IFNβ in Influenza

Pandemic flu – a continuing threat

In the spring of 2009, a novel H1N1 influenza of swine origin (‘Swine flu’) caused human infection and acute respiratory illness in Mexico and began to spread around the world resulting in the first pandemic since 1968. By March 2009, the World Health Organisation (WHO) stated that almost all countries had reported cases. While many have died (440 in the UK, 77% of whom had underlying risk factors1) and even more have been infected, a global mass mortality scenario, last seen during the 1918 flu pandemic when an estimated 50 million people died, or 3% of the world’s population, failed to materialise. This was due to a combination of fortuitous circumstance and forward planning driven by concerns over outbreaks of highly pathogenic ‘Bird flu’ strains over recent years. If the virus had been more pathogenic and less responsive to current antiviral drugs, the picture might have looked very different.

There remains a clear unmet medical need for new treatments to bridge the gap between the outbreak of a novel strain of influenza and the development of a vaccine in conjunction with the implementation of mass vaccination programmes should the worse case scenario arise.

Seasonal flu kills thousands of people each year

In a study conducted in the 1990s, the American government agency CDC (Centers for Disease Control) estimated that deaths from seasonal flu in the US ranged from 17,000 during the mildest season to 52,000 during the most severe season (36,000 average)2. This was despite vaccination programmes targeting ‘at risk’ populations. By comparison, it is estimated that the 2009 H1N1 pandemic resulted in 12,000 flu-related deaths in the US. One of the reasons that the effects of seasonal flu go unreported is the age group which is affected. Most seasonal flu deaths occur in the over 65 year olds. By contrast, nearly 90 per cent of deaths due to Swine flu occurred among people younger than 65 years of age. Therefore, pandemic flu aside, there remains a need to develop more effective therapies to reduce morbidity and mortality associated with seasonal flu. An added driver is the fact that many of the current circulating H1N1 strains of seasonal flu are resistant to Tamiflu, the neuraminidase inhibitor3.

IFN-β – a new therapeutic approach against influenza

There is now strong evidence that the increased risk of flu is highly dependent on the level of immunity of a population and individuals within it4. As far as the immunological defence mechanisms against H1N1 or any other strain of influenza virus are concerned, the early induction of primary interferons such as IFN-β is crucial as the first line of defence5. Synairgen has therefore investigated the utility of IFN-β against influenza.

IFN-β protects human lung epithelial cells from infection with pandemic swine flu (H1N1 2009)

Working with the Health Protection Agency at Porton Down, we showed that our IFN-β formulation was very effective at protecting cells from Swine flu infection.

Similar data has been obtained to show that IFN-β protects cells from infection with seasonal influenza.

Post-infection treatment with IFN-β inhibits influenza re-infection

Synairgen has successfully developed a novel influenza ‘re-infection’ model. In this model a small amount of virus is initially introduced to lung cell cultures and over the following days an increasing number of cells become infected. This in vitro model is intended to replicate the spread of viruses from the upper (nose and throat) to the lower (lungs) respiratory tract and therefore has the potential to predict the impact of therapeutic intervention.

Re-infection model showing a gradual increase in infection over time.

Having developed the in vitro re-infection model, we demonstrated that IFN-β was able to alter the course of flu infection even when given two days into the infection. These data suggest the potential to treat even once the virus has taken hold in the lungs.

This opened up a third novel indication for Synairgen’s IFN-β programme: the use of inhaled IFN-β for patients with severe lung illness, the major complication associated with flu infection, triggered by an initial influenza-like illness. A patent has been filed and this discovery was presented at the American Thoracic Society meeting in May 2010.

 

References

  1. McLean E et al. Pandemic influenza A (H1N1) 2009 and mortality in the United Kingdon: Risk factors for death, April 2009 to March 2010. Eurosurveillance. 2010 May 20;15(20).
  2. Thompson WW et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 2003;289(2):179-186.
  3. Janies DA et al. Selection for resistance to oseltamavir in seasonal and pandemic H1N1 influenza and widespread co-circulation of the lineages. Int J Health Geogr. 2010 Feb 24;9:13.
  4. Mathews JD et al. Prior immunity helps to explain wave-like behaviour of pandemic influenza in 1918-19. BMC Infect Dis. 2010 May 25;10:128.
  5. Osterlund P et al. Pandemic H1N1 2009 influenza A virus induces weak cytokine responses in human macrophages and dendritic cells and is highly sensitive to the antiviral actions of interferons. J Virol. 2010 Feb;84(3):1414-22.