ウィスパリング同時通訳研究会コミュのOxford AstraZeneca development with Professor Sarah Gilbert

accine vs the Virus: This race, and the next one

I know that the newly-discovered Omicron variant is on everyone’s minds. And I will say what I can about that later on.

But I would like to start by asking you all to think back to New Year’s Day 2020. A pre-pandemic time. No one had ever heard of Covid-19 – a disease that has since taken millions of lives, emptied schools, savaged economies, kept us from our loved ones, closed down entire societies. Most people neither knew nor cared what a spike protein was. And had never worn a surgical mask in a lecture hall. We each of us had our hopes and expectations for the year ahead.

As a vaccinologist, I was planning to continue my work on developing vaccines against influenza, Lassa fever, Nipah and various other unpleasant diseases. I was also working out which flowers I wanted to grow for my garden, and when to start sowing the seeds.

At some point on New Year’s Day 2020 I found myself at my computer, checking emails and browsing websites, including one on infectious diseases. There was a report of ‘pneumonia of unknown cause’ in Wuhan, China. Four cases. Not responding to antibiotics. The first patient worked at a seafood market. A mention that this might be SARS – Severe Acute Respiratory Syndrome. This caught my attention. I made a mental note to check back later.

The next day, a new report on the same website said 27 people had now been hospitalised and the market – which, it now appeared, sold rabbits, snakes and pheasants as well - had been closed.

By the 3rd I was checking in regularly for updates, looking for new details – new clues – and running through the possibilities in my mind.

Perhaps whatever it was would simply fizzle out. A crucial - and so far missing - piece of information was whether the disease could be passed from one person to another – we call this human-to-human transmission -- or whether people could only catch it from infected animals. One possible scenario was that there was no human-to-human transmission and everyone affected had come into contact with the same group of infected animals at the market. If that was the case, the outbreak would quickly be contained by closing the market, removing the livestock and deep cleaning the site. There would be no time to develop a vaccine, and no need for one.

Another possibility was that this was SARS, or SARS-like. In which case, we were in trouble. In 2002, a previously unknown virus that came to be known as SARS had caused a disease outbreak starting in China. It killed 10% of those infected. There was no vaccine and no treatment.

And of course there was also the possibility it was not SARS, or SARS-like, but something even worse.

By Monday the 6th of January, when I went back into the office, I was following developments closely, as were many of my colleagues.

Very late at night on the Wednesday came official confirmation that what we were dealing with was a novel coronavirus. There were other coronaviruses that regularly infected people, but this was a new one.

Experts in the spread of infectious diseases immediately started saying ‘I told you so.’ And they had. They had been warning for some time that we needed to be ready for an outbreak of a novel coronavirus, probably starting in China.

This was the third novel coronavirus that had spread from animals to humans in the last 20 years. The first, SARS, had been relatively easy to eradicate using the centuries-old methods of isolating the infected and their contacts. So there had been no immediate need for a vaccine and none had been developed. The second, causing MERS -- Middle Eastern Respiratory Syndrome -- still causes cases every year, although there have been no large outbreaks recently. Work on vaccine development had begun, but it had not been seen as a high priority and progress had been slow.

On the Friday, China reported its first fatality. By the end of the day, my long-time colleague and friend, the immunologist Dr Tess Lambe, and I had decided that as soon as we had its genome sequence, we would start work on a vaccine against this virus, and go as fast as we could.

Tonight I am going to tell you how, during those frightening, dislocating, urgent days, weeks and months of 2020, thousands of heroes – dedicated scientists here in Oxford and across four continents, but also clinicians, regulators, manufacturers, and volunteer citizens – came together to achieve something extraordinary. Within less than a year, together we had designed, made, tested, manufactured at scale and started to distribute a vaccine that was very safe, that was highly effective, and that would be available around the world in huge quantities at low cost. Together we had made a vaccine for the world.

At the same time others were working out how to prevent this disease spreading, how to treat those infected, and how to make other vaccines using alternative materials and technologies. As a result, a year after the virus was first identified, the world had surveillance systems in place to track the evolution of the virus as it mutated; knowledge of which drugs worked, and which ones didn’t; and several very safe and highly effective vaccines. In recent years we have been told that the public is tired of hearing from experts. It is now clear that it is experts who have provided and will continue to provide the route out of the pandemic, as well as the communication of reliable information at every new turn.

I will explain, tonight, why we were confident we could do it. How we were able to go so fast. What went right. What went wrong.

And I will leave you with my thoughts on the future for the struggle I and my colleagues are, quite obviously, still engaged in: humanity against the viruses. Can we beat this one? I am confident we can. Omicron notwithstanding. Can we beat the next one? That depends.

Some of the most important moments in this story had actually happened well before I first read that report from Wuhan, China. A large part of the reason we were able to move so fast in 2020 was the work we and others had already done, both on other vaccines against other diseases, and on planning for Disease X. Disease X was a placeholder representing a future, hypothetical disease. No one knew what it would be, or when it would emerge, but experts agreed that the emergence of something, sometime soon, was inevitable.

Viruses are fascinating. Visually fascinating, as Angela Palmer’s powerful and beautiful representation of the SARS-CoV-2 virion demonstrates. And biologically fascinating. They cannot replicate themselves unaided, and when not inside a living cell they are completely inert. But once they do get inside a living cell, they can take it over, turning it into a factory to make more copies of the virus instead of doing whatever it would normally do. This process usually kills the host cell. So viruses have to be able to spread from one cell to another, in order to survive. As a virus spreads to more and more of our cells, and those cells stop doing their normal jobs, we start to get symptoms.

