Coronavirus Pathogenesis and Broadly Protective Vaccine Development

目前引起大流行的新出现的SARS-COV-2病毒已经对世界范围内的发病率和死亡率产生了重大影响，并对全球经济和社会产生了毁灭性的影响。总体影响无法量化，其中一些是由于全球公共卫生反应，而不是病毒本身。对人群中存在的抗体水平的了解可以为当前和未来的应对努力提供很好的见解。我们需要更多的信息来充分了解免疫将对这种疾病的传播和严重程度以及疾病的真实程度产生什么影响。这些信息可以帮助我们把重点放在有风险的人身上，而不是继续对整个人口进行大规模隔离/社会距离。这一知识还可能改变我们处理这场大流行下一阶段的方式，为可能的第二波做好准备，并可能影响我们对未来大流行的反应。因此，我们启动了一项全国性的血清调查，招募了10,000名具有代表性的美国人口样本，以确定有多少人在疫情初期接触/感染了SARS-CoV-2。然后，我们将对这些患者进行纵向跟踪，并在6个月和12个月时对他们进行复查，以寻找血清转换和有记录的感染史。这将允许评估保护的相关性和抗体滴度随时间的轨迹。这项研究结合其他类似研究产生的数据可能会在未来几个月内迅速提供，可以更好地指导随着这场大流行的继续而做出的决定。我们推测，可能有更多的人感染或接触到这种病毒，而不是目前证实的感染情况。由于无症状或未诊断的感染，很可能有相当数量的人已经对该病毒产生了抗体。 除了我们在全国范围内的血清调查外，我们还发起了一个研究患有罕见疾病的个人的项目。这项研究与NCATS RDCRN合作，将评估COVID19大流行如何影响患有500多种不同罕见疾病的个人。RDCRN已经启动了一项在线调查，我们正在启动生物采样，以使我们能够更好地确定这一利基社区的暴露和免疫水平。我们期望，在未来一年里，这项纵向研究将使我们能够更好地了解如何更好地满足这个经常被忽视的社区的流行病需求。 我们已经开始与Jeff TaubenbergersVPES合作，开发一种广泛保护、通用的贝塔冠状病毒疫苗。我们在这些疫苗的设计和制造中发挥着主导作用。在这个项目中，我们从四种不同的贝塔冠状病毒分支中提取了各种具有代表性的贝塔冠状病毒，包括SARS-CoV-2，并制作了这些病毒的灭活版。我们还在寻求这两个版本的VLP版本。一旦VPES完成临床前工作，我们能够在今年晚些时候完成GMP生产，我们希望开始第一阶段的试验。 最后，我们正在致力于开发针对贝塔冠状病毒的挑战模型，该模型可用于研究发病机制以及测试疫苗。我们目前已经从OC43β冠状病毒中制造出一种种子病毒，并希望启动GMP生产。我们还在领导创建SARS-CoV-2挑战模型方案的努力，并在制造GMP挑战病毒方面与DMID密切合作。

The newly emerged SARS-COV-2 virus currently causing a pandemic has had a major impact on morbidity and mortality worldwide, as well as having devastating global economic and societal impact. The overall impact cannot be quantified, some of which is due to the worldwide public health response and not the virus itself. Knowledge of the antibody levels present in a population could offer great insights into current and future response efforts. We need far more information to fully understand what impact immunity will have on the spread and severity of this disease and the true extent of the disease. That information could help us focus on those at risk rather than continuing large-scale quarantines/social distancing of the entire population. This knowledge could also change how we handle the next stages of this pandemic, prepare for a possible second wave, and could influence our response to future pandemics. Therefore, we initiated a nationwide serosurvey to enroll a 10,000 person representative sample of the US population to determine how many individuals have been exposed/infected with SARS-CoV-2 during the initial stages of the pandemic. We will then follow these individuals longitudinally and retest them at 6 months and 12 months to look for seroconversion and history of documented infection. This will allow for assessment of correlates of protection and trajectory of antibody titers over time. The data yielded from this study, in conjunction with other similar studies may be available rapidly in the next few months, can better guide the decisions that are made as this pandemic continues. We hypothesize that more people likely have been infected or exposed to this virus than is currently documented by confirmed infections. It is likely that a significant number of individuals already have antibodies to the virus due to asymptomatic or undiagnosed infections. In addition to our nationwide serosurvey we have also initiated a project to study individuals with rare diseases. This study in collaboration with the NCATS RDCRN, will evaluate how the COVID19 pandemic has affected individuals living with over 500 different rare diseases. The RDCRN has initiated an online survey and we are initiating biological sampling to allow us to better identify the level of exposure and immunity in this niche community. We expect that over the next year this longitudinal study will allow us to better understand how we can better address the pandemic needs of this community that is often overlooked. We have initiated work in collaboration with Jeff Taubenbergers VPES to develop a broadly protective, universal beta-coronavirus vaccine. We are playing a lead role in the design and manufacture of these vaccines. In this project we are taking various representative beta-coronaviruses, including SARS-CoV-2 from the four distinct clades of beta-coronaviruses and making inactivated versions of the viruses. We are also pursuing a VLP version of each as well. Once the VPES completes preclinical work and we are able to complete GMP manufacturing later this year, we hope to begin with phase I trials. Lastly, we are working on developing challenge models for beta-coronaviruses that may be used to study pathogenesis as well as testing vaccines. We currently have made a seed virus from an OC43 beta-coronavirus and hope to initiate GMP manufacture. We are also leading the efforts to create a SARS-CoV-2 challenge model protocol and are working closely with DMID in the manufacture of a GMP challenge virus.