Coronavirus particles

The race to develop a coronavirus vaccine

Image credit: Science Photo Library

With the novel coronavirus now a worldwide problem, scientists across the globe are doing all they can to develop a vaccine. Emerging technologies are vital in speeding up this process.

Using the robust, fast-multiplying cells of the fruit fly, Danish scientists are among those racing to create a vaccine against Covid-19. A biotech consortium based near Copenhagen is joining an international mix of start-ups, academics and established drug makers from Israel to Australia using novel techniques to turn around a vaccine in record time.

“It’s a hot topic for sure,” agrees Bent Frandsen, whose company Expres2ion has just received an EU grant to work with scientists from Danish, German and Dutch universities to find a vaccine. His company has been working for a decade with insect cells to create malaria vaccines – before Covid-19 came along.

Rather than the usual 15 to 20 years it takes to produce a safe vaccine, newcomers are attempting a breakneck speed of one to one-and-a-half years in the face of a pandemic that has caught the world off guard. First human trials of early candidates are beginning, and scientists are building on what’s been learned from earlier coronavirus outbreaks such as SARS and MERS.

Vaccines work by exposing the immune system to a small dose of the pathogen, so the body can remember and defend itself against future attack. Vaccination is one of medicine’s greatest success stories, all but eradicating the likes of smallpox and polio and limiting other killers, and today save an estimated 2.5 to 3 million lives a year.

Desperate times call for desperate measures, say scientists. Traditional methods – weakening a live version of the virus until it’s harmless – are safe and highly effective, but take way too long. Using the genetic code of the virus supplied by China in early January, it’s time to test new vaccine technologies that haven’t yet made it to market. Developing numerous candidates simultaneously gives medics the best chance of a successful vaccine in the long run.

‘The latest coronavirus is a miracle of engineering. It’s a trojan horse wrapped up and studded with a ‘spike’ protein that allows it to invade human cells.’

Dr Bharat Pankhania, University of Exeter

“The latest coronavirus is a miracle of engineering,” says Dr Bharat Pankhania, a senior clinical lecturer at the University of Exeter Medical School. “It’s a trojan horse wrapped up and studded with a ‘spike’ protein that allows it to invade human cells – and then the blighters multiply.” If you can get the body to react to the spike protein – safely delivered in a vaccine – it blocks it when the real thing comes along.

Expres2ion and its joint venture AdaptVac works with harmless virus-like particles (VLP), to which it attaches a copy of the protein of SARS-CoV-2 which causes Covid-19. “Think of it like a basketball with tennis balls (the protein antigen) stuck on with a sort of biological superglue,” says Frandsen. This VLP technology – proven to work in preclinical trials in mice – has the benefit of being at the safer end of experimental, he says. If all goes well, the consortium could produce a candidate vaccine to begin human trials in a year.

Just as staff at global vaccine alliance CEPI (Coalition for Epidemic Preparedness Innovations) returned from their Christmas break, news of the outbreak struck. Set up in 2017 in the wake of the Ebola outbreak with a mission to be better prepared for such events, CEPI currently is funding six experimental vaccines in development, including projects with the University of Oxford, and US-based biotechs Moderna – whose vaccine is the first to begin human trials, Novavax and Inovio Pharmaceuticals.  

“The aim is to get them into clinical testing as quickly as possible,” says Dr Melanie Saville, director of vaccine research and development at CEPI. To date the organisation has received just $186m (£154m) of the $2bn (£1.7bn) it’s seeking to invest in a vaccine – with the UK, Norway and Germany all chipping in. “We hope these candidates will be in clinical trials by the middle of the year,” says Saville.

Moderna broke a record to create an experimental vaccine in just 42 days, before preclinical trials on animals were completed. This experimental vaccine, funded by the US National Institutes of Health, is being administered to a small number of healthy adults who’ll receive two doses given a month apart. Inovio Pharmaceuticals plans to begin clinical trials on a vaccine this April.

This is money well spent, says CEPI – the global cost of a severe pandemic is thought to be as high as $570bn (£470bn) – whereas the cost of progressing a vaccine for potential pandemic diseases will cost a minimum $2.8-$3.7bn (£2.3-£3.1bn). “We need access to a vaccine irrespective of who or where we are and whether we can pay,” says Saville. “Our aspiration is to have millions of doses available within 12 to 18 months if everything goes well.”

