From the moment the coronavirus spilled out of China and spread around the world, the great hope for the return of normal life lay with safe and effective vaccines. While wearing masks and washing hands helped to reduce the flood of infections, they would never be enough to hold back the tide. Social distancing – a phrase that does nothing to convey the hardship of the act – suppresses the virus, no doubt. But what kind of life is a life lived apart?
In response to the pandemic, the first great shock of the 21st century, scientists around the world came together in a staggering effort to tackle the crisis. No element of that work has been more impressive than the rapid development and testing of vaccines. To have shots in the arms of the most vulnerable people, which protect them against a virus unheard of 12 months ago, is an achievement worth reflecting upon.
The desk of Sarah Gilbert, a professor of vaccinology at the University of Oxford and co-founder of Vaccitech.
Scientists at Oxford University were among the small number of teams at the forefront of the race to find a Covid vaccine. In the space of 10 months, they designed and manufactured a candidate vaccine and proved its safety and efficacy through rigorous clinical trials in tens of thousands of volunteers in multiple countries. The shots are now being churned out in their millions, and by agreement with Oxford’s partner, AstraZeneca, will be sold at cost price to poorer countries.
It all starts at the Jenner institute at Oxford University. Named after Edward Jenner, the 18th-century pioneer of immunisations, the institute ranks as one of the world’s premier vaccine research centres.
Jeremy Aboagye, a research assistant, and Helen Sanders, an immunologist, at the trial blood samples reception, where samples are received from the trials clinic to be unpacked, checked and logged on the system before being used in tests.
Step one was to design the vaccine. In modern vaccine research facilities, much of this work is performed on a computer. On the morning of Saturday 11 January, within hours of the virus’s genetic sequence being published online, a team led by Sarah Gilbert, a professor of vaccinology at Oxford, downloaded the code as a text file. They found the genetic instructions for the “spike” protein that studs the surface of the virus. This tiny club-like protein is swiftly recognised by the immune system.
Helen Sanders analyses ELISpot (enzyme-linked immunospot) assay results taken from vaccine-trial volunteer blood samples, to measure T-cell activity. An ELISpot plate has 96 wells and each plate houses white blood cell samples taken from two vaccine trial volunteers. Each spot on the read-out corresponds to a T-cell response produced against the virus spike protein. Responses tend to be different from person to person. The more spots there are, the better the response.
The Oxford vaccine is based on a virus that causes common colds in chimpanzees. This adenovirus is engineered so that it cannot replicate in human cells, meaning it cannot cause an infection. It is then modified further to carry the genetic instructions for the coronavirus spike protein. A shot of the vaccine releases vaccine virus particles into the body. Once inside, these particles enter cells and deliver their cargo of spike protein instructions. The cells then start to make spike proteins – each one a tiny, harmless fragment of the coronavirus – and these are ferried to the surfaces of the cells. Protruding like red flags, the immune system swiftly spots them. It raises an army of antibodies and T cells that are then primed to fight the coronavirus.
Prof Katie Ewer (with hands up), a cellular immunologist, inside a high containment lab at the Jenner institute where responses to the vaccine are being tested on samples taken from HIV+ vaccine-trial volunteers.
Federica Cappuccini, a postdoctoral research scientist, at work in the liquid nitrogen room where all of the white blood cells taken from clinical trial samples are stored at -150C (-238F) for potential future testing.
The heart-shaped clone: Brad Damratoski, a pre-GMP scientist at Oxford’s clinical biomanufacturing facility, shows an image taken of the Oxford/AstraZeneca vaccine at four days old, shortly after he introduced a single virus particle into a plate of modified human cells. The virus particle infected a single cell, which burst and infected the cells around it, which in turn burst and infected the cells around them and so on, until a hole developed to show that the vaccine was successfully taking hold from a single progeny. All of the Oxford/AstraZeneca vaccine that is now being produced around the world is cloned directly from this specific microscopic event.
As scientists at the Jenner institute ran tests in the lab and arranged for the necessary animal studies, the clinical biomanufacturing facility geared up to produce the medical-grade doses that would be needed for human trials. It is a meticulous, multi-staged process performed under increasingly stringent clean room conditions to ensure none of the raw materials, the final doses or vials become contaminated before they reach trial participants.
The work starts with a strand of DNA brought across the car park from the Jenner institute. The DNA contains the genetic instructions for the vaccine adenovirus, complete with the code for the spike protein. Add this to modified human cells and they will take up the instructions and churn out adenovirus vaccine particles. Eventually, the cell makes so many that the vaccine particles burst out.
The step is repeated multiple times. The vaccine particles that erupt from the single cell are added to a fresh batch of modified human cells, infecting those and producing yet more vaccine adenovirus. These are then added to more human cells, and on it goes, until a decent stock of sterile vaccine doses has been built up. Only genetically modified human cells can make the vaccine because these alone contain a gene, named E1, that the adenovirus needs to replicate.
