Flu watch:Community study of behavioral & biological determinants of transmission to inform seasonal & pandemic planning

The current concern about bird flu is because very occasionally new strains of influenza can emerge from animals and adapt to spread rapidly from person to person. In the past this has led to worldwide epidemics (pandemics) of severe influenza. The most dramatic event was in 1917/1918 when an influenza pandemic killed more people than the second world war. A strain of influenza which can spread from birds to humans and which leads to very severe illness has emerged and is beginning to spread globally. Fortunately it does not spread easily from person to person so the number of cases are small. If the virus mutates to spread easily amongst humans then there could be another pandemic. Every year strains of influenza that can spread very easily between humans (seasonal influenza) cause many people to become unwell and lead to many extra hospitalisations and deaths particularly in elderly people and those with chronic illnesses. We need to understand how flu spreads through society and how our immune system fights the infection. This large community-based study of influenza in households will increase our understanding of seasonal influenza. A better understanding of how seasonal influenza spreads and how our immune system responds will also help us understand how pandemic influenza might spread and may help us develop strategies to reduce the impact of a pandemic. If a pandemic does happen we will need to respond quickly with studies that will help us to understand how the virus is affecting humans and what treatments are most effective. This proposal will increase our understanding of seasonal influenza, help us prepare for a pandemic and ensure that we are ready to study a pandemic if it does occur.

During an influenza pandemic studies of antiviral effectiveness, transmission dynamics, immunological and clinical response will need immediate implementation. It will be impossible to set up such studies without having a pre-enrolled cohort and established data collection methodologies.

Current empirical understanding of influenza transmission dynamics primarily rests on studies from the 1950s-1970s and limited data from previous pandemics. These studies were undertaken without the benefits of modern molecular technology at a time when social structures and mobility patterns were very different from today. Many of our mathematical models which inform planning are based on these historical data.

Studies of immunological correlates of protection have focused on neutralizing antibodies but there are no data on T-cell mediated protection in humans in natural respiratory infection. T-cells responses exhibit cross-reactivity between different virus subtypes so if pandemic influenza was imminent, it would be possible to enhance this type of immunity by vaccination.

In a collaboration between the UCL Centre for Infectious Disease Epidemiology, the MRC Human Immunology Unit, the MRC General Practice Research Framework (GPRF) and the Health Protection Agency we propose to establish a preparedness cohort of 2000 enrolled participants enabling timely study of a pandemic and to use this cohort in the pre-pandemic period to conduct a series of behavioral, virological, immunological and clinical studies of seasonal influenza. Through the GPRF we will recruit 1000 individuals in 2006/7 and a further 1000 in 2007/8 in households throughout the UK. We will follow each cohort through the following influenza season. In the event of a pandemic the entire cohort will be re-instated. Cases of influenza infection will be defined through pre-and post season serology and divided into symptomatic and asymptomatic cases based on symptom diaries. Viral shedding will be identified through self-submitted nasal swabs for RT-PCR identification of influenza. Information on patient contact patterns will be collected providing empirical data to inform models of pandemic and seasonal influenza transmission. In nested case control studies pre and post season blood samples from patients with confirmed influenza and controls will be used to assess the T cell response to influenza using a validated interferon-gamma elispot assay. We hypothesize that pre-existing T cell immunity will be greater in those with symptomatic influenza infection and in confirmed viral shedders than in those with asymptomatic infection.

We will use methodology and data from the study to enable the development of empirical trials of antiviral and behavioural interventions.