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Outfoxing the flu

With this year’s flu season over, most of us can breathe a sigh of relief. But taming a virus as notorious and unpredictable as influenza requires year-round research efforts. Carmen Chai looks back at how far we’ve come since the deadly 1918 outbreak of Spanish Flu, and what lies ahead.

Virus particles of the H3N2 subtype of influenza, known as the Hong Kong Flu virus.
Image credit: CDC/Science Photo Library

It’s been labelled as one of the greatest pandemics in history. 100 years ago, the 1918 influenza virus, more commonly known as the Spanish Flu, brought the international medical community to its knees.

About one in three people were infected, with estimates suggesting between 50 and 100 million people died – roughly 5% of the world’s population.

Other flu pandemics have taken hold, most recently in 2009. But the Spanish Flu’s notoriety still lingers within the scientific community.

“The reason why we remember 1918 more than others, is because it was so severe in humans. It is the deadliest influenza we’ve dealt with,” says Professor Steven Riley, Professor of Infectious Disease Dynamics at the MRC Centre for Outbreak Analysis and Modelling.

Falling numbers

Virus inoculation of an egg at the NIMR World Influenza Centre in the 1970s. Hen eggs are still used to culture viruses for research.

Compare the Spanish Flu’s fatality rate to that of 2009’s H1N1. This strain killed about 1 in 10,000 infected patients. That’s 100 times less deadly than the 1918 strain, according to Steven.

The changes in both rates and absolute numbers are not solely due to changes in the virus, but in how we’ve been able to deal with the flu.

“There’s a striking difference between the Spanish Flu and subsequent pandemics. There was virtually no intervention for any infectious agent at the time,” says Professor John McCauley, Director of the Worldwide Influenza Centre at the Francis Crick Institute. John is a leading global expert in influenza, with decades of experience researching influenza viruses.

Taming the beast

A century later, the flu research landscape has changed dramatically thanks to major milestones – some with the MRC at the helm.

One of the first major discoveries occurred in 1933 when scientists at the MRC National Institute for Medical Research (NIMR) at Mill Hill* successfully propagated the influenza virus by passing the virus from humans to ferrets, and then between infected and naïve ferrets.

Propagating the virus paved the way to studying it and finding ways to treat it. Eventually scientists found the virus could be grown in hen eggs and tissue culture. This, ultimately, provided the foundation for the dawn of mass vaccination.

To this day, the ferret remains the benchmark model for studying influenza infection.

From classification to vaccination

Ferrets sneeze in the same way as humans when infected by a flu virus.

Now that scientists could grow and study the virus, MRC funding helped to understand the battle between the body and the virus.

As we now know, there are numerous different strains of the flu. But it all started with the realisation, in the 1940s, that there were two different groups of the virus, known as A and B. Serotyping allowed researchers to classify viruses and, eventually, find a way to beat them through vaccination.

The first flu vaccine approved for use in 1945 had not one but two different types of virus – inactivated influenza A and B. Its testing was successful and after World War II was over, the vaccine was administered to civilians.

Boosting our body’s defences

MRC-funded researchers continued on to study how our bodies fight the virus. And in the 1950s, back at the NIMR, they discovered one of the body’s defences against the virus: the family of proteins known as interferons, coined for their ability to interfere with viruses. They are antiviral substances released in response to the presence of viruses, bacteria, parasites or tumour cells, preventing a worsening infection.

John calls the discovery of interferons a ‘pivotal step’ in understanding how the body responds to virus infection.

With an understanding of how the body fights – and sometimes loses to – the virus, MRC researchers were learning how to boost the immune system to fight off infection.

The birth of global flu surveillance

In 1947, the influenza laboratory of the NIMR became the World Influenza Centre of the World Health Organization. There are now 144 National Influenza Centres in 114 countries that comprise the WHO Global Influenza Surveillance and Response System. Centres collect virus specimens, perform analyses and conduct risk assessments, sharing their data with partner institutions.

By the 1980s, scientists working on influenza began sequencing the genes of the viruses. Now ever more crucial to flu research, this allows researchers to compare circulating influenza viruses with older ones and to help identify new viruses that are likely to be predominant in the next flu season.

A moving target

Scientists at the NIMR World Influenza Centre testing for different strains of flu (using their mouths to draw samples into pipettes), 1960s.

We’ve made major strides in understanding and taming the flu. But flu vaccine production is a major concern.

“We have existing technologies to make strain-specific vaccines, we just can’t make them very quickly,” Steven says. A flu pandemic can travel around the world in less than 12 months, but it takes about four to six months for the current flu vaccine to be rolled out for use.

Because influenza viruses constantly change and mutate, vaccine composition is updated twice each year – once each for the flu season of the Northern and Southern Hemisphere. Currently, WHO experts choose which strains to include based on what’s circulating at the time and what’s likely to be dominant over the subsequent months.

While this method is effective, it’s not perfect and has led to mismatches. And Professor Sarah Gilbert, a professor of vaccinology at Oxford University, thinks we can do better.

Building a universal flu vaccine

With MRC funding, Sarah is developing a universal flu vaccine, to protect against all influenza A viruses.

Currently, the flu vaccine builds antibody response to the virus in the seasonal vaccine. When the virus changes its appearance, the antibodies may not be as effective in the following year.

The universal option would shift the response from antibodies to a different regiment of our immune defence forces – T-cells. T-cells can identify and combat against more than one type of influenza virus. They focus on the virus’ internal proteins, which are common for large numbers of strains.

“With a universal flu vaccine, you don’t have to worry about predictions, mismatches, stockpiling or production. If everybody in the world was vaccinated with an effective universal flu vaccine, there would be no more pandemics,” Sarah says.

It would be a new frontier for scientists on the lookout for the next pandemic.

“We’ve never had a vaccine soon enough to interfere with a pandemic strain. We’ve never seen the strain that caused the pandemic until it was a pandemic,” she explains.

Covering all bases

From John’s vantage point at the Crick, influenza’s unpredictability is its only certain feature. But that’s what captivates researchers, according to Steven.

“It’s absolutely fascinating science. There are very few pathogens that continuously circulate through the human population from one corner of the world to the other, constantly change, get refreshed from an animal reservoir every so often, then re-infect us.

“There are so many different angles to study, from individual proteins, through to cells, tissues, individuals, to towns, countries, regions around the globe – there are active questions being pursued at every single level.”

*The MRC National Institute for Medical Research and Cancer Research UK’s London Research Institute became part of the Francis Crick Institute on 1 April 2015.

From the archive

Find out more about the role played by ferrets in flu research. 

Read about mouth pipetting, a commonly-used technique in the 60s and 70s.

This article was updated on 23 May to add the word ‘effective’ into the first line of Sarah’s quote about the universal flu vaccine.

2 Comments Post a comment
  1. norman duncan #

    Should we fighting AD be hopeful for a vaccination that counters early onset?

    June 6, 2018

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