There was no fever, just a sore limb. “It was the level of ache you’d get if you hit a wall heavily,” Ewan Birney told me, describing the pain in his arm after being injected. Was he nervous as he waited to be jabbed? “I don’t like needles so I had to look away. But mentally I was in the right place. Someone’s got to do it and I’m happy if it’s me. It’s one of the ways of making the world a bit better.”
Birney is taking part in perhaps the most significant clinical challenge in modern history: the hunt for a Covid-19 vaccine. Being squeamish about needles was the least of his worries; before rolling up his sleeve, he was read out a list of things that could go wrong. “There’s a particularly nasty disease a bit like multiple sclerosis and you think, ‘Really? I don’t want that.’ It gives you pause for thought.” But, as a distinguished scientist, he had already done his research: Birney is deputy director-general of the European Molecular Biology Laboratory and directs its bioinformatics institute near Cambridge. Aside from the rare possibility that the vaccine, developed by Oxford University’s Jenner Institute, might exacerbate an infection (a risk for any vaccine trial), he was reassured by the animal studies and the already completed initial safety trials.
The Oxford University vaccine is one in a crowded and fast-moving field: around 25 Covid-19 vaccines have moved into clinical trials, in countries including the UK, China, the US and Germany. China has just approved a vaccine, created by the Beijing Institute of Biotechnology and the biotech firm CanSino, for use in the military. There is a growing sense of optimism that a success story lurks somewhere in these laboratories and that a vaccine could emerge this year.
But we should be wary of popping champagne corks too early. There are plenty of stumbling blocks that could push the arrival of a vaccine well into 2021 – if one arrives at all. Testing whether vaccines stop infection requires the virus to be circulating, so plummeting infection rates – normally good news – mean a trial can take longer. Even if a vaccine produces antibodies, does this translate into long-lasting protection? How quickly can any winning formula be scaled up and deployed to potentially billions of people? Can a vaccine be distributed equitably across the world, rather than being monopolised by wealthy nations? If a vaccine does become available, will it halt transmission – and will enough people agree to have it to stop the virus in its tracks?
“When mass vaccination programmes start, they will involve a public health logistics endeavour of manufacture, distribution, vaccination and monitoring, bigger than anything humankind has ever attempted,” said Danny Altmann, who heads an immunology laboratory at Imperial College London. “Think along the lines of mobilising for a world war. I’d be gratified to see that arrive some time during 2021.”
Robin Shattock, who leads the UK’s other major Covid-19 vaccine project, based at Imperial, said that funding and logistics, rather than the science, have posed the biggest challenge to his team, as well as the unprecedented pace. Instead of the usual staged, serial nature of vaccine development, everything is being done at light speed in parallel: “While we are working to determine if the vaccine works in clinical trials, we are also having to plan for the manufacture of hundreds of millions of doses in advance.” Imperial’s vaccine, using untried RNA technology, has just entered initial human trials. If it succeeds, the synthetic formulation will be a molecular mini-marvel: one litre contains two million doses.
Shattock said he is more optimistic today than he was two months ago that the vaccine will work – but the prospect of success is one of the things that keeps him awake at night: “One concern is developing a vaccine that works but failing to meet global demand. Our dilemma is that it’s hard to build global manufacturing capacity before demonstrating the vaccine works, but if – and it’s still a big if – it does, everyone will be wanting it immediately.”
In short, everything about making a viable vaccine in the middle of a pandemic is an enormous gamble. Then again, doing nothing would be a terrible mistake.
There are now more than 12 million confirmed cases globally of Covid-19; more than half a million people have died. The pandemic is accelerating, according to the World Health Organisation (WHO). It took from January until early April to reach the first million confirmed cases; it took less than a week to add the most recent million.
“The world is in a new and dangerous phase,” WHO director-general Tedros Adhanom Ghebreyesus warned in June. “Many people are fed up with being at home; countries are understandably eager to open their societies and economies. But the virus is still spreading fast.”
The powerful desire to get back to normal life, or something like it – exemplified by crowded streets in London’s Soho when pubs in England reopened – is serving only to feed the Covid-19 beast. Most people are still susceptible, which means they can become infected – and then potentially transmit to others. Infected individuals can pass on the disease before they show symptoms, if they develop them at all. The death rate is notoriously difficult to compute but estimates hover between 0.5 and 1 per cent. While the disease hits the elderly hard and those with existing health conditions, particularly diabetes, a subset of young and healthy people are at serious risk. That subset cannot yet be predicted in advance, though genetics is thought to play a role. The virus is a discriminatory pathogen; it kills more men than women, and disproportionately affects black and minority ethnic communities, for reasons that have not been fully teased out.
