Directly-transmitted acute RNA viruses (ARVs) - such as the influenza A and measles viruses - cause many important human diseases. ARVs typically generate violent epidemics which are terminated by the build up of herd immunity, as hosts' immune systems acquire the ability to combat reinfection. Herd immunity can impose enormous selection pressure on ARVs for immune escape, working on the extensive genetic variation generated by high mutation rates and large population sizes. The evolutionary effects of this selection can be clearly seen in influenza virus, where mutation and selection of viral surface protein genes enables the virus to re-infect hosts, subverting herd immunity. Measles lies at the other end of the evolutionary spectrum: with little immune-driven adaptive evolution and near-perfect herd immunity. Understanding the comparative dynamics and control of ARVs therefore depends on characterizing the interaction between epidemiological and evolutionary processes. However, there is currently no quantitative framework linking data on spatio-temporal disease incidence with epidemiological dynamics and phylogenetic analyses of viral evolutionary dynamics. The goal of the proposed research is to develop and apply such a framework, in a nonstationary world of anthropogenic change. We shall approach this synthesis at both viral gene sequence level and the group level of viral subtypes and serotypes. The specific objectives and methods of this work are: 1. Epidemiological dynamics and sequence evolution of ARVs. To develop and analyze computational models that superimpose both neutral viral evolution and immune escape on the current generation of stochastic gravity models for spatio-temporal transmission dynamics of ARVs. Using this simulation framework as a test-bed, we shall refine current coalescent methods to explicitly estimate the parameters of population growth and decline in ARVs and to properly account for spatial subdivision. 2. Group level strain dynamics of ARVs and the impact of anthropogenic change. To explore a new approach to the interaction between viral immune escape and the impact of anthropogenic/demographic change based on the concept of demographic buffering of environmental fluctuations by loss of immunity. We shall develop models to explore how buffering of birth pulses and anthropogenic change operates in age- and spatially-structured host populations across the observed range of ARV life histories. 3. Case studies. To combine models and phylogenetic methods with disease incidence and viral gene sequence data to explore key issues in the epidemiology, evolution and control of five contrasting and important ARV infections of humans: measles, influenza, rotavirus, respiratory syncytial virus and parainfluenza. The synthesis of population dynamic and evolutionary processes is a key problem in infectious disease ecology. With their potential for rapid evolution, RNA viruses present a major opportunity for exploring how epidemic dynamics drive pathogen evolution, and vice versa, and how both are affected by anthropogenic change. The study will provide new insights into RNA virus evolution, clarify key evolutionary and epidemiological issues, and develop generally applicable statistical and modeling tools. ? ? ? ?
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