The story behind the Oxford vaccine starts long before Covid-19. Before the genetic coding for the virus was sequenced back in January. Before the first infections were detected in Wuhan. Even before the World Health Organisation introduced the concept of Disease X – a placeholder name for an unknown future pathogen that could, one day, reap global havoc.
Indeed, the vaccine which is expected to play a vital role in ending the coronavirus pandemic has been many years in the making. Sarah Gilbert, a professor of vaccinology at the University of Oxford, first started developing the technology used for AZD1222 – its official name – in the wake of the 2014-2016 Ebola outbreak.
In terms of the science, Ms Gilbert’s vaccine platform uses a genetically engineered chimpanzee adenovirus – which causes the common flu in apes – to carry the genetic coding for certain viral features into human cells, triggering the immune system in response.
This approach had already been adopted by the Oxford team to produce vaccine candidates against a number of pathogens, including influenza, Zika and Middle East Respiratory Syndrome (Mers) – another member of the coronavirus family.
That’s why, when a mysterious pneumonia-like disease surfaced in China towards the end of 2019, Ms Gilbert and her colleagues were already poised to hit the ground running.
“When I started seeing reports of an outbreak in China at the beginning of the year, I saw that and thought, ‘Is that going to be something we should be making a vaccine for?’ I was thinking in terms of our technology,” she told The Independent in August.
“Even if it was a small outbreak and didn’t really get very far, it would be an interesting demonstration of what we could do to take one of the genes [of the virus] as soon as the genome sequence was released, make a vaccine and show that we could do it quickly.”
It proved to be anything but a “small outbreak”, with the virus rapidly spreading to every known corner of the globe. But the Oxford team’s previous work meant it was able to similarly move at pace. After the genetic code for Sars-Cov-2 was released on 11 January, a vaccine template, designed by Professor Teresa Lambe, was ready to go 48 hours later.
The first step back to normality had been taken, at a point when life as we once knew it still remained relatively untouched by Covid-19.
The next challenge to overcome was securing the funding and investment needed to run the clinical trials. By February, Professor Andrew Pollard, the director of the Oxford Vaccine Group, had already contacted Ms Gilbert to pool their resources – but it wasn’t to be enough to get the project off the ground.
More money was needed, yet at this early stage of the pandemic – when headlines were still being dominated by Donald Trump’s impeachment – it proved a challenge attracting the necessary investors.
Only once the situation in the UK had deteriorated, on the same day that the country was placed into lockdown, did the government announce a funding package of £2.6m for the Oxford team. Much more was to follow in the weeks ahead, but it was enough to start large-scale production of the vaccine and begin injecting early volunteers with doses.
One of those individuals was Elisa Granato, a molecular microbiologist at the University of Oxford who became the first trial participant to receive the vaccine. Her story highlights the problem of disinformation which has haunted the globe’s vaccination programme from day one of the pandemic.
According to a flurry of false reports that emerged in late April, Ms Granato had died two days after being injected with the vaccine. Four other volunteers were incorrectly claimed to have been hospitalised after suffering adverse reactions to AZD1222.
The stories were rapidly debunked but it set the tone for what was to come. Global efforts to develop a vaccine – and convince populations of their worth and safety – have been routinely undercut by anti-vaxx movements, which have spun grand delusions involving Bill Gates, microchips and “big pharma”.
These conspiracies have added to the burden of expectation facing Ms Gilbert and her peers. Not only have they been asked to construct a way out of the pandemic, they’ve also been handed the additional role of settling humanity’s anxieties over such matters.
“I’d like people to make decisions on whether to be vaccinated to be based on facts – not misinformation or absence of information,” Ms Gilbert said. “Public engagement is important to us. We try to explain things so that the general public can understand it. We’re not trying to hide things, we’re tying to make information available.”
By this stage, the government had begun to pump more and more money into the Oxford vaccine. On 21 April, £20m in funding was committed to the candidate, and nine days later the university announced that it had entered into an agreement with AstraZeneca for the further development, large-scale manufacture and distribution of AZD1222.
The following month, an additional £65.5m was invested into the project by Downing Street, which had begun to prioritise the vaccine as the critical tool for bringing the UK’s Covid-19 crisis under control.
Although efforts were underway to build up a portfolio of different vaccines and secure plenty of supplies for the UK population, it was clear by this stage that the Oxford vaccine would be Britain’s crown jewel, with the government agreeing to pre-order 100 million doses of the candidate.
All the while the team at Oxford was working at breakneck speed on its clinical trials, moving from phase one, which determines the safety of the candidate, to phase two and three, which measure the vaccine’s effectiveness in inducing an immune response and preventing disease among volunteers.
The large-scale trials were launched midway through the summer, in the UK and Brazil – two nations that had struggled to contain Covid-19 and were still recording relatively high rates of infection – before being later expanded to South Africa and the US.
“You need somewhere to conduct your trial where there is high transmission rates and infections going on in the background,” Dr Gillies O’Bryan-Tear, chair of the Faculty of Pharmaceutical Medicine, told The Independent. “Without that, you won’t know if the vaccine works as it’ll take ages for it to show up [among volunteers].”
This meant that, as the UK’s situation deteriorated throughout autumn, more and more cases were recorded among the trial participants, allowing researchers to collect the relevant data that would eventually be put to the UK’s Medicines and Healthcare products Regulatory Agency (MHRA).