While that’s too late to help current sufferers, medical experts say a vaccine will be needed well into the future.

No one knows yet whether Covid-19 will disappear – as did SARS, which petered out in the early 2000s – though that’s unlikely, say virologists, because it’s so infectious. It might, like flu, recur and mutate as a seasonal disease. Back in 1918, Spanish flu came around again, with devastating effect, Saville says.

“Traditionally the vaccine process is long and complex,” says Dr Chris Chiu, clinical senior lecturer at the faculty of medicine at Imperial College London, where his colleagues are working on an experimental vaccine.

Vaccine development infographic inline

Image credit: E&T

Because of the emergency, companies may now work in parallel on steps that normally would happen sequentially. That makes sense, given the current emergency, says virology specialist Professor Paul Digard, of the University of Edinburgh’s Roslin Institute. “We’re living in unusual times. In a real emergency it makes sense to do things as fast as possible. There’s a balance between risk and benefit,” he says.

There is no getting around clinical trials: first, with a small number of healthy volunteers to ensure a vaccine is safe. A second phase sees several hundred receive a shot in an area suffering an outbreak over six to eight months. And in the third phase, companies need to recruit thousands to repeat the process in the midst of an outbreak – which can create bottlenecks. “But if everything goes to plan, a year-and-a-half would be feasible,” says Chiu.

Weakened pathogens, or proteins from the surface, are the mainstay of routine vaccination used in MMR, rotavirus and more. “They’re safe and they’re great,” says Digard. Inactivated vaccines, as used for polio, use a killed version of the germ. They’re used in flu, rabies and more, and may require a booster.

Adjuvants – substances that can strengthen the response of a vaccine – might be added, though in some cases they cause side effects. Leading vaccine-maker GSK is giving the CEPI-funded University of Queensland access to its adjuvant platform technology, and has also been collaborating with a Chinese firm in the search for a vaccine candidate.

Much of the science underway at the biotech companies currently seeking a coronavirus vaccine is new and experimental. Maryland-based Moderna’s method uses messenger ribonucleic acid (mRNA) technology. That isn’t yet used in any licensed vaccines, but has huge potential, say pharmaceutical companies.

This mRNA acts as an ‘instruction manual’ for the body’s cells, telling them to make their own dummy bits of virus protein, which the body can learn to attack. The body becomes its own vaccine ‘factory’.

“If read correctly, the body will make exactly the right kinds of proteins it needs to mount an immune defence – no more, no less, at the right time and in the right place,” says senior research scientist Sven Even Borgos at Norwegian-based independent research organisation Sintef.

This vaccine development can be swift, potentially safer and the mRNA doesn’t require large cell culture labs for production, he says, because the cells are making the active protein themselves. Making synthetic mRNA is a demanding process requiring complex purification and synthesis.

Maryland-based biopharmaceutical company Altimmune is busy working on a vaccine that could be delivered as one dose by a nasal spray. Spraying something up your nose is potentially more effective than the one or two jab regime, say its creators, and the first vaccine to market might not ultimately be the most successful.

Altimmune already has an intranasal flu vaccine in development. As soon as news broke of the new coronavirus, the company set about synthesising a vaccine based on its existing platform and is now moving towards animal testing, with an aim to begin human trials in August.

“The simplicity is important,” says Dr Scot Roberts, chief scientific officer at Altimmune. Recent human trials of his company’s flu vaccine showed that this type of intranasal delivery can stimulate a broad immune response, and is well suited for respiratory infections. “An intranasal route creates a special type of immunity – mucosal immunity – in the body’s boundaries; the first line of defence. Think of it as creating a barrier at the point of entry into the human body... the idea is to generate immunity before the virus gains a foothold.”


Where it all began

Vaccines have famously conquered smallpox, a disease which once ravaged the world. At least a third of all Aztecs died after Spanish invaders introduced the illness in the early 16th century, when pockmarked faces were commonplace. Smallpox scars are visible on the mummified face of ancient Egyptian pharaoh Ramses V.

