This time 100 years ago the Spanish flu pandemic was at its peak. It resulted in 50-100 million fatalities, making it the most deadly flu pandemic in recent history.
The MRC’s National Institute for Medical Research (MRC NIMR), which became part of the Crick in 2015, has a long history with flu research, having been the first to propagate the virus in 1933 (see timeline below). Here, we speak to Crick researchers building on that legacy today. By investigating some of the most challenging questions in flu research, they are helping to prevent a pandemic on the same scale as Spanish flu.
This is the principal question that the Worldwide Influenza Centre (WIC) here at the Crick aims to answer. The centre is part of the WHO’s Global Influenza Surveillance and Response system, designed to monitor flu strains and inform vaccination development. This vast network is made up of six main centres and more than 150 laboratories and institutions in 114 countries.
Directed by John McCauley, the WIC is the WHO’s reference centre for Europe, with other centres located in Australia, China, Japan and two in the United States.
Hemagglutinin (HA) is the protein on the surface of the virus.Image: Donald Benton
Since the flu virus is constantly evolving, a different strain circulates each season. The hemagglutinin (HA) protein on the surface of the virus is the part primarily involved in mutation and disguises the virus from the body’s immune system.
The team receives samples of flu viruses from infected patients across Europe, North Africa, the Middle East and the Far East. They compare the samples with a bank of antibodies that recognises previous viruses and flags up new ones. From this, they can predict which strains will become dominant and subsequently recommend the composition for the season’s vaccine.
Saira Hussain, a postdoc within the WIC, says: “From the samples we receive, we predict what we think will prevail based on what is circulating now. But, of course, this is only a prediction.”
Prediction is necessary because it takes four to six months to develop and produce the 1-2 billion doses of vaccine required for each season. The decision for next year’s seasonal flu vaccine will be taken during February and March, for example.
By looking at the stage of evolution of virus samples, the WIC also predicts whether a virus will develop the ability to transmit between humans - the crucial factor for pandemics. On receiving a potentially pandemic strain, the WIC advise the WHO on its properties and the risk the virus might pose to humans.
However, predicting a flu pandemic is even trickier than predicting the annual circulating strains of the virus, says Saira: “Anticipating pandemics is difficult because surveillance is difficult - the flu virus could come up anywhere. Domestic animals, such as livestock, are closely monitored not only due to their ease of accessibility, but because of their commercial and economic value as well.
However, monitoring all animal populations across the world is impossible. The flu virus has even been found in seals.”
Although the most widespread and fatal, Spanish flu was not the last pandemic to affect the human population. Four notable pandemics have occurred since, most recently Swine flu of 2009-2010, belonging to the same subtype as Spanish flu: H1N1. With improved global surveillance, we know that H1N1 is a common virus in pigs and that the Swine flu pandemic was caused by direct transmission from pigs to humans.
Research in Andreas Wack’s lab is looking for answers to this question. Counterintuitively, they have found that people with severe flu symptoms have stronger immune responses to the virus than those who suffer only mildly. This means factors within the host (the person infected) have a greater influence on the severity of flu, than the virulence of the virus.
By using mouse models to control conditions, researchers have been able to focus on the host's immune response to determine its impact on flu symptoms. Upon entering the host, the flu virus infects lung tissue and subsequently, lung tissue is targeted by the immune system.
However, the immune response is not always very specific when attacking the flu virus and also damages lung tissue. Therefore, the stronger the immune response, the more damage to the lungs. Another effect of the tissue damage is that it leaves the lungs vulnerable to bacterial infection.
During the Spanish flu pandemic, the majority of victims were soldiers, living and being treated in close proximity. Recent autopsies have shown that more than 90% of these flu fatalities also had a bacterial infection, says Andreas. Currently, from the 3–5 million cases of severe flu every year, there are up to 650,000 deaths.
Ultimately, Andreas admits: “Flu is a fact of life that is unlikely to ever go away. I certainly won’t be giving up on my research anytime soon.” Though we probably have not seen the last flu pandemic in the human population, there is reason to be optimistic. Flu prevention has made significant steps forward since the 1918 Spanish Influenza and research at the Crick continues to build on this.
As someone who works day-to-day on seasonal vaccine composition, a universal vaccine for the flu virus would be “the holy grail”, says Saira. Ideally, this would replace the current annual process of predicting the dominant flu virus strain with one single vaccine.
The theory behind this relates to a recent study by postdoc Donald Benton, in Steve Gamblin’s lab. Researchers have been looking specifically at HA - the primary part of the virus that varies the most. HA is the part that binds to host cell receptors and allows the release of the genetic material to cause infection.
Donald and his colleagues have provided new insights into the structure of HA. Until recently, only the structure of the part lying outside the virus was known. Using cryo-electron microscopy, the researchers have shown the full structure of HA, revealing the part inside the virus not involved in year on year variation. This differs to the part outside the virus, which evolves as it circulates in the human population.
If a vaccine could generate antibodies that bind further down, in the part that varies much less, it would not have to be updated to catch up with the circulating strain of the virus so frequently.
However, there are more questions to answer before a universal vaccine is realistic. Scientists currently view it as a long-term endeavour that requires much more research.
The difficulties surrounding flu prevention are not a reason to be pessimistic, says Andreas: “Our surveillance of the flu virus is the best it has ever been and we are more protected from flu than ever before,” he says. “The immense global infrastructure in place is often underestimated.”
While a universal vaccine remains the best option for preventing a pandemic, improving the accuracy of strain prediction will help improve the effectiveness of seasonal vaccines.
The WHO is working on implementing a digital bank of antibodies, based on virus evolution data, to operate alongside traditional sample surveillance to improve strain prediction.
In terms of new therapies, research from Andreas Wack’s lab is pointing towards harnessing our own immune systems to fight off flu. This ‘host-directed therapy’ would attempt to replicate the ‘perfect’ immune response to flu by giving people interferons, which switch on genes with direct antiviral function.
Yet, as with the universal vaccine, there are a number of obstacles to implementing host-directed therapies. Ideally, this treatment would be given to patients prior to infection, but exactly when someone will get the flu virus cannot be known. And since patients only have flu for a relatively short period, recruiting participants to trial treatments is tricky.