By this stage, researchers and scientists had stripped back the burdensome bureaucracy which has complicated the implementation of past clinical trials.
Dr Mark Toshner, a clinical doctor involved in running and recruiting volunteers for the Oxford trials, said that people have become too hung up on the idea that it takes more than a decade to make a vaccine. “What happens in those 10 years: most of the time it’s a lot of nothing.”
“During the course of those 10 years I’ll be spending significant proportions of it writing grants, having grants rejected, rewriting them, resubmitting them.” This process, he said last month, “can take two to three years in itself”.
“Then when you’re actually lucky enough to get a grant, you have to go through a very extensive regulatory process that normally takes months and you have contract negotiations. They can sometimes take years.”
He said that the urgency to develop a vaccine had done away with much of the usual delays and accelerated the various moving parts of the testing phase.
However, Ms Gilbert insisted that no corners were cut at any stage, arguing that the team was “able to find ways to save time when going through all the normal processes".
“We’ve worked with the regulators and ethical committee to minimise the time it takes to get to approval, but the approval is still the full approval – it’s not missing anything,” she said.
She pointed to “accelerated procedures” that have helped to cut away unnecessary waiting time. “Normally we can’t mention the trial and ask anyone to consider taking part until it’s all completely approved,” she said. “This time we were allowed to advertise the trials and contact people.”
Individuals who expressed an interest were then vetted and prepared for vaccination, which only followed once approval was secured. “So we had a cohort of people ready to vaccinate. That doesn’t normally happen.”
On the production front, the Oxford project encountered its fair share of “technical hurdles” – as Ms Gilbert puts it. Early on, when attempting to produce a second batch of the vaccine at the university’s manufacturing facility using a new purifying process, “things just went wrong”. Fortunately, a contract with a manufacturer in Italy, which was already making another supply load, meant the university was able to keep the early trials on track.
But the Italian manufacturers implemented a different production approach to the Oxford team, meaning the dosage for their batch was too strong. This twist of fate had major repercussions that would not be fully felt until the results of the phase three trial were revealed towards the end of 2020.
Once the discrepancy had been detected, researchers agreed that volunteers should be given a half measure of this particular supply of the vaccine, assuming it would equate to the regular dosage that had been administered at the start of the early trials.
Following this, it became apparent that something wasn’t right. Side effects such as fatigue, headaches or arm aches were milder than expected in roughly 1,300 volunteers, leading to the eventual discovery that they had only received a half dose. Regulators were immediately notified of the error but signed off on the plan to continue testing the vaccine in different dosages.
AstraZeneca has admitted this dosage was initially applied in UK trial participants as a mistake. “The reason we had the half-dose is serendipity,” said Mene Pangalos, the head of AstraZeneca’s non-oncology research and development.
However, such a development added complexity to the trial results that were eventually released in late November.
The half dose-full dose regime was shown to deliver an efficacy rate of 90 per cent among the UK volunteers – all of whom were aged under 55. In contrast, the effectiveness of the vaccine in preventing disease was only 62 per cent in those participants who had been given two full doses.
When it came to explaining the discrepancy, Oxford’s scientists were stumped. Ms Gilbert suggested the initial half-dose primed the body’s immune system before the second, full dose kicked it into action with a strong boosting effect.
Overall, the data, which was pooled from the UK and Brazilian trials and included a variety of subgroups that had been given different dosages at different intervals, demonstrated the vaccine was safe and 70.4 per cent effective. To date, no cases of hospitalisation or severe disease have yet to be reported among those people who received the vaccine.
This naturally raised questions among experts and regulators throughout the world. Were the findings statistically significant? Could conclusions be drawn from pooled data? Why was the smaller dose regime more effective? Had the vaccine been tested in enough elderly people?
The US reacted with caution to the results. Critics claim the UK and Brazilian trials did not include enough ethnic diversity, gender and age balance to satisfy the American regulator, the Food and Drug Administration (FDA).
A separate trial involving 30,000 volunteers is currently underway in the US, and it’s expected that the findings from this will be used to shape the FDA’s decision on whether or not to approve the vaccine.
As for the MHRA, the green light of approval was finally given on Wednesday – more than two weeks after further data released by Oxford University alleviated many of the lingering scientific concerns.
Having assessed the trial findings with a fine-tooth comb and scrutinised the different subgroups of volunteers, the regulatory body ruled that the Oxford vaccine should be administered in two standard doses up to 12 weeks apart, rather than four.
According to data which will be published shortly, this three-month interval helps to induce an immune response that is 80 per cent effective in preventing Covid-19. Ultimately, the MHRA decided against endorsing the half-dose, full-dose regime, concluding that the “results were not borne out by the full analysis”.
Nearly 12 months after the experts first set to work on the Oxford vaccine, it’s arrival comes at a time of great need in the UK, with the pandemic spinning further and further out of control, fuelled by a new coronavirus variant that has overwhelmed hospitals and infected thousands.
While the scientists and regulators will continue to monitor the vaccine – keeping an eye out for any adverse reactions, attempting to determine whether it halts transmission and ensuring guidance is up to date – it’s now the turn of others to step in and deliver the doses to those most in need.
The approval – described as a “triumphant moment” for Britain and the world – marks the end of a long and difficult journey for all those involved, but also the beginning of a new chapter that will prove just as challenging.
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