Country doctor Edward Jenner used cowpox pustules for vaccination in 1796 after noticing that the milder disease gave immunity against the more dangerous smallpox. But there’s evidence the Chinese had inoculated people as early as the 10th century, by blowing powdered smallpox scabs up people’s noses to create a mild bout of the disease. By 1979, a global programme had eradicated the disease.

In 1885, Louis Pasteur created the rabies vaccine, and more followed over the years – diptheria, anthrax, cholera, typhoid and tuberculosis with varying success. Childhood diseases were conquered in the 20th century with vaccines against polio, measles, mumps and rubella (MMR).

“Half of us probably wouldn’t be here without vaccines,” says Dr Bharat Pankhania, senior clinical lecture at the University of Exeter Medical School.

How companies will cope with making massive doses of any vaccine, once approved, and delivering and administering them safely will be challenging, and smaller companies will need to collaborate. Many vaccines need to be kept cold or frozen, but Altimmune says its vaccine is likely to be stable for months at room temperature. “We all have to work together for one solution rather than one company taking on everything,” says Vipin Garg, Altimmune’s chief executive.

There remain many unanswered questions. Will the virus mutate and recur, as flu does – is there a SARS-CoV-3 on the horizon? Will it become a regular seasonal infection and will natural immunity improve?

Who will receive any vaccine once approved? Manufacturers are talking about a couple of million doses initially. How many of the potential vaccines currently in development will establish themselves in the future? “We’ll probably end up with two to three vaccines out of a potential ten or so candidates,” says Professor Hanneke Schuitemaker, global head of viral vaccine discovery at Janssen Vaccines, which is currently testing candidates in mice and monkeys. Vaccines tend to be less effective in the over-65s, so it may be that those in regular contact such as healthcare workers will be vaccinated too. “That’s a decision for regulators and the government,” says Schuitemaker.

Producing a vaccine by mid-2021 remains a dauntingly fast schedule. Waiting is hard for a frightened public, but a successful vaccine will be critical protection for the future.

We need to get good at swift turnarounds, says Garg, for whatever diseases arrive. “Covid-19 is making everybody realise around the world that we can no longer be complacent. There will be another virus. We have to develop plug-and-play technologies so we are ready and we can move even faster next time.”


Vaccines gone wrong

One of the biggest success stories of modern medicine, vaccines remain highly controversial. After discredited doctor Andrew Wakefield sounded a false alarm linking the MMR vaccine to autism and bowel disease in 1998, vaccination rates among children declined, and cases of measles are now on the rise worldwide. Scientists say colleagues are now more hesitant to report potential side effects from vaccines in light of parental refusal to vaccinate children. But the previous century has seen several cases where early vaccines have caused injury and death. “Today the vaccine pipeline is geared towards being really sure a vaccine won’t cause more problems,” says Dr Chris Chiu at Imperial College London.

In 1942, a yellow fever vaccine was contaminated with hepatitis B, causing 100 deaths in the US military. Five years later a mass vaccination against smallpox in New York caused six deaths.

In 1948, 606 babies and children fell ill and 68 died in Kyoto from a diptheria immunisation – the toxoid preparation had reverted to toxin.

In the US Cutter incident of the 1950s, 10 people died and 164 were paralysed from an inadequately inactivated polio vaccine.

In 1998 Rotashield, the first vaccine for rotavirus – a cause of diarrhoea in children – was approved but withdrawn the following year after scientists said the vaccine was associated with a potentially fatal intestinal bowel problem.


A financial payout over vaccine blunders

Six million people in Britain – including a million British children between 6 months and five years – and more across Europe received the Pandemrix vaccine (made by GlaxoSmithKline) during the 2009 to 2010 swine flu outbreak. Finnish and Swedish authorities reported an unexpected increase in cases of juvenile narcolepsy. In November last year, the Irish government settled a legal case with a woman who said she’d developed the sleeping disorder after receiving the vaccine, which is no longer in use, but the state admitted no liability. UK families are entitled to a £120,000 payment if they report they are severely disabled as a result of a vaccination, and in 2016, a boy from Somerset received damages after developing narcolepsy subsequent to receiving the jab.

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