Quantifying pandemic risk caused by within-host evolution of influenza A/H5N1 viruses

量化 A/H5N1 流感病毒宿主内进化引起的大流行风险

• 批准号: MR/K021885/1
• 负责人: Judith Fonville
• 金额: $ 33.25万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK021885%2F1
• 关键词: Quantifying; pandemic; risk; caused; within

Throughout history, influenza pandemics have caused widespread illness and death. The ability of influenza to transmit between humans through the air allows it to spread rapidly, and makes it difficult to design efficient countermeasures. Understandably, the possibility of a next influenza pandemic is therefore a constant cause of concern. Influenza viruses found in birds are particularly suspect, as they have been the source of previous pandemic viruses.Since 1997, the primary influenza strain of pandemic concern has been A/H5N1, often referred to as "bird flu". The H5N1 virus is common in countries such as China, Indonesia, Egypt and Thailand, and kills all birds on a poultry farm within 48 hours after it arrived. There have been over 600 instances where a human was infected with an H5N1 virus, often as a result of very close contact with sick animals. In over half of the cases of human infection with H5N1, the patient dies. However, to date, there is no hard evidence of an H5N1 infected human infecting another human. If the virus could spread easily from human to human and travel over the world, it could be a disaster. Therefore, it is important to understand why we do not see transmission between humans, even though human infections with H5N1 are possible.Until recently, one explanation for the lack of human-to-human transmission was that maybe it just was not possible for the H5N1 virus to spread through air. However, earlier this year, two research groups showed that with a specific set of mutations in the virus genome, the virus can transmit between mammals. This puts us ahead of the game for pandemic preparedness, and we could do everything in our power to stop an H5N1 pandemic from ever starting. But an important question remains: will a virus with the key mutations ever evolve in nature? The elimination of the virus would be time-consuming, expensive and difficult. If it is too difficult for the virus to actually get this set of mutations, a pandemic may never occur. And then we should have spent our time and research and healthcare money differently.I addressed this question of what is the risk of a transmissible H5N1 virus evolving in nature, by building a mathematical model that the described the evolution of the virus during infection of a human. The results from this model were published in the highly-respected scientific journal Science, and also used to inform advisory boards and governments in the USA and the Netherlands on the risk of transmissible H5N1 viruses evolving in nature. This is exactly what I want to do: researching fundamental principles, whilst having a direct translational impact.For this proposal, I will refine this risk assessment of an H5N1 pandemic. I will work closely with the world's leading research groups on influenza virus transmission to assess if which mutations appear during human H5N1 infections, and how often. I will refine our estimates and understanding of key parameters and processes. While doing this, I will gain an understanding of fundamental processes of evolution that occur within an infected host. For these studies, I will use advanced genetic sequencing technology to study the evolution of H5N1 viruses within the human host. I will develop new quantitative methods to analyse the data during a training period at the UK's prominent institute for genetic data analysis: the Sanger Institute.I have a wide range of collaborators to obtain the information I need, will be working in a host group specialised in evolution and influenza, and have designed a training programme to improve my skills. With this construction, I will be able to combine the outcomes of these studies and to provide input to basic science and knowledge on evolution of viruses during infection. By refining the model on evolution of H5N1 viruses during infection, I will be able to provide the much-needed estimate for the risk of H5N1, and contribute to improvements in global health.

