超过1.25亿人死亡， 在短短一年多的时间里，全世界有250多万人感染和死亡。全球测序工作 确定了几种引起关注（VOC）和关注（VOI）的病毒变体，导致传播率增加 和/或增加感染新SARS-CoV-2毒株的死亡率。尽管开发了 多种强大而有效的疫苗，进一步的病毒进化可能导致对当前疫苗水平的抵抗力， 中介保护。持续的病毒基因组监测是必要的，以确定和表征已知的， 新的病毒变种，为正在进行的公共卫生工作和未来的疫苗设计策略提供信息。这是一 特别是迫切需要机构发展奖（IDEA）的国家，其中知识的流通 SARS-CoV-2变种非常有限。驱动SARS-CoV-2多样化的机械力量， 变种的出现当然是多因素的。有效的天然和疫苗抗病毒保护被认为是 由有效的广泛反应性中和抗体（nAb）介导。最近开发的基因分型测定法 免疫球蛋白（IG）基因座内的广泛多样性，越来越多的证据表明， 编码抗体库的基因的集体排列在不同种族人群中差异很大。此外，委员会认为， 最近的报告表明，生物性别可能会影响免疫发病机制和个人的适应力， 变种的传播和传播受到地理限制，沿着预先存在的社会脆弱性 也可能影响SARS-CoV-2变异动力学。有充分的证据表明，COVID-19不成比例地影响了 代表性不足的人口，包括黑人，土著人和有色人种（BIPOC）和拉丁人。 在这些人群中，关于SARS-CoV-2循环和变异特征分析的数据也报告不足。 正在进行的病毒监测工作。评估病毒VOC和VOI如何受到差异遗传的影响， 生物和社会背景将是至关重要的，以提供公平的代表性的频率和 SARS-CoV-2变异体的特征，并作为产生机制假设的第一步 未来的研究。使用稳健、高通量和具有成本效益的单分子，实时测序 方法，我们建议进行大规模的SARS-CoV-2基因组监测约7000样品来源 整个肯塔基州（KY），以（1）大幅提高有关SARS-CoV-2动态和变异的数据可用性 循环，（2）评估变异出现和进化的生物和社会相关性，以及（3）杠杆作用 这个管道开发一个独特的病原体监测课程。为了实现这一目标，我们建立了一个多- 机构合作努力，在学术，医疗保健， 和工业利益相关者，定位这个团队建立一个病原体监测中心， 未来的努力。

PROJECT SUMMARY The emergence and circulation of SARS-CoV-2, the virus that causes COVID-19 disease, has led to >125 million infections and more than 2.5 million deaths worldwide in just over 1 year. Global sequencing efforts have identified several viral variants of concern (VOC) and interest (VOI) that result in increased transmission rates and/or increased mortality for those infected with the new SARS-CoV-2 strains. Despite the development of multiple robust and effective vaccines, further viral evolution may result in resistance to current levels of vaccine- mediated protection. Ongoing viral genomic surveillance is necessary to identify and characterize known and new viral variants, to inform both ongoing public health efforts, and future vaccine design strategies. This is a particularly urgent need for Institutional Development Award (IDeA) states, for which knowledge of circulating SARS-CoV-2 variants is extremely limited. The mechanistic forces driving SARS-CoV-2 diversification and variant emergence are certainly multifactorial. Effective natural and vaccine antiviral protection is thought to be mediated by potent, broadly reactive neutralizing antibodies (nAbs). Recently developed genotyping assays have characterized the extensive diversity within immunoglobulin (IG) loci, with increasing evidence suggesting that the collective array of genes that encode antibody repertories differ widely across ethnic populations. Moreover, recent reports suggest that biological sex may impact immunopathogenesis and individual resilience, and that geographically restricted circulation and transmission of variants, along with pre-existing social vulnerabilities may also impact SARS-CoV-2 variant dynamics. It is well documented that COVID-19 disproportionately impacts underrepresented populations, including Black, Indigenous and people of color (BIPOC) and Latinx peoples. Data regarding SARS-CoV-2 circulation and variant profiling in these populations in also underreported in ongoing viral surveillance efforts. Evaluating how viral VOC and VOI are impacted by differential genetic, biological and social backgrounds will be critical for providing equitable representation of the frequency and characteristics of SARS-CoV-2 variants, and act as a first step towards mechanistic hypothesis generation for future studies. Using a robust, high throughput and cost-effective single molecule, real-time sequencing approach, we propose to perform large scale SARS-CoV-2 genomic surveillance from ~7000 samples sourced across Kentucky (KY) to (1) substantially improve data availability regarding SARS-CoV-2 dynamics and variant circulation, (2) evaluate biological and social correlates of variant emergence and evolution, and (3) leverage this pipeline to develop a unique curriculum in pathogen surveillance. To achieve this, we have built a multi- institutional collaborative effort, developing key partnerships among a deep network of academic, healthcare, and industrial stakeholders, positioning this team to establish a pathogen surveillance center for ongoing and future efforts.