Integrating immunology, epidemiology, and evolution to understand and control per

描述（由申请人提供）：百日咳仍然是一个主要的流行病学负担，每年全世界约有30万人死于百日咳，其中大多数是儿童。20世纪50年代和60年代婴儿免疫计划的早期成功导致发病率大幅下降，并使人们乐观地认为消除百日咳可能是可以实现的。然而，在过去的二十年中，在一些接种了良好疫苗的人群中记录的百日咳爆发，指出了我们对百日咳流行病学、免疫学、进化和控制的理解存在重大差距。各种疫苗的有效性和免疫特性尚不清楚，但它们的可获得性和使用情况助长了不确定性。我们建议将百日咳传播的这些重要决定因素分成可管理的单位，以提高我们的理解。通过对来自不同国家的疫苗前时代的长期、空间复制和年龄特异性数据的多种替代假设进行全面的比较测试，我们将旨在确定感染衍生免疫的持续时间、重复感染的流行病学影响、亚临床免疫增强的作用，以及人口统计学、年龄特异性接触者和季节性的各自贡献。下一阶段的研究将着眼于解决该问题的疫苗特异性方面，重点关注已知使用疫苗（全细胞vs细胞）和免疫计划的国家。我们对百日咳的理解是否有了显著进步的最终检验将是解释一个神秘的数据体，即过去三十年来美国百日咳发病率的变化模式。这项工作将依靠

DESCRIPTION (provided by applicant): Pertussis remains a major epidemiological burden, accounting for roughly 300,000 deaths worldwide each year, most of them children. The early success of infant immunization programs in the 1950s and 1960s led to a substantial reduction in incidence and a sense of optimism that elimination of pertussis might be a achievable. Over the past two decades, however, documented outbreaks in a number of well vaccinated populations has pointed out major gaps in our understanding of pertussis epidemiology, immunology, evolution, and control. The availability and use of various vaccines with poorly understood efficacy and immunity profiles contributes to the uncertainty. We propose to improve our understanding of these important determinants of pertussis transmission by splitting the problem into manageable units. By conducting a comprehensive, comparative testing of multiple alternative hypotheses on long-term, spatially replicated, and age-specific data from different countries in the pre-vaccine era, we will aim to pin down the duration of infection-derived immunity, the epidemiological impact of repeat infections, the role played by sub-clinical immune boosting, and the respective contributions of population demography, age-specific contacts, and seasonality. The next phase of research will aim to address the vaccine-specific aspects of the problem by focusing on countries with known vaccine usage (whole cell vs. a cellular) and immunization schedules. The ultimate test of whether our understanding of pertussis has significantly advanced will be to explain an enigmatic body of data, namely the changing patterns of pertussis incidence in the US over the past thirty years. This work will rely heavily on the use of mathematical models of pertussis transmission and statistical methods for extracting information from data. A major ingredient in this project, therefore, is the development, use, and dissemination of novel methodological tools that will be implemented in open-source public software. Finally, we will bring together the intellectual fruits of this effortin order to develop optimal, cost-effective immunization policy. PUBLIC HEALTH RELEVANCE: The control of infectious diseases by means of immunization remains a critical public health priority. In some nations, including the US, recent decades have coincided with a notable increase in pertussis notifications, despite high vaccine uptake estimates pinpointing significant knowledge gaps in pertussis biology. Therefore, understanding the complex interaction of factors that affect pertussis epidemiology, immunology, evolution, and control is an urgent priority. This is what we propose to do using an extensive database of pertussis reports from a number of countries, including information on age, geography and serotype. We will test alternative competing hypotheses using these data and cutting edge statistical methods. Finally, we will distill the intellectual fruits of this effort into optimal, ost-effective immunization policy.