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

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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.