Influenza: Reports of my death have been greatly exaggerated
As we move towards the seasonal ‘Flu’ time of year, there have been several reports relating to our struggle to combat influenza (or Flu). Every year, new strains of Flu pop up in the population – this is due to the amazing and fascinating evolutionary biology of Flu. We are not the only natural host of the Influenza virus – it is what we refer to as a Zoonotic infection and circulates in a range of wild and domestic species such as chickens, waterfowl and pigs (We call these ‘reservoirs’). It is this ability to move between different hosts that causes influenza viruses to evolve rapidly, picking up small changes called mutations that can aid their survival in new hosts. Coupled with this, influenza has segmented genome. Each of the eight segments of the genome encodes a separate protein (or two), and each segment is required for the virus to grow and reproduce itself. However, influenza can swap these segments with other strains of influenza quite readily. Interestingly, it is when strains of influenza are moving between reservoirs that they can acquire extra rapid ‘shifts’ in evolution. It is also possible for two strains to co-infect the same host simultaneously and swap entire genome segments – potentially gaining large evolutionary advances. It is these jumps that result in the emergence of new influenza strains. Two genome segments that are particularly important in influenza infection are those that encode the major surface proteins of the virus (Haemaglutanin [HA] and neuraminidase) and these regularly change to help influenza hide from the host immune system. It is these processes which often work in tandem that result in the new strains of Flu each season.
Recently, reports emerged of a potential universal Flu vaccine based on two articles – one in Science Magazine and one in Nature Medicine. These are both fascinating studies based on the development of vaccines that target the most consistent portion of the HA protein. HA proteins resemble a lollypop, where the head of the lollypop is constantly changing its flavour to outwit the host immune system, however the stick of the lollypop is always present and the structure is constant. It is the ‘lollypop stick’ that both these studies chose to target. The idea behind this work is that by targeting and encouraging the body to raise antibodies against the most consistent portion of the HA protein, the new vaccines should be more ‘universal’ and be less vulnerable to rapid influenza evolution. This would stop the need for a new vaccine each year. Whilst both of these studies show great promise in generating protective antibodies in mouse and ferret (a good model for respiratory infections), neither have been tested in clinical trials in humans yet, although the results are encouraging.
Another recent report has suggested that flu vaccines may be a thing of the past anyway, as researchers reported that over producing a component of the human immune system, IFITM3, a type of Interferon, limits the severity and duration of influenza infections. The authors showed that by manipulating another cellular protein (E3 ubiquitin ligase), it was possible to increase levels of IFITM3 consistently in cells, resulting in greater influenza resistance. This work is still at a very early stage and, whilst it has currently only been shown to be effective in cultured cells of mouse and humans, there is great potential for this kind of therapy to remove the need for flu vaccines, especially given that we need to generate new influenza vaccines each year. The authors suggest that this approach works best prior to infections, so would require the future development of drugs to manipulate E3 ubiquitin ligase activity in cells, so that IFITM3 is always over produced. One caveat to this work is that the consequences of constant suppression of E3 ubiquitin ligase is unknown, as are the long term effects of over producing IFITM3, so much more work is required, but this kind of therapy may have broad consequences for treatment of all viral infections.
Another recent report on influenza has also highlighted the role of IFITM3 and suggests that this gene in humans may have the potential to act as a genetic marker for influenza risk – with certain members of the population (about 1 in 400) containing a variant of the gene that increases their risk from influenza infection. Currently, those in the population that are most at risk from influenza infection are targeted for vaccination, such as people over 65, pregnant women, and those with underlying health problems, such as asthma. The discovery that IFITM3 has these variations may aid the identification of members of the population that are at risk from the virus and adds to our armoury, allowing better targeting of medication to specific groups within society (So called ‘stratified medicines’). Ultimately, this type of research will help reduce serious illness and make cost savings in terms of vaccine administration.
In conclusion, as we enter the winter flu season, there are promising news in terms of how we cope with this important disease. Alas, all these findings are a long way from transforming our medical care. As they say with any new drugs and potential new therapies, it’s a long road to the clinic.
Impagliazzo, A. et al. (2015). A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen. Science. DOI: 10.1126/science.aac7263
Yassine, H. M. et al. (2015). Hemagglutinin-stem nanoparticles generate heterosubtypic influenza protection. Nature Medicine. DOI: 10.1038/nm.3927
Chesarino, N. M. et al. (2015). E3 Ubiquitin Ligase NEDD4 Promotes Influenza Virus Infection by Decreasing Levels of the Antiviral Protein IFITM3. PLOS Pathogens. DOI: 10.1371/journal.ppat.1005095