Avian Influenza: Modeling, Analysis and Implications for Control

这项跨学科的研究整合了数学家和生物学家在开发模型和解决与禽流感的复杂生态学和进化有关的问题方面的努力。H5N1亚型的高致病性禽流感（HPAI）现在有发生变异并引起大流行的威胁，它是由在家禽中传播的低致病性禽流感（LPAI）演变而来的。了解病毒病原体的进化需要详细分析不同遗传类型的病毒在宿主种群结构背景下的相互作用。本项目第一部分研究野生鸟类和家禽中高致病性禽流感和低致病性禽流感的相互作用，特别是低致病性禽流感可能对高致病性禽流感产生交叉免疫的相关问题。首席研究员和她的同事们在一个双宿主物种系统（对应于家禽种群和野生鸟类种群）中开发并分析了多毒株年龄结构模型，以研究高致病性禽流感和低致病性禽流感毒株的竞争排斥和持久性。此外，数学技术的发展，阐明了系统的动态行为。初步结果表明，低致病性禽流感和高致病性禽流感共存时，交叉免疫与恢复后时间结构的耦合可能导致了它们更为复杂的振荡行为。该项目的第二部分以这些模型为基础，研究用于控制家禽高致病性H5N1流感的多种控制策略的共生效应。初步结果表明，在减少H5N1在人类中的流行方面，适用于家禽的策略（如接种疫苗和扑杀）应比适用于人类的策略（如佩戴防护装备）有效得多。正在进一步努力了解家禽疫苗接种和扑杀作为目前采用的两种主要控制措施之间的相互作用，以便定量了解疾病控制的其他潜在措施。该项目产生高致病性禽流感（由H5N1流感病毒引起的禽流感）模型，这些模型以病毒的复杂生物学为基础，并得到现有数据的验证。需要这些模型来了解基本的疾病动态，并制定和实施有效的控制措施。这些模型的设计目的是拟合H5N1人间病例累积数量的现有数据，并能够对未来病例进行合理预测。此外，H5N1引起的世界范围人间流行病的威胁要求对该病毒采取严格的控制措施。这些控制措施（特别是扑杀，即在发现H5N1感染时扑杀所有家禽）给世界许多地区的家禽业造成重大经济损失。作为该项目一部分制定的模型和方法评估了替代控制措施在减少H5N1人间病例数量方面的有效性。对这些数学模型的分析扩展了我们选择最佳控制措施的能力。此外，本项目还研究了低致病性菌株从高致病性菌株的出现及其在野生鸟类和家禽中的传播情况。能够感染人类的高致病性毒株的进化是大流行毒株可能出现的主要途径。了解促成这种演变的各种情况，有助于我们在确定和防治禽流感造成的潜在大流行威胁方面做好准备。

This interdisciplinary study integrates the efforts of mathematicians and biologists in developing models and addressing questions related to the complex ecology and evolution of avian influenza. Highly pathogenic avian influenza (HPAI) of the subtype H5N1, which now threatens to mutate and cause a major pandemic, evolves from the low pathogenic avian influenza (LPAI) while circulating in poultry. Understanding evolution of viral pathogens requires a detailed analysis of interactions between different genetic types of the virus in the context of host population structure. The first part of this project studies the interplay of HPAI and LPAI in wild birds and domestic birds, particularly questions related to the cross-immunity that LPAI potentially provides to HPAI. The principal investigator and her colleagues develop and analyze multi-strain age-structured models in a two-host-species system (corresponding to domestic bird stocks, and wild bird populations) to study competitive exclusion and persistence of HPAI and LPAI strains. Furthermore, mathematical techniques are developed that elucidate the dynamical behavior of the system. Preliminary results suggest that time-since-recovery structure coupled with cross-immunity may be responsible for more complex, oscillatory behavior of LPAI and HPAI when there is coexistence in birds. The second part of the project builds on these models to study the symbiotic effect of multiple control strategies applied to control highly pathogenic H5N1 influenza in poultry. Preliminary results suggest that strategies applied to poultry, such as vaccination and culling, should be significantly more efficient than strategies applied to humans, such as wearing protective gear, in reducing the prevalence of H5N1 among humans. Further efforts are made to understand the interplay of vaccination of poultry and culling as the two primary control measures applied today, in order to provide quantitative insight into alternative potential measures of disease control.This project produces models of highly pathogenic avian influenza (bird flu, caused by an H5N1 influenza virus) that are well-grounded in the complex biology of the virus and validated with available data. Such models are required both to understand the basic disease dynamics, and to develop and implement effective control measures. The models are designed to fit available data on the cumulative number of human H5N1 cases and to be able to perform reasonable projections of future cases. Furthermore, the threat of a world-wide human epidemic (pandemic) caused by H5N1 requires strict control measures for the virus. These control measures (especially culling, the killing of all birds in a poultry operation when H5N1 infection is detected) cause significant economic losses in the poultry industry in many parts of the world. The models and methods developed as a part of this project evaluate the effectiveness of alternative control measures in reducing the number of H5N1 human cases. Analysis of these mathematical models expands our ability to choose the best control measures. In addition, the project studies the emergence of highly pathogenic strains from low pathogenic strains and their circulation in wild birds and domestic birds. The evolution of highly pathogenic strains capable of infecting humans is a major pathway through which a pandemic strain can emerge. Understanding the circumstances that foster such evolution increases our preparedness in identifying and combating potential pandemic threats caused by avian influenza.