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Inside the Cambridge lab in pole position to create a new coronavirus vaccine




The race is on to create the first vaccine for the coronavirus - and the laboratory of Prof Jonathan Heeney believes it has something of a head start.

Professor Jonathan Heeney at the Laboratory of Viral Zoonotics in Cambridge. Picture: Keith Heppell
Professor Jonathan Heeney at the Laboratory of Viral Zoonotics in Cambridge. Picture: Keith Heppell

Within the Department of Veterinary Medicine at the University of Cambridge lies a laboratory capable of handling some of the very worst foes that nature can throw at us.

From the bacteria that causes tuberculosis, to the West Nile virus and on to SARS, the Laboratory of Viral Zoonotics has housed a plethora of deadly pathogens.

Operating at containment level 3 – there is a level 4, but you really don’t want to go there – it is designed for tackling microbes that can cause serious and potentially lethal disease.

The lab, headed up by Prof Jonathan Heeney, is working on an improved vaccine for influenza and has developed a vaccine for Ebola, Marburg and Lassa fever.

And its spin-out company –DIOSVax – has been on the case of tackling coronavirus since the Chinese released its genetic sequence on January 9, 10 days after the first cases from the city of Wuhan were reported to the World Health Organization.

“Within days we started to do our molecular modelling to identify the most antigenic regions,” says Prof Heeney, alluding to areas of the virus that a molecule could bind to and provoke an immune response.

“But we are working in a vacuum because nobody has blood samples yet to give us information on how those people who are getting through the respiratory disease and surviving are responding. So it’s like working in the dark, but we’re hopeful we’ll get antiserum soon.”

Prof Heeney has been in contact with Chinese authorities, and with colleagues in Bavaria, where there has been a cluster of cases, in pursuit of blood from survivors that could illustrate the human immune response.

He has also been in contact with Public Health England.

“It’s a beta-corona virus, derived from a family of bad coronaviruses and it’s a close cousin to SARS,” says Prof Heeney. “We know it’s highly contagious but this infection, thankfully, looks to be less pathogenic, meaning it has a lower case fatality rate.

“If it does cause fatal disease, it is usually in the elderly or immune-compromised people who have some other cardiovascular disease, or perhaps have an immune system that is suppressed because they are undergoing cancer treatment. It is much like flu, where the elderly are more susceptible in most cases.”

Professor Jonathan Heeney at the Laboratory of Viral Zoonotics in Cambridge. Picture: Keith Heppell
Professor Jonathan Heeney at the Laboratory of Viral Zoonotics in Cambridge. Picture: Keith Heppell

As of Wednesday March 4, there have been more than 94,000 confirmed cases and more than 3,200 deaths.

Within a month of it emerging, coronavirus had already claimed more lives than SARS did in a nine-month period in China.

Despite this, it appears a lower proportion of those infected actually develop serious illness. This, however, may make containment a challenge as those with mild symptoms – a high temperature, cough and shortness of breath – may not seek medical help.

“Coronaviruses are relatively common in veterinary medicine,” says Prof Heeney, who is a virologist and a vet. “They are relatively new on the horizon of human medicines because normally in humans they cause a sub-clinical gastro-intestinal infection.

“But these particular viruses, like SARS, are nasty respiratory pathogens for two reasons. One is that nobody has ever, globally, seen them before so there is no immunological memory. And secondly they are interacting with our immune systems in such a way that they drive a very acute lung pathology. Without good specialist medical care, it can kill people, as we’re seeing.”

This coronavirus is thought to have originated in bats, which are particularly efficient at carrying such pathogens. They are also carriers of Ebola, Marburg and SARS – diseases that have impacted on humans in the last 50 years, as people and their farm animals impinge further into typical bat territory.

Bats roost together, aiding the spread of viruses, but typically survive them, thanks to extraordinary DNA damage repair mechanisms thought to have been crucial in enabling them to deal with the impact of high energy flight.

But as no bats were sold at the Huanan seafood and wildlife market in Wuhan where the outbreak began, it is thought another animal on sale there acted as a stepping stone on its way to infecting humans.

“Viruses don’t respect species borders,” notes Prof Heeney. “They’ve always co-existed in various species. But when human populations grow to such an extent that we come into contact with species that we’ve not normally been in contact with, it’s a bit like going to a poker game: You never know who is sitting at the table.

“You bring in all these variables like wildlife into a market and that’s when you get these ‘spillover’ events.

“That’s what happened with so many of these viruses that we study. HIV is an example.

