Exploring Risk Factors for Sequential and Concurrent Dengue and Zika Outbreaks in a Naïve Population

黄病毒对世界人口构成了一个日益严重的问题。1970年以前，只有9个国家经历过严重的登革热流行；现在登革热在100多个国家流行。同样，在20世纪80年代之前，人类感染寨卡病毒的情况非常罕见；现在有86个国家报告了蚊子传播的寨卡疫情。预测哪种黄病毒将导致下一次流行是具有挑战性的，而共同传播的病原体之间的动态可能是导致发病率增加的原因。已知当人群连续感染不同血清型登革热时，抗体依赖性增强（ADE）会增加登革热相关疾病的严重程度。据信，登革热和寨卡病毒之间也可能出现这种机制，因为它们的结构几乎相同，这尤其令人担忧，因为它们具有相同的载体，即埃及伊蚊和白纹伊蚊。由于气候变化，这些蚊子的栖息地正在扩大，近年来，白纹伊蚊的种群一直持续到加拿大安大略省南部，前几年还发现了埃及伊蚊。目前，还没有批准的登革热或寨卡疫苗。对于登革热，部分原因是由于ADE的影响，如果之前没有接触过ADE的接种过疫苗的个体随后感染，可能会出现严重的副作用。因此，登革热血清型内部及其与寨卡病毒之间的动态对未来的预防和控制政策至关重要。本项目旨在通过统计和机制模型阐明考虑ADE的黄病毒共循环动力学。通过将加拿大公共卫生保健局（PHAC）目前用于代表伊蚊在加拿大分布的统计模型与考虑ADE的登革热和寨卡病毒的机制模型相结合，我们将能够预测考虑气候变化影响的连续和并发登革热和寨卡病毒爆发的风险变化。该项目将确定连续和同时发生疫情所需的输入病例和携带登革热和/或寨卡病毒的媒介数量，以及哪些环境和人口变量对未来入侵风险影响最大。传染病建模需要跨学科的方法，该项目将充分利用通过Greer博士和她的实验室小组可获得的各种各样的专家。她每月的实验室小组会议由PHAC的个人参加，这促进了学者和政策制定者之间的思想和专业知识交流。将有机会与其他学者合作，如约克大学专门研究合并感染的赫弗南博士和卡尔加里大学的生物统计学家罗布·迪尔登博士。此外，昆虫原公司（Entomogen Inc.）是一家监测蚊子数量并进行病毒检测的公司，总部设在安大略省。对这一群体的访问将增进对如何收集蚊子数据的理解，并阐明报告数据中可能存在的偏差。最后，2020年，美国热带医学与卫生学会将在多伦多举行年会，这将为与黄病毒研究专家建立联系提供一个理想的机会。在该项目结束时，我们将开发一个模型，用于确定考虑到未来气候变化的加拿大登革热和寨卡病毒爆发的风险。该模型的产出将直接传达给我们在圭尔夫大学和PHAC的合作者，从而为将来加拿大黄病毒爆发的应急规划提供信息。

Flaviviruses pose an ever increasing problem for the worldwide population. Before 1970 only 9 countries had experienced severe dengue epidemics; now dengue is endemic in over 100 countries. Similarly, before the 1980s human infection from Zika was a very rare occurrence; now 86 countries have reported mosquito-transmitted Zika outbreaks. It is challenging to predict which flaviviruses will result in the next epidemic and the dynamics between co-circulating pathogens may be responsible for increased morbidity. Antibody dependent enhancement (ADE) is known to increase the severity of dengue-related illnesses when a population is infected with different serotypes of dengue consecutively. It is believed that this mechanism may also occur between dengue and Zika owing to their near identical structures, which is particularly concerning as they share the same vectors, Aedes aegypti and A. albopictus. As a result of climate change, the habitat of these mosquitoes is expanding and in recent years persistent populations of A. albopictus have been found as far north as Southern Ontario in Canada with A. aegypti being found in previous years. Currently, there is no approved vaccine for dengue or Zika. For dengue this is in part due to the effects of ADE, which could see vaccinated individuals with no prior exposure experiencing severe side effects should they be subsequently infected. Therefore, the dynamics within dengue serotypes and between them and Zika is crucially important for any future prevention and control policies. This project aims to elucidate the dynamics of co-circulating flaviviruses considering ADE through the use of statistical and mechanistic models. By integrating the statistical models used currently by the Public Health Care Agency of Canada (PHAC) to represent the distribution of Aedes across Canada with a mechanistic model for dengue and Zika considering ADE, we will be able to forecast the change in risk for sequential and concurrent dengue and Zika outbreaks that take into account the effect of climate change.This project will determine the number of imported cases and vectors carrying dengue and/or Zika required for sequential and concurrent outbreaks to occur and which environmental and demographic variables have the biggest impact upon future invasion risk.Modelling infectious diseases requires an interdisciplinary approach and this project will take full advantage of the wide variety of specialists accessible through Dr Greer and her lab group. Her monthly lab group meetings are attended by individuals from PHAC which facilitates an exchange of ideas and expertise between academics and policy makers. There will be opportunities to collaborate with other academics such as Dr Heffernan who specialises in co-infection, from York University, and Dr Rob Deardon, a biostatistician at the University of Calgary. Furthermore Entomogen Inc., a company which monitors the mosquito population and carries out viral testing, is based in Ontario. Visits to this group will improve understanding of how mosquito data are gathered and elucidate any possible biases in reported data. Finally, in 2020 the American Society for Tropical Medicine and Hygiene are holding their annual conference in Toronto, which will provide an ideal opportunity to network with experts in the flavivirus research.At the conclusion of this project we will have developed a model that can be utilised to establish the risk of outbreaks of dengue fever and Zika occurring in Canada that takes into account future climate change. The outputs of this model will be communicated directly to our collaborators at the University of Guelph and PHAC, thus informing contingency planning for outbreaks of flaviviruses in Canada in the future.