Influenza
MRC researchers identified the influenza virus and, for many years, investigated how it invades healthy cells. After establishing one of the world flu centres, the MRC continues to work on models of a potential spread – to prepare for a real-life pandemic.
In 1933, MRC researchers identified human influenza virus1 at the National Institute for Medical Research (NIMR) in London – which was to become one of the most important centres in the world for flu research.
Flu is a contagious respiratory illness caused by a virus, which can cause mild to severe illness, and even death. In annual flu epidemics, there are between three and five million cases of severe illness and between 250 000 and 500 000 deaths every year around the world. Most deaths occur among the elderly.
In contrast, flu pandemics, which occur every 20 to 30 years, affect age groups differently. The age group affected most severely by the 1918 pandemic – cited as the most devastating epidemic in recorded world history – was between 20 and 40 years, which accounted for almost half of flu deaths during the pandemic.
Following the introduction of influenza vaccine in the 1940s, and the understanding that the virus regularly mutates and becomes resistant to current vaccines, the MRC established the World Influenza Centre (WIC) at NIMR, after the World Health Organization (WHO) had just been formed. Today the WIC is one of four WHO Collaborating Centres (CCs) for Reference and Research on Influenza which, together with 112 National Influenza Centres (NICs) in 83 countries, comprise the WHO Global Surveillance Network.
The NICs collect specimens in their country, perform primary virus isolation and preliminary antigenic characterisation. They send isolated strains to WHO CCs for antigenic and genetic analysis, the result of which forms the basis for WHO recommendations on the composition of flu vaccine for countries all over the world each year.
The basics of flu
Between 1975 and 1993, Professor Sir John Skehel, one of the world’s leading virologists, was the Director of the WIC at NIMR. Sir John has played a large part in the development of basic flu research.
Viruses need to enter the cells of host organisms in order to make copies of themselves, which they do by hijacking the cell’s own machinery for replication. The virus must first bind to a receptor on the surface of the cell and enter it.
Sir John analysed the events in this process; studying the structure of the virus proteins involved in binding of the virus particles to the outer surface of human cells that they are infecting. Once bound to the cell surface, a virus is drawn into the cell into membrane-bound compartments called endosomes. Sir John and collaborators revealed the chemical changes within the endosomes and how the genetic material of the virus is released.
Fusing ideas
From the late 1970s, Sir John collaborated with Professor Don Wiley at Harvard University, a partnership that continued until Professor Wiley’s death in 2001. Together they uncovered the mechanism of membrane fusion by haemagglutinin – the protein on the outside of the virus that mediates the binding and the fusion of the virus with the compartments inside cells. In 1981, they described the structure of haemagglutinin2. The work indicated how the structure of haemagglutinin varies between epidemic flu strains.
In 1982, Sir John showed that a low pH triggers a structural change in haemagglutinin, and that this leads to the fusion of the flu virus with the membranes inside cells3. He also elucidated the conformation of haemagglutinin, after fusion, and the molecular mechanisms that result in the injection into the cell of the virus’s genetic information.
International partners
The widespread occurrence and continued spread of a highly dangerous bird flu virus (H5N1) in poultry in south-east Asia since 2003 has increased concern that this could provide the basis for the emergence of a new human flu virus with the potential to cause a pandemic. It has been almost 40 years since the last pandemic took place. Sir Liam Donaldson, the Government’s Chief Medical Officer, said in 2002: “Most experts believe that it is not a question of whether there will be another severe influenza pandemic, but when.”
In the late 1990s, Sir John and Dr Alan Hay, the current Head of NIMR’s WIC, began collaborating with flu researchers in the US, Hong Kong and The Netherlands to study the epidemiology of H5N1 in Southern China. In 2005, the MRC sent a group of scientists to south-east Asia with an aim to encourage collaboration and gather information about the surveillance of bird flu in China. Following this mission, the MRC made additional funding of up to £15 million available for high quality research proposals that aim to strengthen preparedness for, and the response to the challenges of, potentially pandemic flu. To date, we have committed £7.5m of this for 17 awards.
Meanwhile, a landmark paper, led by Sir John, showed that the haemagglutinin of the 1918 human pandemic flu virus bound to human cells, even though the virus binding sites were characteristic of bird flu4. This suggests one way in which the 1918 virus was able to adapt to and spread in the human population, giving rise to a pandemic. NIMR scientists, collaborating with researchers in Japan, identified the structural changes in the virus that have allowed some strains to spread from poultry to people4.