Each batch of vaccine made this way is purified to remove the ruptured cells that litter the nutrient-rich liquid. But another step is needed before the doses are ready for awaiting arms. Some adenovirus particles are duds: they assemble as empty shells that are missing their DNA. To separate them out, the liquid is spun down in a centrifuge. The valuable DNA-filled adenovirus particles settle into a band from which doses can then be taken, ready to administer as jabs.
The Oxford scientists launched trials in Britain and around the world. To make enough doses for the volunteers, they sent “starter material” to factories far and wide – to Advent in Rome, Halix in the Netherlands, and the Serum Institute of India. Those who signed up for the trials were randomly assigned to receive the Oxford vaccine or a control vaccine. Most received two full shots, four weeks apart, but others received a half dose followed by a full dose a month later.
Throughout the trial, clinicians on the team took blood samples from the participants to measure how their immune systems responded. But whether the vaccine worked would only become clear with time: who went on to fall ill with the virus? The vaccinated group or the control?
Kirsten, a trial volunteer from Buckinghamshire, has blood samples taken before being given the Oxford/AstraZeneca Covid vaccine.
In late November, interim results from Oxford’s trials showed the vaccine had an efficacy of 62% in those who received two full shots, rising – intriguingly – to 90% in those who had half a dose followed by a full one. It is not yet clear why this would be, but research is afoot to solve the puzzle.
Oxford Biomedica is manufacturing tens of millions of doses of the vaccine on behalf on AstraZeneca. Production involves various stages, starting with a vial of a frozen master bank of cells, which are thawed out and transferred into larger and larger solutions of media, each time being given time to grow. This takes several weeks until eventually there is enough vaccine to fill a 1,000-litre bioreactor. The solution then goes through a process of separation, purification and concentration before being frozen into 15-litre bags which are stored in special trays, ready to be transferred into individual dose vials at a fill/finish house at a different location.
A biotechnologist conducts tests on the atmosphere inside a vector suite at Oxford Biomedica, during large-scale production of the vaccine. Petri dishes containing agar are positioned around the lab in order to ensure that the environment remains clean and free from unwanted microbes.
The freezers set to -81C, and a drawer with face masks, beard snoods and large gloves at Oxford Biomedica.
At Wockhardt in Wrexham, one of the largest generic pharmaceutical companies in the UK, the vaccine that was manufactured at Oxford Biomedica and developed by the Oxford Vaccine Group is transferred into vials before being packaged ready for distribution.
Bio-technologists at Oxford Biomedica at work with the 1,000-litre bioreactor in a vector production suite at their facility in Oxford, England.
‘Fill Finish’ work taking place on a combination line, putting the Oxford AstraZeneca Covid-19 coronavirus vaccine (ChAdOx1 nCoV-19) into vials, at Wockhardt in Wrexham.
In December, following 11 intense months of vaccine development, manufacture and trials, the Oxford vaccine is poised for approval by medicines regulators. In the UK, the Medicines and Healthcare products Regulatory Agency, has been conducting a rolling review of clinical trials data so it can reach a decision swiftly. Other regulators will perform their own assessments.
Upon approval, a major operation will swing into action to distribute the vaccine from storage facilities to countries around the world. Here, the Oxford vaccine has an advantage. Two other frontrunner vaccines, from Pfizer/BioNTech and the US National Institutes of Health/Moderna, must be stored at ultra-low temperatures until shortly before they are used. This makes distribution of the shots a formidable challenge in some parts of the world. The Oxford vaccine isn’t as fragile and can be stored for long periods at 2C to 4C, or standard refrigeration temperatures. The Oxford vaccine is much cheaper too: about one-tenth of the cost of the other two.
Bio-technologists at Oxford Biomedica check a sample of the Oxford/AstraZeneca vaccine, taken mid-production from a 1,000-litre bioreactor in a vector production suite at their facility in Oxford, England. They are about to do a routine cell count to monitor progress of cell growth in the bioreactor.
AstraZeneca, Oxford’s industrial partner, has agreed a deal to supply the vaccine at about £2 a dose through Covax, a system set up by the vaccine alliance Gavi, the Coalition for Epidemic Preparedness Innovations and the World Health Organization, to ensure all countries, rich and poor, have equitable access to tests, treatments and vaccines. Delivery of the first 300m doses should begin by the end of the year, with 2bn shots available by the end of 2021. A separate agreement with the Serum Institute of India – the world’s largest vaccine producer – secures 400m doses before the end of 2020.
Only once the shots reach people’s arms will the benefits be felt from this staggering and unprecedented scientific effort. There was a time when the cavalry brandished sabres and rifles. Today they arrive bearing needles.