Is it game over for coronavirus? Judging by headlines in the first week of November, it seemed the end of the pandemic had been spied over the horizon.
The first whiff of excitement came courtesy of Pfizer/BioNTech, one of the leading teams in the race for a Covid-19 vaccine. An early readout of an advanced clinical trial suggested its vaccine was 90 per cent effective. That result smashes the 50 per cent minimum threshold set by American regulators and lies well beyond the expectations and hopes of most observers, prompting jubilation all round. “Today is a great day for science and humanity,” gushed Albert Bourla, Pfizer’s chairman and CEO.
The news came with a thrilling back- story about the modest married couple, Ugur Sahin and Özlem Türeci, behind German start-up BioNTech. The pair, each the child of Turkish immigrants and already rich from the sale of their first company, are now billionaires. The prospect of an end to the crisis also sent a surge through the markets: cinema chains and airlines got a much-needed fillip in their share prices, while companies that have benefited from lockdown such as Zoom, whose value surpassed $100bn earlier this year, tumbled.
The small print, though, gave pause for thought: the results were revealed in a Pfizer press release, not a published scientific paper; it is unknown how long immunity lasts or whether the symptoms of those who did contract Covid-19 were mild or severe; it has not been revealed how well the vaccine, called BNT162b2, worked in older age groups – the key targets of any nationwide vaccination strategy. Neither do we know whether the vaccine curbs transmission as well as easing disease symptoms.
There were also logistical issues. The formulation needs ultra-cold temperatures to stay stable and is packaged as if James Bond might courier it back to London for M16: special suitcases, lined with dry ice and GPS trackers, are each capable of storing 5,000 doses at -70˚C for ten days, as long as they are not opened more than four times. Even Professor Sahin admitted the logistical challenges meant it would be summer 2021 before the pandemic started to recede.
That first dose of good news was followed by a booster from Moderna, which claimed its vaccine was nearly 95 per cent effective. The US company’s data showed it appeared to work in older people and to stop severe disease. The Moderna vaccine, called mRNA-1273, has the edge on Pfizer in terms of practicality: it can be stored for six months at -20˚C and, once thawed, for a month in a fridge.
These encouraging results, while preliminary, justify restrained optimism. The gamble by many vaccine teams, including Pfizer and Moderna, to build their vaccines by copying the spike protein – the portion of Covid-19 that most readily presents itself to the immune system – is apparently paying off (the Russian Sputnik-V vaccine is also claimed to be more than 90 per cent effective, but details are scant).
“It’s fantastic news because we now know that spike protein vaccines probably work against coronavirus,” says Saul Faust, professor of paediatric immunology and infectious diseases at Southampton University. Professor Faust directs Southampton’s National Institute of Health Research Wellcome Trust Clinical Research Facility, one of the centres that recently started testing a Covid-19 vaccine from Novovax, a small US company, and has just begun a trial of the Janssen Covid-19 vaccine (also known as the Johnson & Johnson vaccine).
The Oxford/AstraZeneca scientists are also widely tipped to report results in the next few weeks. The race for a vaccine is proceeding so rapidly and smoothly that health centres around the UK have been asked to start preparing to administer it, by extending opening hours and running seven days a week.
[see also: Why the Oxford Covid-19 vaccine is crucial for the UK]
Moderna is now expected to apply in the US for “emergency use authorisation” so its vaccine can be rolled out to high-risk groups. But the arrival of the first official vaccine may bring new headaches. Other clinical trials, which could yield excellent second, third, fourth and even fifth Covid vaccines, will not have finished.
That could throw the ongoing trials into ethical doubt. As the BMJ’s Journal of Medical Ethics puts it: “There are compelling reasons why it would be unethical to trial a novel vaccine when an effective product already exists.” Volunteers on other clinical trials would be entitled to pull out to receive a licensed vaccine. The possibility of other vaccine trials collapsing would be a grave setback, according to Kate Bingham, head of the UK government’s vaccine task force: “If we don’t continue all the trials, we won’t know if we have better vaccines coming behind the front-runners.” Bingham adds that nobody has seen the fine detail on the Pfizer/BioNTech results yet.
Some of the immunity snapshots revealed in the preliminary data were taken just weeks after trial volunteers received boosters. Professor Robin Shattock, who is leading a Covid vaccine project at Imperial College London, warned in a tweet that the observed immunity might not endure: “Very concerned over the potential use of percentage efficacy results to champion one vaccine over another – no idea what the efficacy will be at 6-12 months. Could be considerably lower. The danger is that the public will be using this percentage to ask for what they think is best.”
There are also practical imperatives for keeping the vaccine race alive despite Pfizer and Moderna’s early dominance: the bid to defeat Covid-19 is not a national effort but a global one demanding billions of doses – beyond the scope of any one manufacturer. The world needs not only Vaccine One, but also Two, Three and Four – as many as science can throw out.
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Advanced clinical trials for potential Covid vaccines all run along the same lines. First, tens of thousands of people are divided into two groups: a test group and a control group. The test group receives the experimental coronavirus vaccine; the control group is injected with a placebo or dummy formulation that offers no protection against Covid-19 (the Oxford trials use a meningitis vaccine as the control; some use saline solution).
The recipient does not know whether she has received the coronavirus vaccine or the control one – and neither does the person who administered it. This “blinding” is important: a person who knows they might be protected might behave more recklessly.