Taking the immune system by storm
MRC scientists, led by Professor Tracy Hussell at Imperial College London, are working on a novel way of combating the disease – the immune response to flu infection – following the onset of symptoms5. They identified that death and disease due to infection is partly caused by a rush of immune cells into the lungs, which blocks air spaces and reduces the amount of oxygen. The new therapies decrease the amount of inflammation and so diminish this response. The work has led to the formation of a company, StormBio Inc, which, together with the team at Imperial College, is conducting trials in non-human primates.
Disease Modelling
MRC researcher Professor Neil Ferguson and colleagues, at Imperial College London, are modelling the spread of a potential flu pandemic by using a powerful supercomputer. He has demonstrated that it would be important, during a pandemic, to diagnose clinical cases and quickly distribute antiviral drugs. Professor Ferguson showed that during the early stage of a pandemic in south-east Asia, elimination is possible by restricting travel and closing schools and workplaces, by having a stockpile of 3 million courses of antiviral drugs and in being able to detect a new pandemic when fewer than 50 cases have accumulated6.
In further work, the researchers looked at what measures could be used to reduce the impact of a pandemic in developed countries such as the US and UK. According to the research, a pandemic in the UK will peak within two to three months of the first case, and be over within four months. Therefore being prepared and responding quickly is essential. Also, a combination of measures could reduce illness rates by up to 70 per cent and potentially save many lives7. However, a substantial stockpile of antiviral drugs may be necessary to achieve such reductions – enough to treat half the population.
Professor Ferguson is applying his model to other countries and is developing a single global simulator. His team has also been studying US data from the 1918 pandemic. Using models of the transmission and historical data on public health measures, the researchers have shown that the differences in when cities started and stopped public health controls explains variation in death rates8. As many of the measures used then – such as closing schools and banning mass gatherings – are being considered again today, the conclusions of this analysis are highly relevant.
Scientists like Professors Ferguson and Sir John Skehel are advising the UK Government and the WHO on how to prepare for a pandemic. Given how fast influenza epidemics spread, it is critical that the best scientific evidence, including the best understanding of the biology of flu viruses, is used to inform public policy.
Swine flu
Swine flu is a respiratory disease caused by the influenza A virus, which affects pigs, and does not usually infect humans. However, the 2009 outbreak of swine flu, caused by the H1N1 strain, can be passed through human to human contact. It combines a previously unseen assortment of genetic material from human, swine and bird flu, with two new pig H3N2 virus genes from Eurasia.
A vaccine for the Influenza A H1N1 virus will be produced by growing the vaccine viruses in either eggs or cells. The WHO Collaborating Centre for Research and Reference into Influenza in Atlanta has identified and prepared candidate vaccine strains of the Influenza A H1N1 virus. These have been sent to other WHO Collaborating Centres, including NIMR, which have also started the preparation of vaccine candidate viruses. Once developed, these strains will be distributed to vaccine manufacturers and the first doses of a vaccine could be available in five to six months following identification of the virus.
Click here for Q&A about influenza A (H1N1)
References
1. Wilson et al. (1933). A virus obtained from influenza patients. Lancet, 1, 66.
2. Waterfield et al. (1981). Disulphide bonds of haemagglutinin of Asian influenza virus. Nature, 289, 422.
3. Skehel et al. (1982). Changes in the conformation of influenza virus hemagglutinin at the pH optimum of virus-mediated membrane fusion. PNAS, 79, 968.
4. Gamblin et al. (2004). The structure and receptor binding properties of the 1918 influenza hemagglutinin. Science, 303, 1838.
5. Yamada et al. (2006). Haemagglutinin mutations responsible for the binding of H5N1 influenza A viruses to human-type receptors. Nature, 444, 378.
6. Ferguson et al. (2005). Strategies for containing an emerging influenza pandemic in Southeast Asia, Nature, 437, 209
7. Ferguson et al. (2006). Strategies for mitigating an influenza pandemic. Nature, 442, 448.
8. Bootsma & Ferguson (2007). The effect of public health measures on the 1918 influenza pandemic in US cities. PNAS, 10.1073/pnas.0611071104 (published online).
MRC, April 2000, updated May 2009’