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

项目摘要 虽然新的变异可能会导致激增，但我们预计SARS-CoV-2将过渡到一个新的阶段， 病毒继续传播，但水平较低。连续免疫暴露，无论是由于感染 或疫苗接种，通过累积增加抗体水平， 并增加抗体对SARS-CoV-2抗原靶向的广度。增加的相对作用 SARS-CoV-2的抗体应答幅度或抗原识别范围的扩大， 感染的人群尚不清楚。引人注目的是，尽管粘膜反应被发现在 在保护个体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。随着大流行病的持续，对公共卫生措施的有效政策和投资 将需要关于特异性免疫反应的相对重要性的信息。收集各种证据 包括低收入和中等收入国家（LMIC）在内的环境尤其重要， 在这些环境中的历史是不同的（在感染和疫苗使用方面）， 从这些设置中可以使用base。我们提出的工作旨在继续审问SARS-CoV-2 我们自2003年以来一直在跟踪巴西一个城市贫民窟社区居民群体的免疫情况。我们 在D 614 G的两次流行波中，发现了非常高的SARS-CoV-2攻击率（75%）， 伽马变种。随后的疫苗接种在我们队列的大部分中产生了混合免疫。 我们提出的研究将调查抗体大小和广度在全身和全身免疫中的相对作用， 粘膜隔室保护该人群免受感染。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 这是世界在继续确定感染特征方面面临一个关键的流行病学挑战 在下一阶段的大流行中。我们的提案利用了与美国科学院27年的科学合作， 巴西卫生部，一个广泛的跟踪记录，询问SARS-CoV-2免疫，新的测定 以及推断感染史和表征多抗原免疫应答的分析方法。我们的研究 将产生关键证据，为新型疫苗（鼻内，多抗原）的开发提供信息， 在有免疫力的人群中追踪SARS-CoV-2感染的方法， 病毒学监测可能无法充分了解病毒传播情况。

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.