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

描述(申请人提供)：百日咳仍然是一个主要的流行病负担，每年在全世界造成大约30万人死亡，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了发病率的大幅下降，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20年里，在一些接种良好的人群中记录的疫情指出了我们在百日咳流行病学、免疫学、进化和控制方面的主要差距。各种效力和免疫状况知之甚少的疫苗的可获得性和使用情况导致了不确定性。我们建议通过将问题分成可管理的单元来提高我们对百日咳传播的这些重要决定因素的理解。通过对疫苗前时代不同国家的长期、空间复制和特定年龄的数据进行全面、比较的假设测试，我们将致力于确定感染衍生免疫的持续时间、重复感染的流行病学影响、亚临床免疫增强所起的作用，以及人口统计学、特定年龄接触者和季节性的各自贡献。下一阶段的研究将致力于解决疫苗问题的特定方面，将重点放在已知疫苗使用(全细胞与细胞)和免疫时间表的国家。要检验我们对百日咳的理解是否有显著进步，最终的考验将是解释一组神秘的数据，即过去30年美国百日咳发病率的变化模式。这项工作将依靠 大量使用百日咳传播的数学模型和从数据中提取信息的统计方法。因此，该项目的一个主要组成部分是开发、使用和传播将在开放源码公共软件中实施的新的方法工具。最后，我们将汇集这一努力的智力成果，以制定最佳、成本效益高的免疫政策。 公共卫生相关性：通过免疫手段控制传染病仍然是关键的公共卫生优先事项。在包括美国在内的一些国家，近几十年来百日咳的报告数量显著增加，尽管疫苗接种量较高的估计表明，百日咳生物学方面存在重大知识缺口。因此，了解影响百日咳流行病学、免疫学、进化和控制的因素之间的复杂相互作用是当务之急。这就是我们建议使用来自一些国家的百日咳报告的广泛数据库来做的事情，包括关于年龄、地理和血清型的信息。我们将使用这些数据和尖端的统计方法来测试可供选择的竞争性假设。最后，我们将把这一努力的智力成果提炼成最优、最有效的免疫政策。

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.