The daily toll of new infections. The number of hospitalisations. The numbers in ICU. The R-0 number. The cases per 100,000 people. For more than eight months now, almost every aspect of our lives has been dominated by daily, grim readings of the Covid-19 data.
And then, last Monday at 11.45am, a press release featuring a whole new set of numbers landed in news editors' inboxes: 43,538 – the number of people enrolled in the trial for Pfizer and BioNTech's BNT1 62b2 vaccine; 94 – the number of confirmed cases of Covid-19 evaluated; 90 per cent – the vaccine's estimated efficacy.
More numbers quickly followed: 300 million – the number of units of the vaccine to be bought by the EU; 3.03 million – the likely number destined for Ireland; 198 – the number of other potential vaccines at various stages of development; 11 – the total number in Phase III trials.
Could these numbers really herald the beginning of the end of Covid-19?
We don't know how long the protection will last. That's an absolutely key question to figure out <br/>
That 90 per cent efficacy rate astounded many working in the field, who had – at their most optimistic projections – been hoping for a rate of between 70 and 80 per cent. Anything over 50 per cent effective would have been considered good enough to be licensed.
So this was an "extraordinary" result, said Dr Anthony Fauci, the US government's top infectious diseases expert. Ireland's chief medical officer, Dr Tony Holohan described the results as "hopeful" but "too early to celebrate". The world markets had no such doubts: stocks in pharmaceutical companies, airlines, hotels and cinemas soared; shares in Zoom plummeted.
So what happens next? How soon can we really expect to get our old lives back? Do the notes of caution causing Holohan and others to hold off celebrating just yet outweigh the causes for optimism?
“A really good day”
Monday "was the happiest day I've had in the context of this pandemic for a very long time," says Prof Gabriel Scally, president of the Epidemiology and Public Health Section at the UK Royal Society of Medicine, and a member of Independent Sage, the committee advising the UK government on Covid-19. "This was great news – and not just because of this one vaccine, because I think it's a pathfinder for what is to come."
Prof Karina Butler, infectious diseases specialist at the Royal College of Physicians in Ireland and chair of the National Immunisation Advisory Committee, greeted the news with "tempered optimism. This is a press release, and we have to wait for the data, but there's no reason to think the data won't confirm what's in the press release."
"It was a really good day for everyone who works in the vaccine field," says Dr Anne Moore, a lecturer in biochemistry in UCC, who previously worked in Oxford with the team behind the AstraZeneca vaccine, one of the 10 others now at Phase III trial stage. "Until we had that news, we didn't know if the vaccine – which worked in animal trials – would actually work in humans. Until you can show that it works in humans, it's still theory."
Caveats
Despite all this, there are some important caveats. We don’t yet know the vaccine’s actual efficacy – it could turn out to be lower than the 90 per cent rate, which was based on just 94 confirmed cases of Covid-19. Pfizer has said it will continue its trial until there are 164 cases.
We aren’t sure how well it will work in older people, who have a more depleted immune system. We don’t know if it prevents asymptomatic spread. We don’t know whether rare side effects might emerge later. We don’t yet have a clear picture of how long it will take to get doses to everyone who needs it.
And, crucially, “we don’t know how long the protection will last. That’s an absolutely key question to figure out,” says Moore. “It would be great for immunologists to be able to look at someone seven days after immunisation and say ‘you’re going to be protected for three years,’ but we can’t. Antibodies might wane over three to six months. Or they might stay high for a year. Or 10 years.”
Do these outstanding questions outweigh the causes for hope? All of the experts interviewed for this article are united on this question: no.
New vaccines
Even if the Pfizer vaccine doesn’t ultimately live up to the early hype, it’s unlikely to be our only one.
The AstraZeneca trial of ChAdOx1, which is being carried out in conjunction with a team at Oxford University, is expected to report results “in the next weeks and months”. Moore, who previously worked with the team in Oxford, believes it “has a very good chance as well”.
Early reports suggest it may produce an immune response in older volunteers. There is also optimism about a potential Johnson & Johnson vaccine, which won’t require the same kind of storage as the Pfizer one.
Crucially, one of the other vaccines being developed by American biotechnology company Moderna, uses the same new technology as the Pfizer vaccine. The mRNA approach – which delivers a piece of genetic coding that instructs human cells to produce their own components of a targeted virus, rather than tiny and safe doses of the virus itself – has never been shown to work in humans before.
Using mRNA technology to develop a vaccine "has been the holy grail of immunology research, and Covid was the impetus to really push on that," says science writer, David Robert Grimes.
Ultimately, a number of these vaccines may work together in concert, with some more effective for particular demographics than others. “It is great from a number of perspectives that there is more than one vaccine to use in the population overall,” says Moore.
Human challenge trials
One of the intriguing next stages will involve human challenge trials – clinical trials in which healthy volunteers are exposed to Covid-19 in a controlled setting.