Experimenting: engineers work on monkey kidney cells for a possible Covid-19 vaccine at a Sinovac Biotech laboratory in Beijing, China. Credit: Nicolas Asfour/AFP via Getty Images
Evidence is emerging that the virus attacks not just the lungs but multiple organs, including the brain; it causes blood clots that are implicated in strokes and heart attacks. In a very small group of children, it causes a serious hyperinflammatory syndrome, or Covid-related “toxic shock” syndrome.
The long-term effects on survivors remain unknown. Some survivors of the 2002-04 Sars epidemic endured lingering ill health (Sars, or severe acute respiratory syndrome, was also caused by a corona-virus, but killed around 10 per cent of those infected). One category of Covid survivor is the “long-hauler”, a person who might not have been sick enough to be hospitalised but who is bedevilled for months by multiple relapses and persistent fatigue. For the critically ill, the cheap steroid dexamethasone can improve the chances of survival but it is no guarantee. This is not a virus that anyone should want to catch.
The safest way to avoid the virus is also the hardest: staying apart. Physical distancing entails suppressing the social instinct that is the very essence of our species. The myriad ways in which society crowds people together – in schools, campuses, shops, restaurants, offices, factories, churches, gyms, transport hubs, refugee camps – have become dangerous nodes in a viral transmission network.
While some countries such as Vietnam, Germany and South Korea have been successful at containment, new outbreaks in those international beacons of vigilance demonstrate that the virus will remain with us for as long as there are people to infect. That is why a vaccine, which should cut susceptibility to infection, is widely seen as the best hope for a return to the pre-coronavirus norm. If enough “susceptibles” are vaccinated, the virus runs out of people to infect and transmission chains come to an end. That is the basis of childhood vaccination and herd immunity.
Fortunately, scientists around the world have risen to the immunological challenge of a lifetime: to develop a vaccine to protect against Sars-CoV-2, the virus that causes Covid-19. A tracker run by the London School of Hygiene & Tropical Medicine showed that, as of 6 July, 205 separate projects were in the pipeline. Most vaccines are designed to masquerade as the distinctive spike-shaped protein found on the surface of the coronavirus; this is the molecular “key” used by the virus to infect cells (coronaviruses are named for their signature spiky, crown-like structure).
This spikiness is the pattern that needs to be seen by the immune system to induce the production of suitable antibodies, which then block the virus from entering cells. Then, when the genuine pathogen comes calling, the immune system is primed and ready to fight back.
Different types of vaccines imitate viruses in various ways: traditional vaccines often use a live attenuated or inactivated dose of the real virus or viral proteins (such as for measles). Live attenuated vaccines must provide sufficient infection to induce an immune response but not so much that it causes disease. Achieving that delicate balance makes them relatively slow to produce. Inactivated types are quicker to make but are regarded as a bit less effective.
Instead of delivering the real virus or viral proteins, newer RNA or DNA vaccines merely deliver a genetic code, or recipe, so that the body’s own cells can generate the corona spike (essentially, getting the body to build its own likeness of the spike in order to kick-start the production of antibodies). These newer vaccines can be manufactured quickly, as soon as a pathogen’s genetic code is sequenced. One sign that the global fight against Covid-19 is pushing the scientific envelope? No RNA or DNA vaccine has ever been licensed for use in humans.
One eagerly anticipated RNA candidate comes from the American biotech company Moderna (spun out of Harvard a decade ago, it originally styled itself ModeRNA), which is running trials with the National Institute of Allergy and Infectious Diseases in the US. Its candidate entered clinical trials a record 63 days after the pandemic virus was sequenced. The Moderna vaccine is one of five picked for financial backing by Operation Warp Speed, the US government’s plan to secure 300 million doses for US citizens by 2021. The other four contenders come from Oxford/AstraZeneca, Johnson & Johnson, Merck, and Pfizer.
It is, Danny Altmann says, almost impossible to pick a winner in advance, partly because the various scientific approaches – from the traditional vaccines favoured in China to the untested RNA vaccines coming on stream elsewhere – brook minimal comparison.
All vaccines follow, broadly, the same testing regime. The first stage is pre-clinical trials, which includes laboratory work and animal studies, to check that the vaccine stimulates antibodies and does not cause obvious harm. Then come the human trials: phase one, in only a handful of individuals to make sure the vaccine is safe in people; phase two, typically involving hundreds of people, to expand safety checks, measure immune response and refine dosing; phase three, involving thousands of volunteers, to ensure the vaccine works at scale and to reveal any rare adverse side-effects.
Efficacy is measured by splitting volunteers into two groups: those in the test group receive the experimental Covid-19 vaccine while those in the control group are given a placebo (the Oxford trial uses a standard meningitis vaccine as the placebo). Infection rates in the two groups are later compared; the Covid-19 infection rate should be lower in the test group. More than 10,000 people, including children and older people, have begun receiving the Oxford vaccine, or meningitis placebo, across the UK in a combined phase two/three trial.