纵观历史，流感大流行曾造成广泛的疾病和死亡。流感通过空气在人与人之间传播的能力使其能够迅速传播，并使设计有效对策变得困难。可以理解的是，下一次流感大流行的可能性因此一直引起人们的关注。在禽类中发现的流感病毒尤其值得怀疑，因为它们曾是以往大流行病毒的来源。自1997年以来，引起大流行关注的主要流感毒株是A/H5N1，通常被称为“禽流感”。H5N1病毒在中国、印度尼西亚、埃及和泰国等国家很常见，病毒到达后48小时内杀死了家禽养殖场的所有家禽。已有600多例人类感染H5N1病毒的病例，通常是由于与病畜密切接触所致。在半数以上的人感染H5N1病例中，患者死亡。然而，到目前为止，没有确凿的证据表明H5N1感染的人感染另一个人。如果病毒很容易在人与人之间传播，并在世界范围内传播，那将是一场灾难。因此，重要的是要理解为什么我们没有看到人与人之间的传播，即使人类可能感染H5N1。直到最近，对缺乏人际传播的一种解释是，H5N1病毒可能只是不可能通过空气传播。然而，今年早些时候，两个研究小组表明，在病毒基因组中有一组特定的突变，病毒可以在哺乳动物之间传播。这使我们在大流行防范方面处于领先地位，我们可以尽一切力量阻止H5N1大流行的爆发。但一个重要的问题仍然存在：具有关键突变的病毒会在自然界中进化吗？消灭这种病毒将是耗时、昂贵和困难的。如果病毒很难获得这组突变，那么大流行可能永远不会发生。那么我们就应该把时间、研究和医疗费用用在不同的地方。我通过建立一个描述病毒在人类感染期间进化的数学模型，解决了H5N1传染性病毒在自然界进化的风险是什么这一问题。该模型的结果发表在备受尊敬的科学杂志《科学》上，并用于向美国和荷兰的咨询委员会和政府通报传染性H5N1病毒在自然界进化的风险。这正是我想做的：研究基本原理，同时产生直接的翻译影响。为了这项建议，我将完善H5N1大流行的风险评估。我将与世界上主要的流感病毒传播研究小组密切合作，评估在人感染H5N1期间是否出现了哪些突变，以及出现的频率。我将改进我们对关键参数和过程的估计和理解。在此过程中，我将了解感染宿主体内发生的基本进化过程。在这些研究中，我将使用先进的基因测序技术来研究H5N1病毒在人类宿主体内的进化。在英国著名的基因数据分析研究所桑格研究所（Sanger institute）接受培训期间，我将开发新的定量方法来分析数据。我有广泛的合作者来获得我需要的信息，我将在一个专门研究进化和流感的主小组工作，我还设计了一个培训计划来提高我的技能。通过这种构建，我将能够结合这些研究的结果，并为病毒在感染过程中的进化提供基础科学和知识。通过完善H5N1病毒在感染期间进化的模型，我将能够提供急需的H5N1风险估计，并为改善全球健康作出贡献。

项目成果

Antigenic Maps of Influenza A(H3N2) Produced With Human Antisera Obtained After Primary Infection.

• DOI: 10.1093/infdis/jiv367
• 发表时间: 2016-01-01
• 期刊: The Journal of infectious diseases
• 作者: Fonville JM;Fraaij PL;de Mutsert G;Wilks SH;van Beek R;Fouchier RA;Rimmelzwaan GF
• 通讯作者: Rimmelzwaan GF

Influenza Virus Reassortment Is Enhanced by Semi-infectious Particles but Can Be Suppressed by Defective Interfering Particles.

• DOI: 10.1371/journal.ppat.1005204
• 发表时间: 2015-10
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Fonville JM;Marshall N;Tao H;Steel J;Lowen AC
• 通讯作者: Lowen AC

Dengue viruses cluster antigenically but not as discrete serotypes.

• DOI: 10.1126/science.aac5017
• 发表时间: 2015-09-18
• 期刊: Science (New York, N.Y.)
• 作者: Katzelnick LC;Fonville JM;Gromowski GD;Bustos Arriaga J;Green A;James SL;Lau L;Montoya M;Wang C;VanBlargan LA;Russell CA;Thu HM;Pierson TC;Buchy P;Aaskov JG;Muñoz-Jordán JL;Vasilakis N;Gibbons RV;Tesh RB;Osterhaus AD;Fouchier RA;Durbin A;Simmons CP;Holmes EC;Harris E;Whitehead SS;Smith DJ
• 通讯作者: Smith DJ

The global antigenic diversity of swine influenza A viruses.

• DOI: 10.7554/elife.12217
• 发表时间: 2016-04-15
• 期刊: eLife
• 影响因子: 7.7
• 作者: Lewis NS;Russell CA;Langat P;Anderson TK;Berger K;Bielejec F;Burke DF;Dudas G;Fonville JM;Fouchier RA;Kellam P;Koel BF;Lemey P;Nguyen T;Nuansrichy B;Peiris JM;Saito T;Simon G;Skepner E;Takemae N;ESNIP3 consortium;Webby RJ;Van Reeth K;Brookes SM;Larsen L;Watson SJ;Brown IH;Vincent AL
• 通讯作者: Vincent AL

Antibody landscapes after influenza virus infection or vaccination.

• DOI: 10.1126/science.1256427
• 发表时间: 2014-11-21
• 期刊: Science (New York, N.Y.)
• 作者: Fonville JM;Wilks SH;James SL;Fox A;Ventresca M;Aban M;Xue L;Jones TC;Le NMH;Pham QT;Tran ND;Wong Y;Mosterin A;Katzelnick LC;Labonte D;Le TT;van der Net G;Skepner E;Russell CA;Kaplan TD;Rimmelzwaan GF;Masurel N;de Jong JC;Palache A;Beyer WEP;Le QM;Nguyen TH;Wertheim HFL;Hurt AC;Osterhaus ADME;Barr IG;Fouchier RAM;Horby PW;Smith DJ
• 通讯作者: Smith DJ