Understanding the Mechanism of Protection Following Challenge and Immunization

疫苗的目标是模拟自然感染，诱导有效的免疫反应，最重要的是，建立免疫记忆。这种经验方法未能诱导对某些病原体的保护，因为疫苗的有效性可能受到多种因素的阻碍，包括病原体遗传多样性、复杂的发病机制和/或病原体逃避免疫系统的能力。与数据分析相结合的数学模型可以帮助促进对保护的相关性和机制的理解。本研究项目提供了一种跨学科的方法来研究这种感染、持久性和保护机制。它结合了数学技术的发展和生物学数据的使用，以研究抗体在清除病毒感染中的作用，诱导外部挑战后免疫启动和记忆的动态机制，以及接种和增强后复杂的免疫细胞相互作用。该项目旨在帮助确定挑战和疫苗接种后免疫记忆形成的关键机制，以指导疾病预防和控制战略。在这个项目中，数学模型将被开发、分析，并与时间数据进行比较，目的是(1)评估病毒攻击后抗体的数量、质量和动态与保护之间的关系；(2)研究先天免疫细胞向炎症或耐受表型倾斜的分子机制；(3)确定免疫记忆与接种诱导的细胞和分子标记物的大小和动态之间的关系。该项目对生物开关的复杂非线性动力系统的研究旨在得出关于渐近全局行为的严格理论标准，以及出现双稳解所需的模型特征。针对数据的模型验证将提供对保护和抗体发展之间关系的深入了解，并将促进对免疫因素和疫苗接种结果之间关系的理解。最重要的是，它将在细胞和分子水平上预测挑战后免疫记忆形成的关键机制。这些知识对于合理设计疫苗至关重要。该项目将促进数学和生物学知识的进步，将为与数学界和医学界的研究人员进行跨学科合作提供机会，并将涉及对本科生和研究生的培训。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The goal of vaccines is to mimic natural infections, induce potent immune responses and, most importantly, establish immunological memory. This empirical approach has failed to induce protection against some pathogens, as vaccine effectiveness can be hindered by a combination of factors including pathogen genetic diversity, complex pathogenesis, and/or ability of pathogens to evade the immune system. Mathematical models in combination with data analysis can help advance the understanding of correlates and mechanisms of protection. This research project provides an interdisciplinary approach into the study of such mechanisms of infection, persistence, and protection. It combines development of mathematical techniques and the use of biological data for the investigation of the role of antibody in the clearance of viral infections, the dynamic mechanisms that induce immunological priming and memory following external challenge, and the complex immune cell interactions following vaccination and boosting. The project aims to help identify key mechanisms involved in the formation of immunological memory after challenge and vaccination with the aim of guiding strategies for disease prevention and control. In this project, mathematical models will be developed, analyzed, and compared with temporal data with the aim of (1) evaluating the relationship between protection and the quantity, quality, and dynamics of antibodies following virus challenge; (2) investigating the molecular mechanisms that tilt innate immune cells into inflammatory or tolerant phenotypes; (3) determining the relationship between immunological memory and the size and dynamics of cellular and molecular markers induced through vaccination. The project's investigation of complex non-linear dynamical systems of biological switches is intended to lead to rigorous theoretical criteria on asymptotic, global behavior, as well as model features needed for the emergence of bistable solutions. Model validation against data will provide insight into the relationship between protection and antibody development, and will advance understanding of the relationship between immune factors and vaccination outcomes. Most importantly, it will predict key mechanisms, at cellular and molecular level, involved in the formation of immunological memory following challenge. Such knowledge is essential for rational vaccine design. The project will promote the advancement of mathematical and biological knowledge, will provide an opportunity for interdisciplinary collaboration with researchers in the mathematical and medical communities, and will involve training of undergraduate and graduate students.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.