Immunological drivers of the transition from epidemicity to endemicity of SARS-CoV-2 in a high transmission LMIC setting

项目总结 尽管新的变种可能会导致疫情激增，但我们预计SARS-CoV-2将过渡到一个新的阶段， 该病毒继续传播，但水平较低。连续免疫暴露，无论是由于感染 或接种疫苗，通过累积增加抗体水平改变了人群的免疫状态 增加抗体对SARS-CoV-2的抗原靶向广度。增加的相对作用 SARS-CoV-2抗体应答强度或抗原识别扩大在保护中的作用 目前尚不清楚受感染的人群。引人注目的是，尽管已经发现粘膜反应起到了关键作用 在保护个人免受感染方面的作用，SARS-CoV-2文献几乎完全集中在 血清学反应。随着疫情的继续，在公共卫生措施方面的有效政策和投资 将需要关于特定免疫反应的相对重要性的信息。在不同的领域收集证据 包括低收入和中等收入国家(LMIC)在内的环境特别重要，因为免疫暴露 在这些背景下的历史是不同的(在感染和疫苗使用方面)，证据较少 从这些设置中可以使用底座。我们提出的工作旨在继续审问SARS-CoV-2 自2003年以来，我们一直在关注居住在巴西城市贫民窟社区的一群人的豁免权。我们 在D614G和D614G的两次流行浪潮中发现了极高的SARS-CoV-2发病率(75%) 伽马变种。随后的疫苗接种在我们队列中的很大一部分人中产生了杂交免疫。 我们建议的研究将调查抗体大小和广度在系统性和广度中的相对作用 粘膜隔间保护这一群体免受感染。为了实现这一目标，我们建议进行 在这个社区进行血清学和病毒学监测，并开发工具来解释 应对世界在继续确定感染特征方面的关键流行病学挑战的感染 在大流行的下一阶段。我们的计划利用了与美国国家航空航天局长达27年的科学合作 巴西卫生部，询问SARS-CoV-2免疫的广泛记录，新的分析方法 以及推断感染史和表征多抗原免疫反应的分析方法。我们的研究 将产生关键证据，为新疫苗(鼻腔、多抗原)和新疫苗的开发提供信息 追踪既往免疫人群中SARS-CoV-2感染的方法 病毒学监测可能对病毒传播的看法不充分。

PROJECT SUMMARY Although new variants may contribute to surges, we expect SARS-CoV-2 to transition to a new phase where the virus continues to circulate but at lower levels. Sequential immunizing exposures, whether due to infection or vaccination, have transformed the immune status of populations by cumulatively increasing antibody levels and increasing the breadth of antigenic targeting of SARS-CoV-2 by antibodies. The relative role of increased magnitude of antibody responses or broadening of antigenic recognition of SARS-CoV-2 in protecting populations from infection is not known. Strikingly, though mucosal responses have been found to play key roles in protecting individuals from infection, SARS-CoV-2 literature has focused almost exclusively on serological responses. Effective policy and investment in public health measures as the pandemic continues will require information on the relative importance of specific immune responses. Gathering evidence in diverse settings including low and middle income countries (LMIC) is particularly important as the immunizing exposure history in these settings has been different (in terms of infections and vaccine use) and a smaller evidence base is available from these settings. Our proposed work seeks to continue to interrogate SARS-CoV-2 immunity in a cohort residing in an urban slum community in Brazil which we have followed since 2003. We identified an extraordinarily high SARS-CoV-2 attack rate (75%) during two epidemic waves with D614G and Gamma variants. Subsequent vaccination has generated hybrid immunity in a large proportion of our cohort. Our proposed study would investigate the relative role of antibody magnitude and breadth within systemic and mucosal compartments in protecting this population from infection. To accomplish this, we propose to conduct serologic and virologic surveillance in this community and develop tools to interpret serological measures of infection that address a key epidemiological challenge for the world in continued characterization of infection during the next phase of the pandemic. Our proposal leverages a 27-year scientific collaboration with the Brazilian Ministry of Health, an extensive track record of interrogating SARS-CoV-2 immunity, novel assays and analytical methods to infer infection histories and characterize multi-antigen immune responses. Our study will generate key evidence to inform the development of novel vaccines (intranasal, multi-antigen) and a new approach to tracking SARS-CoV-2 infections in populations with pre-existing immunity where symptom-based virologic surveillance may give an insufficient view of viral transmission.