key: cord-0861929-463flcuc
authors: Boseley, Sarah
title: The race to make a COVID-19 vaccine
date: 2021-09-02
journal: Lancet
DOI: 10.1016/s0140-6736(21)01902-4
sha: b80e27d7f152ac3a17e49c34e60b858305a09135
doc_id: 861929
cord_uid: 463flcuc

nan

The race to make a COVID-19 vaccine Sarah Gilbert, Catherine Green, and their scientific colleagues at the University of Oxford who made a vaccine against the novel coronavirus, SARS-CoV-2, that has brought the world to a standstill, are heroes of our time, already decorated in the UK by the Queen and, in Gilbert's case, lauded by Mattel, which has made a Barbie doll in her image. Fired by a mission to save the world, these researchers are dedicated, altruistic, and determined that their vaccine would not only be safe and effective, but also cheap and easy to use in the poorest corners of the globe.

In less than a year, with collaboration from the giant pharmaceutical firm AstraZeneca, the vaccine was ready for use. Millions of doses have been shipped to more than 160 countries. AstraZeneca has pledged to deliver 3 billion doses by the end of 2021. Thousands of lives are being saved every day, said Pascal Soriot, AstraZeneca Executive Director and Chief Executive Officer, in a piece for the US website Project Syndicate.

It should be a glorious and triumphant tale, something to widen the eyes of the children of the future once COVID-19 is no longer a threat to humanity. And yet the progress of the Oxford-AstraZeneca vaccine has been anything but smooth. The best of intentions were at times thwarted by bad luck, poor communications, and political posturing.

In summary, the bumps in the road for the Oxford-AstraZeneca vaccine included the US Food and Drug Administration's pause of 7 weeks in the US trial because of a serious adverse event, while the UK regulator allowed a resumption after 4 days; a dosing discrepancy which ended in confusion over efficacy in the UK; some uncertainty about how well the vaccine worked in older people because too few people older than 55 years were recruited to the first phase 3 trials; and rare but serious blood clotting events in Europe. Additionally, in March, 2021, concerns were raised by the Data and Safety Monitoring Board (DSMB) in relation to information released by AstraZeneca on initial data from the US COVID-19 vaccine clinical trial and the US National Institutes of Health issued a statement: "The DSMB expressed concern that AstraZeneca may have included outdated information from that trial, which may have provided an incomplete view of the efficacy data. We urge the company to work with the DSMB to review the efficacy data and ensure the most accurate, up-to-date efficacy data be made public as quickly as possible." 2 days later, AstraZeneca produced updated results that confirmed the vaccine efficacy, but some damage had been done. As of August, 2021, the vaccine is still not approved in the USA.

Even if you ignore the furore that blew up in Europe over supply of this vaccine, which ended in a court case and may have been shaded by the Brexit row, the Oxford-AstraZeneca folk suffered a considerable amount of bad luck. It is easy to understand why some of them think their anticommercial stance must have made them enemies. "Never a good deed goes unpunished", said one to me.

If you are looking for a full analysis of all these events, you will not find it in Gilbert and Green's book Vaxxers: The Inside Story of the Oxford AstraZeneca Vaccine and the Race Against the Virus. This book focuses on the hard work and achievements of the two women and their teams through that first year, from early January, 2020, when Gilbert realised the novel coronavirus in China might be a candidate for their vaccine platform, ChAdOx1. Vaxxers is a detailed and informative account of scientific endeavour, of struggles to get funding, and of finding innovative ways to speed up the process of vaccine development which hopefully will stand the world in good stead in difficult times to come.

For Gilbert and her co-workers, the emergence of SARS-CoV-2 was initially an opportunity to try out the platform she first used in 2012 with influenza. This was a "plug and play" technology that could allow scientists to make vaccines against any newly emerging disease. Just slot in the genetic code of the virus, which the Chinese made publicly available in early January, 2020, and away you go. Some of the most important work "actually happened before anyone had ever heard of COVID-19", she explains in the book. The researchers had seen the pandemic coming, she writes, "and we had started preparing, but we had not been able to persuade anyone to spend the money that we needed to do what was required."

In Vaxxers Gilbert describes how "What I actually spend my time doing these days is, mostly, bringing in the money". It meant she had the experience to make her way through "the fiendish funding maze that sprang up in the first part of 2020, and get our vaccine project so far so fast". It wasn't until late April, 2020, when the UK Government gave "Let's hope people who have not yet taken up the vaccine read Vaxxers and decide to have the jab. The other, very real, value of this book is to show how effective vaccines can be safely produced faster than anyone thought possible." them £20 million, which later rose to £31 million, that their money worries went away.

