University of Cambridge’s Prof Jonathan Heeney answers call from Bill Gates to transform flu vaccine

A Cambridge professor has been awarded funding from the Bill and Melinda Gates Foundation and the charity Flu Lab to help tackle the threat of a global influenza pandemic.

Prof Jonathan Heeney, head of the Laboratory of Viral Zoonotics at the University of Cambridge, is one of seven recipients so far of a $12million fund designed to make progress towards a game-changing universal influenza vaccine.

Speaking to the Cambridge Independent from Singapore, where the funding was announced at the Options X for the Control of Influenza conference, Prof Heeney said his lab aimed to create a new vaccine candidate ready for human trials within two years.

He will apply next generation sequencing and computational techniques that have proved fruitful in developing a new hemorrhagic fever vaccine to tackle the scourge of Ebola, Marburg and Lassa fever, which is due to be tested next year.

With predictions that a flu pandemic, like the one that struck in 1918, could kill 33 million people globally in just six months, the stakes could hardly be higher.

“Part of the problem is that the technology for flu vaccines is very old and they work very poorly,” said Prof Heeney. “Seasonal flu vaccine efficacy at best is maybe 50-60 per cent.

“Depending on the season, it may be as low as 10 per cent – which means one in 10 people who get vaccinated would be protected from that particular flu strain.”

He cited the recent example of the H3N2 strain, which earned the nickname ‘Aussie flu’ because it badly affected Australia, where more than 230,000 cases of influenza were confirmed in 2017.

“It caused a significant number of clinical cases and hospital ward shutdowns,” said Prof Heeney. “It’s a major problem for organisations like the NHS but also globally.

“The other big concern and one of the drivers of the donation [from the Bill and Melinda Gates Foundation and Flu Lab] is concern about pandemic flu, which is when a new flu strain emerges, and that happens randomly. It’s very difficult to predict, but we can observe it using new sequencing technologies.

“When it does, it races through populations and causes higher mortality than expected.

“So there’s a big motivation not only to improve seasonal flu vaccines but to get vaccines out there that would stop a human pandemic and create loss of life.”

Like other vaccines, the flu jab works by stimulating the body’s immune system to make antibodies to fight the virus.

It is trivalent or quadrivalent – meaning it offers protection against three or four strains.

These are determined by the World Health Organization following meetings with experts every February and September looking ahead to the next flu season.

Candidate vaccine viruses are then grown in eggs and provided to private sector manufacturers.

They inject these into fertilised chicken eggs, which are incubated for several days so that the virus replicates. Fluid containing the virus is then harvested from the eggs. The viruses are then inactivated and the virus antigen purified to make the flu shot.

For the nasal spray, another production process is required using weakened viruses.

The use of eggs to grow the virus stretches back decades.

But Prof Heeney warned: “That process has problems – you have to adapt the virus to eggs. It doesn’t always grow well in eggs and when the virus gets adapted, it changes.

“There are new technologies that are being tried and some seem to be incrementally better.

“But what was needed was a whole new look at how we might address this huge problem.”

Prof Heeney’s lab, part of the Department of Veterinary Medicine at Cambridge, has been working on a vaccine to tackle hemorrhagic fever – a group of highly contagious viruses – and a spin-out company, DiosVax has been formed.

A £2million Innovate UK and Department of Health and Social Care grant was awarded to take the work into human clinical trials, as reported last September.

The researchers are using deep sequencing, a vaccine design process enhanced by artificial intelligence and bioinformatic algorithms, and synthetic gene technology.

“We went back to the drawing board and took a new approach that changes how vaccines are made,” explained Prof Heeney.

“We do that using new technologies like next generation sequencing.

“Nearly all outbreaks of disease these days get sequenced and that allows us to follow how these pathogens are changing over time.

“Computer scientists have become very good at looking at the sequences of pathogens so we can predict the structures that are constant and that the virus cannot change, compared to the parts that do change and mutate. It’s all about finding the Achilles heel for these viruses.

“By doing this we can then bring in another new technology in addition to the computational or what we call digital sequencing technology, and that’s synthetic gene biology.

“We are actually able to synthesise these genes so we don’t have to isolate viruses or grow them in the lab, or work in high containment. We don’t have to worry about egg adaptation.

“We synthesise these genes in a way that we can evaluate them and see if they are really good antigens.”

The implications of this approach are potentially huge.

“It’s a game-changer in that we don’t use any of the old technologies,” said Prof Heeney. “We can move really rapidly into designing new vaccines for new pathogens – not just new flu strains, but other pathogens.”

Despite the presence of an Ebola vaccine, the disease represents an ongoing emergency.

The 2014-16 Ebola outbreak across West Africa infected 28,652 people and killed 11,325, according to the US Centers for Disease Control and Prevention, and about 2,000 people have died in the Democratic Republic of Congo since last August in what is the second worst outbreak in history.