“It naturally occurs in 30 monkey species in Africa that carry these viruses without any concern. But within nature, there are accidents. Chimpanzees hunt monkeys and one particular chimpanzee must have caught two monkeys each carrying a different type of SIV [Simian Immunodeficiency Virus], which then recombined in that chimpanzee.

“Then through the bushmeat trade, where people ate whatever they could get their hands on, it made the jump to human beings. There is a stepwise progression, and we see that through influenza as well.

Professor Jonathan Heeney at the Laboratory of Viral Zoonotics in Cambridge. Picture: Keith Heppell
Professor Jonathan Heeney at the Laboratory of Viral Zoonotics in Cambridge. Picture: Keith Heppell

“Ducks that migrate around the east coast of China – a migration flyway – touch down in chicken farms or goose farms and pick up these avian viruses. They are not used to them and get infected.

“If there are humans are around, there’s recombination and you get a virus that hasn’t been in humans before but now has the machinery from a human virus to replicate.”

This coronavirus is part of a group of viruses that have genomes highly suspectible to mutation.

“Their genomes are made of RNA, rather than DNA,” says Prof Heeney. “DNA is more robust – it’s a better solid copy. This makes it much harder to make a vaccine for coronavirus. But our technology has been developed to address that problem.

“We look at what is absolutely critical in the life cycle of these viruses and reconfigure those structures within the virus to make them highly immunogenic, meaning when you put them into a vaccine, the vaccine will respond with laser specificity to that region of the virus that can’t be changed.”

Targeting this critical, unchanging region of the RNA code is like targeting its Achilles heel, disabling it.

“Our approach uses next-generation sequencing and links up with structural biology. We know there are immune targets that are successful versus those that aren’t,” says Prof Heeney.

DIOSVax – of which Prof Heeney is CEO – stands for Digitally designed, Immune Optimised Selected and Synthesized Vaccines.

The company is among those aiming to change the normal vaccine development process, which typically takes 12 years and costs £500million.

Its approach begins with a novel sequencing database, combining information on the virus itself with the immune response from humans.

Artificial intelligence-enhanced bioinformatic algorithms are then applied to design more broadly effective vaccine candidates.

Synthetic gene technology is used to create a library of candidate sequences for high-throughput screening. Those that show promise are selected for pre-clinical trials in animal models.

“We screen these in mice and look at the immune response, which tells us if we are on the right track,” explains Prof Heeney.

“Before you put a vaccine into humans, you want to ensure it’s not going to make the disease worse. That’s why an animal model of the disease is very useful.

“Right now, there are teams putting the coronavirus into various animals to get a model to make sure whatever we do, we don’t make the disease worse.”

But bringing a vaccine to the public will require the help of a pharmaceutical company.

A positive sample
A positive sample

“We are just a small start-up, so to scale up into the very large quantities needed to protect 100,000 or a million people would be impossible in the time needed,” says Prof Heeney.

“Anyone saying they will have a vaccine in 40 days is misleading, I think. But if we could partner up very shortly with big pharma, we could move as fast as they could move.

“A GMP [good manufacturing practice] lot of vector viral vaccine can take less than four months.”

Human trials will take further time, of course, but if and when a successful vaccine is created – and there are a number of other groups and pharma companies also working on the problem – the priority will be to protect those on the frontline.

“The immediate need is to contain the epidemic. Therefore, people in the first line of exposure – meaning healthcare workers – and people working in regions where there are cases, would be first,” says Prof Heeney.

“If there is a community where there is one or two cases, you would want to immunise that whole community and ask them all to stay and work from home for 14 days.”

Prof Heeney hails from Toronto in Canada, which was hit hard by SARS in 2003.

“There were a number of deaths and the epidemic was hard to contain,” he recalls.

But along with face-to-face monitoring for fever, the use of infra-red thermometers – which can be used to sense heat as people arrive at airports, for example – helped to get the outbreak under control.

“If you had fever, automatically you went to quarantine. If you had been in contact with someone with fever, you would be told to stay at home and your temperature would be taken every four hours. Eventually, that’s how we contained the SARS outbreak – because we were able to detect fever.

“But what’s very different and concerning about this particular epidemic is that there is now clear evidence of people who are becoming infected who a) have never been to Wuhan and b) have not been in contact with anybody who is ill.

“So apparently the virus is being transmitted before there is any sort of clinical evidence in people.”

This means the tactic used to battle SARS may not work, and a ‘contact-facing’ approach may be required.

“This becomes more difficult,” notes Prof Heeney. “You don’t know who you sat next to in the Tube. All you can say is I was travelling at that time in this direction and you would ask others to quarantine themselves. You can see that would probably be unsuccessful.”

Although still some months off under even the best case scenario, a vaccine may prove critical this time around.

Read more

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