Understanding the Mechanism of Protection Following Challenge and Immunization

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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.