However at the same time as the virus is infecting us, it is also being detected by our immune system, which has evolved to be able to detect intruders and then destroy them, in the process laying down a memory so it can respond quicker next time.

Our immune systems are generally very good at this. The reason viruses can nevertheless make us ill is that they act so quickly. A viral infection can take hold before the immune system has had time to mobilise. This is where vaccines come in. Vaccines give your immune system the memory of what a virus looks like, but without you having to get sick with that virus in the first place. And vaccines all work on the same basic principle: they all present your immune system with some kind of harmless mimic of the virus.

The famous vaccine against smallpox developed in the late eighteenth century by Edward Jenner, for example, used a related but less harmful virus, cowpox. Traditional vaccines present the body with a weakened or inactivated version of the virus. Modern platform or ‘plug and play’ technologies show the immune system only the part of the virus that it needs to recognise to produce an immune response. Usually this will be a protein on the surface of the virus, completely harmless on its own.

The work that had gone into platform technologies by the end of 2019 was crucial to the world’s ability to move fast in 2020. A platform technology is a multi-use vaccine ‘vehicle’ that can be adapted to make many different vaccines. Its great advantage is that it means we don’t need to repeat every one of the many, many aspects of vaccine development every time we make a new one. We can build up and bank our knowledge of how to manufacture it, how to store it, what dose to give and so on. That saves time and it saves money.

So, even when confronted in 2020 with a virus we had never seen before, we did not need to start from scratch.

Work on our platform and on others -- the vaccines from Pfizer and Moderna are also built on platform technologies – really took off in the wake of the world’s inadequate response to the 2014 outbreak of Ebola, in West Africa.

The world had known about Ebola since 1976, but there had been no sense of urgency. By 2014, there was no specific treatment, no vaccine, and no plan to develop one. Around 28,000 people became infected, of whom more than 11,000 died. Liberia lost 8% of its doctors, nurses and midwives. Around 30,000 children were orphaned.

Vaccines were developed and tested, but too slowly and too late. Afterwards, relief that the outbreak had finally been contained - through public health measures, not vaccines - was tempered by anxiety that there were still plenty of other viruses out there that could wreak similar havoc, or worse. It was a wake-up call and a turning point. International organisations, including the World Health Organisation began to draw up lists of dangerous diseases against which we really should be developing vaccines.

Platform technologies would be key: using the same technology to produce multiple vaccines would reduce development time and, crucially, development cost.

There was a further development in 2018 when to this list of dangerous diseases was added ‘Disease X’. This was recognition that we needed to prepare not just for the diseases we already knew about, but also for those we didn’t. How do you prepare for a disease you don’t yet know about? By developing platform technologies suitable for rapid response.

Funding was still slow to materialise though. Research crept forward at a frustratingly slow pace. Our particular platform technology was recognised as promising, but our bid for funding to work on speeding up the early part of our process was not successful. The reviewers were not convinced that we could move quickly enough in the event of a Disease X outbreak. Luckily – at the time we could not know just how lucky - the UK government had in the meantime decided to channel some of its overseas aid budget into vaccines. And I had secured some of that funding, to work on a vaccine against MERS.

I wish I had time to talk about all the many other fortuitous moments that led up to January 2020. Whenever you are working at the cutting edge of science you are building on decades of meticulous and laborious work that has come before. I have to mention in particular the debt we owe to Professor Adrian Hill, the Director of the Jenner Institute where I am based, and to PhD student Matt Dicks and post-doctoral researcher Matt Cottingham, without whom our platform, ChAdOx1, would not exist.

What it all meant was that as soon as Tess and I knew, on the 8th of January, that we were dealing with a coronavirus, we knew we could make a vaccine against it, and we had a template to follow. We knew vaccines made with our platform generated a strong immune response and were safe, including for children, older adults, and people with suppressed immune systems. More specifically, we had made a vaccine against MERS, another coronavirus. It had already been through two early clinical trials and it had raised immune responses as we hoped it would.

At this point this all felt quite theoretical. It was still very possible that the outbreak would be controlled quickly and a vaccine would never be needed. But if it was going to be needed, it would be needed fast. There was no time to test different vaccine designs. We had one shot. So the decision was straightforward. The design for our new vaccine would be based on the design for our MERS vaccine.

The next day, Saturday the 11th of January, Chinese scientists made the genetic sequence of the novel coronavirus publicly available online. That code – specifically, the 3, 819 letters that coded for the spike protein – was what we needed to finalise our design. Within 48 hours, we had worked out the exact genetic sequence we needed to make our vaccine.

Those years of preparation were also what enabled us to make the first doses of vaccine so quickly.

The very first, very small batch of vaccine was made in my lab. We started to test it on mice and sent some to our long-time collaborators at the National Institutes of Health, Rocky Mountain Labs – who had sprung into action in January 2020 just as we had -- to be tested on monkeys.

But vaccines that are going to go into human bodies – clinical-grade vaccines -- have to be produced in highly specialised, highly regulated facilities, not university research labs. Happily, since 2005 we had had such a facility – the Clinical BioManufacturing Facility or CBF now run by my colleague Dr Cath Green - right on our doorstep. The first vaccine the CBF had made for us, back in 2007, had taken eighteen painful months. Since then, we had worked to reduce the time, and the pain. As we set out this time, Cath’s most optimistic estimate was that she might have 500 doses ready within six months – so by the end of July. Although to hit those dates, she was keen to emphasise, everything would need to go right.