Green was in charge of the Clinical BioManufacturing Facility (CBF) set up by the University of Oxford to manufacture vaccines for trials, but on nothing like the scale that would be needed for a global pandemic, which is why an alliance with the pharmaceutical industry was always going to be necessary. Green and her colleagues had to take the risk of delaying other projects, including an Ebola virus vaccine, to make a vaccine against SARS-CoV-2. She walks the reader through the making of the vaccine, from what she famously compares to a sourdough starter material through to labelling the vials and distribution-and all the many twists and complications they encountered along the way.

Their unstinting efforts to develop the vaccine took a massive toll. "We are two ordinary people who, with a team of other hard-working, dedicated people, did something extraordinary…There were days when we swore or cried with frustration… There were days when we met a prince, or a prime minister, and other days when it seemed that we had to both save the world and get the central heating fixed", writes Gilbert.

Despite the pressures, the researchers persevered. The book chronicles the race against SARS-CoV-2. Vaxxers lays out the work that had to be done and the pitfalls avoided and in that it is a blueprint for the future. COVID-19 was Disease X, which they had known would some day emerge. "Disease Y is coming. There will be a next time. It is inevitable", warns Green in the final chapter. "We need to make sure that when Disease Y arrives, we are better prepared for it than we were for X", she urges. The work they did and the risks they took-to the university and to themselves, as they repeatedly point out, not to vaccine safety in any way at all-will hopefully give us a much better place on the starting grid when the next pandemic begins.

Gilbert in her first chapter makes it clear that the researchers were unhappy with the obstacles that appeared in their way. She describes their troubles in Europe as "an unedifying mix of politics, business, science and emotion". They wanted to save lives, not make money, she writes. "What none of us foresaw was how the vaccine would become a political football. Our year of constant, painstaking attention to detail resulting in a vaccine with the potential to save millions of lives around the world could be dismissed by a politician with a grudge. Carefully worded statements to the media, explaining the science behind the vaccine, would disappear in a Twitter storm of bias and misinformation, with incorrect statements repeatedly cited as fact."

Vaxxers does throw light on the half dose and full dose issue. We knew that some trial volunteers effectively got a half-dose of vaccine followed by a full dose, which resulted in 90% efficacy, while efficacy among others on two full doses was 62%. That discovery was at one point (although not in the book) described by Sir Mene Pangalos at AstraZeneca as "serendipity"not a word to reassure regulators. And yet, when the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK looked at the data to authorise the vaccine, they decided it was the dosing interval, not the quantity of vaccine, that made the difference. Why did it happen at all? Pfizer-BioNTech did not stumble in the same way. Green explains in the book that some of the initial trial doses had been made by her CBF, while others were made by Advent in Italy. And their tests and methods were different. "The issue appeared to be that our spectrophotometric test was not accurate when combined with Advent's purification method", she writes. The MHRA allowed the volunteers who had received a lower dose to continue in the trial, but the discrepancy in the results had initially sowed some doubt and it could have been better communicated. Green writes that the issue was complicated and they had to report their results in a peer-reviewed paper, not in the media. It was, she says, "your basic scientists' nightmare in a world that wanted simple, clear answers and a good headline". But, she acknowledges: "We also maybe did not always explain it well ourselves."

Gilbert mentions the emergence of rare blood clots, which led the UK and European nations to restrict the use of the vaccine in younger age groups. "What was clear was that the risk, if there was one, was vanishingly small", writes Gilbert. She goes on to explain: "Indeed, it is known that a confirmed risk of a fatal blood clot from a common drug that people took for years at a time, the contraceptive pill, was much higher. The risk of a fatal blood clot after being infected with COVID-19 was much, much higher."

Part of the reason for writing the book, say Gilbert and Green, was to counter misinformation. Vaccines make some people anxious, Gilbert says, and "fears and doubts often rush in to fill gaps in people's knowledge. So we wanted to try to fill in those gaps ourselves." They very usefully describe in great detail how the vaccine is made and even provide a list of ingredients, countering claims that it contains mercury (it doesn't and nor do any vaccines in the UK these days) or substances prohibited by religious groups. Let's hope people who have not yet taken up the vaccine read Vaxxers and decide to have the jab. The other, very real, value of this book is to show how effective vaccines can be safely produced faster than anyone thought possible. Maybe we should be content with that and leave others to answer the questions about the rocky road it then had to travel.

@sarahboseley

) National Institutes of Health. NIAID statement on AstraZeneca vaccine

Dosing error turns into lucky punch for AstraZeneca and Oxford. Reuters