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The search for a life-long flu vaccine

Each year, everyone needs to get an influenza vaccine. A vaccine from a previous year won’t protect you. This is because there are three strains of the virus – A, B and C – that cause seasonal influenza and they change each year.

But the annual vaccine may soon be relegated to the past thanks to a “paradigm shifting” discovery by University of Melbourne Professor Katherine Kedzierska and her team.

Working with Fudan University in China, the team studied the immune responses of patients to the first outbreak of the avian-derived influenza A virus subtype H7N9 (bird flu) in China in 2013. Infection with this strain of flu hospitalised more than 90 per cent of infected people and 35 per cent of them died.

The research found that those patients who recovered within two to three weeks had robust killer T cell responses, whereas those who died had few ‘killer’ cells.

“Our next step was to discover how the killer T cells worked, and if we could mimic this in a flu vaccine,” says Professor Kedzierska.

The team analysed which parts of the flu virus were common in strains A, B and C in order to find out which would be the best target for a universal vaccine.

When infected, our cells recognise only parts of the virus that are displayed in an HLA molecule, alerting the immune system that an infection is present.

This HLA and viral peptide combination act as a passport or a unique identifier, known as an epitope. ‘Killer’ cells recognise it, triggering them to kill off the infected cell. The researchers therefore focused on which epitopes were common among all three flu strains.

“We started with 67,000 viral sequences to look for epitopes common among all the flu viruses,” explains University of Melbourne postdoctoral researcher Dr Marios Koutsakos from Professor Kedzierska’s group.

“These tens of thousands were eventually narrowed down to three epitopes that were cross-reactive, that is they are common to all flu viruses.

“We identified the parts of the virus that are shared across all flu strains, and sub-strains capable of infecting humans.”

To achieve this, Dr Koutsakos worked with Professor Anthony Purcell’s lab at Monash Biomedicine Discovery Institute using the analytical technique of mass spectrometry.

Having established which sections of the virus were conserved or cross-reactive, they then conducted tests to see if those viral parts did produce a robust immune response.

These flu virus epitopes were found in blood samples taken from healthy humans, and influenza-infected adults and children. The research team next conducted vaccination tests on mice by using the peptides responsible for activating the killer cells as a form of vaccination.

“Our vaccination test studies revealed remarkably reduced levels of flu virus and inflammation in the airways in animal models,” Dr Koutsakos says.

“These results show that killer T cells provide unprecedented immunity across all flu viruses, a key component of a potential universal vaccine.”

These killer T cells are found in over half the world’s population.

Professor Kedzierska’s group is now researching immunity for high-risk ethnic groups such as Indigenous Australians and Indigenous Alaskans who might not share the same immune response as those investigated by this project.

These people may be protected by a revolutionary approach that involves boosting a person’s killer cell armoury with peptides that recognise all viruses.

Professor Kedzierska says that now this groundwork has been done, the team can apply similar technologies and approaches to those high-risk populations that flu has a huge impact on – offering protection to everyone.

Meanwhile, in 2017, University of Melbourne Dr Linda Wakim and her team discovered a population of influenza-fighting T cells in the nasal tissue, which showed they could protect against influenza virus.

“We now have a vaccine candidate in the pipeline providing broad spectrum protection against the flu by generating these cells along the respiratory tract,” says Dr Wakim.

Professor Stephen Kent and his team have two vaccine strategies they’re working on against the flu.

“We’re trying to identify antibodies to conserved regions of the flu virus that might enable protection from multiple isolates,” explains Professor Kent.

“And we’re also trying to understand how B and T cells co-operate to determine which parts of the influenza virus are the main target of the immune system, and how we might be able to change that focus to areas that are more protective.”

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