Then the scientists sit back and wait for participants to get Covid-19 in the real world. In the Pfizer/BioNTech study, 94 people out of more than 43,000 participants developed symptomatic infections. At that point, the study was “unblinded” to find out how the infections were spread across the two groups. The majority of infections happened in the control group that received the dummy, suggesting the coronavirus vaccine was indeed protecting the test group.
Trials vary in how quickly they reach the numbers that allow these statistically meaningful early readouts, depending in part on how much virus is circulating. It can take weeks, sometimes months, to accumulate the necessary numbers. The wait can be longer if the dosing regime requires a booster. The two doses of the Pfizer vaccine are 21 days apart; the Janssen vaccine requires a gap of 57 days between injections. The Moderna doses are a month apart.
The prospect of volunteers dropping out of ongoing trials if they are summoned in spring or early summer to be given an approved vaccine is, according to Professor Faust, “a really important question. Will it affect the trials? We hope not but of course it could. Participants in the Novovax trial have already started asking us about this when they come for their appointments.”
He is heartened that they haven’t cancelled, instead quizzing researchers about the Pfizer news. When people hear why it’s important to science for vaccine trials to continue regardless of developments elsewhere, he says, they have been persuaded to continue.
Mark Honigsbaum is a volunteer who might well face this dilemma next year. The City University journalism lecturer and writer has joined the Novovax vaccine trial, receiving recently his first dose at the Chelsea and Westminster Hospital.
Honigsbaum, author of The Pandemic Century, signed up after being emailed by his GP practice: “I immediately wanted to do it, mostly out of curiosity, if I’m honest, and because it might be useful when I write about it. I think people like me, who promote vaccines as safe and important medical interventions, should be prepared to be guinea pigs for the sake of the wider community. I also have an 88-year-old mother who I see regularly, with social distancing, and it would make it easier if I knew I couldn’t transmit the virus to her.”
Having just turned 60, Honigsbaum might end up being called for a licensed vaccine before the Novovax trial is finished. What will he do? “That’s a difficult one,” he admits. “I think I’d probably continue with Novovax because it’s my civic duty.” He is also keen to see the trial through to the end “because I like the feeling of participating in a scientific adventure”.
[See also: Phil Whitaker on how GPs are preparing for a Covid vaccine – and the hurdles they face]
Professor Faust says that vaccine manufacturers, scientists (including those at Oxford University and Imperial College, home to the UK’s two major vaccine projects) and regulators are working on what to do if participants drop out. “What happens if you’re in a certain age group and you’re called for the vaccine? It’s extremely complicated because people would need to step off the study to take the vaccine, and that’s completely within their rights. That work is now being done in great detail… and we will have a plan by the time those decisions have to be made.”
One question, for example, is whether companies will “unblind” a participant’s status – in other words, tell them whether they’ve received the experimental vaccine or a dummy. That might influence their decision. Will a dropout also agree to come back for check-ups? Follow-up checks are used to gather long-term safety data, which regulators will want to see.
There is an additional safety issue: if a person has received one or two experimental shots, what will be the effect of adding a second vaccine, even if it has been approved? It is unlikely to be a worry, Professor Faust explains, but it will be important to monitor those who end up having multiple different vaccines. One option being discussed is a national study that collects blood samples from this mix-and-match cohort of patients.
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If the Pfizer vaccine is the first to be licensed, the UK is well-placed to benefit: it has signed a deal for 40 million doses. It has ordered five million Moderna doses as well. Altogether, the task force has ordered 355 million doses of six different vaccines for UK citizens, giving it one of the most extensively stocked – and broadest – vaccine portfolios in the world. The UK has additionally paid into Covax, the collective purchase scheme coordinated by the World Health Organisation that provides countries access to vaccines outside national portfolios and secures doses for low- and middle-income countries.
The UK also has a provisional national vaccination strategy, devised by the Joint Committee on Vaccination and Immunisation, which is focused on cutting death and disease and minimising disruption to the NHS. Care home residents and staff, plus healthcare and front-line workers, will be jabbed first (most formulations require injection, though some nasal formulations are being tested).
Provided the vaccine reduces disease in older people, who are most at risk of death and disease, the general population will then be vaccinated by age from the oldest first and down to those aged 50 and over. Younger age groups will be included depending on supply. Children, who seem virtually immune to coronavirus, may be considered for immunisation depending on their contribution to transmission, and the vaccines’ safety profiles.
The fact that Covid-19 vaccines will find their way into such a wide range of people – young and old, sick and healthy – means that the promising news from Pfizer and Moderna is the beginning, not the end, of the story. Researchers are still urging people to sign up for trials; more than 300,000 in the UK have obliged. They are especially keen to recruit from black, Asian and minority ethnic communities, who are underrepresented in clinical testing but are up to twice as likely to become infected with coronavirus.
“It’s enormously important that we have a range of vaccines, not just for the volume of doses, but so we have vaccines that work in different ways,” says Adam Finn, professor of paediatrics at Bristol University, who has also begun testing the Janssen vaccine. “There will of course be an ethical imperative to allow people to receive a vaccine when that age group or risk group is being offered it routinely, but we don’t have a licensed vaccine yet. It would be entirely premature to take our foot off the gas at this point.”
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This article appears in the 18 Nov 2020 issue of the New Statesman, Vaccine nation