Investigation of sarbecovirus exposure patterns and development of pan-SARS-CoV-2 neutralizing antibody responses in high-risk cohorts in Myanmar

项目总结 新出现的严重急性呼吸综合征冠状病毒2(SARS-CoV-2)变异引起关注 对现有和未来疫苗有效性的全球挑战。这个项目将解决问题 围绕着对不同肉瘤病毒暴露模式的免疫反应，并暗示 通过对独特的人类群体进行纵向重复监测来开发疫苗， 以前被确定为高度接触多种与SARS-CoV-2相关的冠状病毒 缅甸。现在有一个及时关注这些社区的机会，特别是紧随其后 SARS-CoV-2感染和/或疫苗接种，以了解以前哪些肉瘤病毒暴露模式 增加发展泛肉瘤病毒中和抗体的可能性。我们将评估 不同自然和接种方式的肉瘤病毒暴露对PAN发病的影响 通过以下三个特定人类队列产生的肉瘤病毒中和抗体：(1)大象伐木者 在#年积极砍伐森林的过程中从事丛林猎杀(包括蝙蝠和穿山甲) 缅甸剩余的柚木森林，(2)HpaAn洞穴系统周围的蝙蝠鸟粪采摘社区 在克伦邦和(3)以前未经调查的在喀斯特地区从事宗教活动的人口 道纳山脉北部的洞穴系统。特异性抗体反应的兴衰将是 通过使用大流行前来自这些人群的存档标本并重复 前瞻性抽样。我们将利用一种新的基于Luminex珠基的多重肌小球病毒检测，能够 同时检测21种不同hACE2结合肉瘤病毒的中和抗体。 将确定特定肉瘤病毒的暴露模式，并评估其病毒特征 对发展泛肉瘤病毒抗体反应的可能性的贡献，包括病毒遗传和 功能表型相似性和宿主可塑性(已知病毒感染的宿主物种的广度)。 既往自然暴露的肉瘤病毒与自然SARS-COV-2感染和/或 然后将评估疫苗接种对广泛反应的抗体反应的贡献。生成的数据 通过该项目，将通报潜在的交叉肉瘤病毒分支疫苗接种策略，这些策略可以保护 针对已知和未来出现的SARS-CoV-2变种。我们还将深入开展 人畜共患肉瘤病毒外溢的行为危险因素调查 在这一至关重要的生态区为冠状病毒的出现制定缓解策略。

PROJECT SUMMARY Emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern pose a global challenge to the effectiveness of existing and future vaccines. This project will address questions surrounding the immunological response to different sarbecovirus exposure patterns with implications for vaccine development by conducting longitudinal repeated surveillance of unique human populations, previously determined to be highly exposed to a diversity of SARS-CoV-2-related coronaviruses in Myanmar. There is a timely opportunity to follow these communities, particularly immediately following SARS-CoV-2 infection and/or vaccination to understand which previous sarbecovirus exposure patterns expand the likelihood of development of pan-sarbecovirus neutralizing antibodies. We will evaluate the impact of diverse patterns of natural and vaccination-based sarbecovirus exposure on development of pan- sarbecovirus neutralizing antibodies by following three specific human cohorts: (1) elephant loggers engaged in bushmeat hunting (including bats and pangolins) during the process of active deforestation of Myanmar’s remaining teak forests, (2) bat guano harvesting communities surrounding HpaAn cave systems in Kayin State and (3) a previously uninvestigated population engaged in religious activities within the Karst cave systems in the Northern Dawna range. Waxing and waning of specific antibody responses will be followed over time through use of pre-pandemic archived specimens from these populations and repeated prospective sampling. We will utilize a novel Luminex bead-based multi-plex sarbecovirus assay, capable of simultaneously detecting neutralizing antibodies against 21 different hACE2-binding sarbecoviruses. Exposure patterns to specific sarbecoviruses will be identified and viral characteristics evaluated for their contribution to the likelihood of developing pan-sarbecovirus antibody responses, including viral genetic and functional phenotypic similarity and host plasticity (breadth of host species a virus is known to infect). Patterns of prior natural sarbecovirus exposure coupled with natural SARS-COV-2 infection and / or vaccination will then be evaluated for contributions to broadly reactive antibody responses. Data generated through this project will inform on potential cross sarbecovirus clade vaccination strategies that could protect against both known and future emerging SARS-CoV-2 variants. We will also conduct an in-depth investigation of behavioral risk factors contributing to zoonotic sarbecovirus spillover that will aid in mitigation strategies in this critically important ecological region for coronavirus emergence.