“Currently, there is one vaccine out there being used to try to contain the Ebola epidemic,” said Prof Heeney. “This is based on one of five different viruses that can cause Ebola disease but it doesn’t protect against the other four.

The current outbreak in DRC features a virus that is very different to the one that affected Bundibugyo in Uganda in 2007-08, for example.

“The problem is these different viruses pop up all the time,” added Prof Heeney. “We were able to take all the different sequences from all these types of Ebola viruses and make a vaccine that would protect each and every one of them, wrapped up in one trivalent preparation.

“It’s like MMR – measles, mumps and rubella – it’s a new vaccine that would work across sub-Saharan Africa and protect against Ebola and its cousins, Mahlberg and Lassa fever.

“That is being scaled up for human clinical trials, which we hope to perform next year.”

The success in developing this vaccine – a truly remarkable achievement if it passes through trials – provides new hope for better protection against influenza, which claims the life of between 290,000 and 650,000 people die each year.

“It’s about understanding what differentiates a bad immune response that may cause a disease to be more severe versus an immune response that would protect you.

“By knowing the difference between good and bad immune responses, and where they attack the virus, we can design our vaccines.

“That’s what we’ve done with the trivalent hemorrhagic fever vaccine and that’s what Bill Gates is asking us to do for the universal flu vaccine,” said Prof Heeney.

“What we would do is make a trivalent or quadrivalent vaccine using this technology. We don’t have to work with the live viruses. We just need to understand the immune responses and the sequences and we’re able to come up with computational designs. We never touch an egg in the process.”

While talk of a ‘universal’ vaccine is rather ambitious, there is genuine hope of developing more potent shots with greater longevity.

“There are many types of flu out there but given that we can put three or four different types of flu, or genes, into one vaccine, it makes it achievable to cover the greatest risk,” suggested Prof Heeney. “Instead of having to update them seasonally, we might only have to do it every four or five years.”

While existing flu vaccines do provide important protection – and reduce the potential of exposure for everyone – they are inevitably less effective in older people, who need it most.

“Sadly, as we age, our immune systems get tired, less energetic and less able to rise to the occasion to fight off a pathogen, so it’s about making better vaccines that stimulate a stronger response in the elderly.

“In the last couple of days here in Singapore, I’ve sat through a lot of lectures about how vaccine companies propose to improve the potency of vaccines we give to the elderly, either by giving them higher doses, or using other immune stimulants that you would put in,” he said.

Adjuvants – ingredients added to a vaccine to generate a stronger immune response – offer hope of improvement in the efficacy of the seasonal flu vaccine.

But Prof Heeney hopes to create an entirely new vaccine in two years.

“It’s a two-year project to come up with a candidate – something that could be upscaled to go into a human clinical trial. That’s going from a standing start, but with our technology, we are able to move faster. We came up with the first hemorrhagic fever vaccine in six months, and we’ve already got studies ongoing. Now we have money coming in, we’ll be able to hire people.”

Bill Gates: Nearly 33 million people could die in six months from flu pandemic

The Bill and Melinda Gates Foundation to announced flu as the subject of one of its Grand Challenges in 2018, a century on from the pandemic that infected 500 million people - a third of the world’s population.

The foundation originally teamed up with Google co-founder Larry Page and his wife Lucy Page, whom the charitable organisation Flu Lab has since replaced on the project.

Announcing the $12million challenge, Bill Gates said: “Worldwide, the 1918 flu killed an estimated 50 million people, perhaps more.

“We have better tools today than we did a century ago. We have a seasonal flu vaccine, although it’s not always effective, you have to get one every year, and most people in the world never get the shot. We also have antibiotics for secondary infections of bacterial pneumonia."

But he said despite these advances, if a “highly contagious and lethal airborne pathogen – like the 1918 flu – were to occur today, nearly 33 million people worldwide would die in just six months”.

He went on: “That’s the sobering news. The good news is that scientific advances and growing interest on the federal level, in the private sector, and among philanthropic funders makes development of a universal flu vaccine more feasible now than 10 or 20 years ago.”

He said the $12million Grand Challenge was designed “to accelerate the development of a universal flu vaccine”.

“The goal is to encourage bold thinking by the world’s best scientists across disciplines, including those new to the field,” he added.

Among the other recipients announced are Yoshihiro Kawaoka, of the Institute of Medical Science at the University of Tokyo, who will use a cocktail of synthetic proteins that amplifies vaccine response by focusing the immune system on conserved influenza virus sequences.

Meanwhile, Patrick Wilson, of the Antibody Biology Lab at the University of Chicago will mine a library of human antibodies to influenza to design a new protein sequence for a novel, potent vaccine that prompts a broader antibody response.

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