Credit: Noma Bar
Often, everything comes down to that final furlong. “Phase three has been by far the biggest bottleneck in vaccine development pipelines in recent years, and there are no guarantees,” Altmann warns.
A hurdle some clinical trials face is that, as infection rates fall in the community, the likelihood of vaccinated volunteers becoming exposed to coronavirus shrinks. Trials are usually heavily stacked with healthcare and other front-line workers, who run a higher-than-average risk of contracting the disease. But if encountering the virus becomes a rare event, it becomes harder – and takes longer – to detect a true difference in infection rate between the two groups. As a precaution, the Oxford team is also trialling the vaccine in Brazil and South Africa, where Covid-19 is on the rise.
Another way of speeding matters up is to think the previously unthinkable. The WHO is contemplating whether vaccinated volunteers could be deliberately infected with Covid-19 to expedite trial results. So-called human challenge trials are ethically permitted to find vaccines against treatable and curable conditions such as malaria.
Covid-19 is not curable. That has not deterred the 30,000-plus who have signed up to 1daysooner.org; these are members of the public willing to be infected with the pandemic virus to speed up vaccine research. Moderna has shown interest. Professor Birney, a husband and father of two, balks at the idea: “I’m not sure I would volunteer for a human challenge trial. I think that might be a bigger responsibility when it comes to your family.”
The AstraZeneca/Oxford vaccine, called AZD1222, is regarded as a front-runner because it is at the final stage of testing, is backed by Operation Warp Speed, and because manufacturing capacity is already in place: AstraZeneca has committed to supplying up to 400 million doses to European countries at no profit, with the first batches due for deployment as early as September.
Imperial has chosen to sidestep Big Pharma by setting up a social enterprise to roll its vaccine out quickly and cheaply to low- and middle-income countries. It feels like a riposte to Donald Trump’s “America First” pandemic response: he has bought up global stocks of remdesivir, an antiviral drug produced by a US company that shortens the hospital stay of the sickest patients (but does not appear to affect survival chances).
Trump wanted to corner potential vaccine spoils, too: earlier this year he reportedly tried to buy CureVac (the firm denied this), a well-regarded German company that has advanced to human trials with an RNA vaccine. The German government recently acquired a 23 per cent stake in CureVac, at a cost of €300m, leading to speculation that the move was intended to forestall the possibility of a foreign takeover.
The prospect of “vaccine nationalism” has led to the setting up of the Access to Covid-19 Tools Accelerator (ACT Accelerator), a collaboration between partners such as the WHO, the European Commission, the Bill and Melinda Gates Foundation, the Coalition for Epidemic Preparedness and Innovations, and various national governments. One goal of the $31bn plan, still to be fully funded, is to secure two billion doses of vaccine, half of which will go to low-and-middle-income countries, by the end of 2021. It recognises the reality that struggling countries cannot be left to go it alone in the age of global contagion.
But, for all the grand plans and big hopes, those who have been at the sharp end of vaccine development are wary of assuming success. Ultan Power, professor of molecular virology at Queen’s University Belfast, spent nine years trying to make a vaccine against respiratory syncytial virus (RSV), a serious respiratory condition that, among infectious diseases, is second only to malaria as a cause of death in babies under a year old. Distressingly, two toddlers died in the 1960s during vaccine testing; there is still no vaccine.
“Tons of RSV vaccine candidates have failed,” Power said. “I was involved in the first one to get to phase three clinical trials – and it failed due to toxicity. This tells me that we must be cautious that lots of things can go wrong, not least of which is the safety of the vaccine, as well as whether it is protective. As you expand to deliver a vaccine to billions of people, even a small frequency of adverse effects will have a significant impact. A vaccine is meant to be given to healthy people and you don’t want it causing more harm than good.” A recent YouGov poll showed that a third of people would likely refuse a Covid-19 vaccine or were unsure if they would have it.
Power cautioned that breakneck development speed meant that some aspects, such as dosing, were matters of educated guesswork. There is also a lack of clarity about the immunological characteristics of the virus itself: not all infected individuals seem to show evidence of antibodies; of those who do, antibodies wane after several months in some. There is no certainty, in other words, that antibodies induced by any of the vaccines will confer useful and long-term protection against infection. There is also a frustrating paradox: the elderly most need a vaccine but might benefit the least because of “immunological senescence”, an age- related deterioration in the immune system.
“The big concern for me is the massive hype and pressure that’s been put on the delivery of a vaccine,” Power said. “If it fails, and it is possible that all of them will fail, then what next?”
In that case, measures such as social distancing, respiratory hygiene, hand hygiene and mask wearing will not be ending any time soon: “The virus will be with us and we will have to live with it,” Power said. “Our personal choices will have a big effect on transmission – and it would be morally repugnant not to take mitigating action to protect the most vulnerable.”
This article appears in the 15 Jul 2020 issue of the New Statesman, Race for the vaccine