The world's first human challenge trial for Covid-19 will be run by an Irish company, Open Orphan, at the Royal Free Hospital in London. Involving 30 to 50 participants, and presuming it gets final regulatory and ethical approval, the first one will begin in January.
Open Orphan got involved in human challenge trials after it acquired a British company, hVIVO last January, which has a long history of running this kind of trial for illnesses such as influenza. “It was in rag order [financially], but it did have one claim to fame. It was the world leader since 1989 in the testing of vaccines and antivirals in human challenge studies,” says Open Orphan’s chairman, Cathal Friel, whose background is in stockbroking and finance.
Last month, Open Orphan signed an initial contract that could be worth approximately £10 million (€11.14 million) with the UK government to develop the Covid challenge study, and another contract for three further challenge studies.
During the trial, young, healthy volunteers will be exposed to small doses of Covid-19 in a safe setting in the dedicated unit. In later trials, they will be injected first with either a potential vaccine or a placebo. “They get two days to settle in, making themselves at home in a private room with a TV, Xbox, iPhone, anything they want and they get hotel-standard food. The only thing you’re not allowed is that you’re not allowed to leave that room for two weeks or to take alcohol,” says Friel.
Two days in, “they get a very small version” of whatever virus is under investigation: in this case, Covid-19. If they test positive, they will be treated with the antiviral remdesivir, which has been shown in trials to speed up recovery times. The study lasts two weeks and volunteers are compensated for their time with a fee of £3,500, about €3,900, a sum set by a UK ethics panel.
Friel announced publicly in March that he would be one of the volunteers in the first human challenge trial for Covid. But at 55, he’s too old, so instead, he will take part in a challenge trial for another virus.
There are serious ethical considerations involved in these trials, so they are “never undertaken lightly,” Peter Openshaw, an immunologist at Imperial College, which is working with Open Orphan on the study, told the journal Nature. But human challenge trials allow researchers to pinpoint the accuracy of vaccines much more quickly.
“With any trial, you are at the mercy of the level of infection in the community. If you only have three positive cases out of your 43,000 participants, you can’t give an answer with any confidence,” says Moore. “Controlled human challenge trials are still very much on the table” as part of the race for a Covid vaccine, she believes.
“It’s not the case that now we have one vaccine on the table, we can shut up shop. As time goes on, and we have more effective therapeutics and more effective methods of understanding if somebody will have a severe infection or not. [Challenge trials] allows us to monitor controlled infection very, very closely.”
Butler says that this kind of experimentation “certainly would provide a definitive answer. With Covid, we’re still learning about antibody responses, and what specific antibody levels might constitute a protective response. So it’s in that interim phase where one could argue that if you go to human challenge trials, you might get a definitive answer and know that your vaccine is effective. But the counter balancing argument would get into the ethics of how safe it is.”
All of those considerations would have to go into the mix, she says.
Friel is not a scientist, but he is bullish about the vaccines he believes are due to come on stream over the next year. “There are nearly a dozen good Covid vaccines coming closer to approval around the world. Every month for the next nine months there is likely to be yet another new one approved,” he believes. “Some will fail, but many will work and will get approved. By next summer, I believe Covid will be close to a bad memory.”
Who gets it first?
For now, however, there is just one vaccine on the horizon, and the big question for governments around the world is who gets it first. Guidance on this has already been published by the World Health Organisation and authorities in the UK and the US. The US National Academies of Sciences, Engineering and Medicine puts healthcare workers and first responders at the top of the list, followed by people with underlying conditions, older adults in nursing homes, essential workers at high risk of exposure such as teachers, people in crowded settings, and then, by degrees, the rest of the population. The UK plans to roll it out according to a simpler, age-based programme, starting with the oldest citizens.
Ireland’s approach hasn’t been made publicly available, but it is understood it could target older and vulnerable people and essential workers first. Teachers are likely to be prioritised above the general adult public.
“You’re aiming to ensure there is equity of access based around justice, fairness, transparency. You’re balancing [factors including] your disease burden, the severity of the at-risk groups; the impact on society, the availability of the vaccine, the vaccine specific information, and the operational feasibility. All of that will come in, and then it will be a phased approach because there won’t be enough vaccine anyway,” says Butler.
Two big challenges
There are two significant obstacles that will need to be overcome in getting the Pfizer vaccine out to people who most need it. The first is logistics – the vaccine requires two jabs to be administered three weeks apart, and it must be stored at temperatures of minus 80 degrees.
“These are very significant logistical challenges, but not challenges that can’t be met,” says Butler. “It may require novel ways of thinking about where and how vaccines are to be delivered. It’s not going to be easy to have a vaccine that needs to be stored in this way in every corner pharmacy.”
The second challenge is persuading the public to trust it. Before the Pfizer news came out, only 55 per cent of the population said they would take a vaccine if offered, according to the monthly Ipsos MRBI IPHA Covid-19 Vaccine Tracker. Twelve per cent would turn it down.
“People see new and they get afraid,” says Grimes. “We are very primed for negative stories, and anti-vaccine propagandists realised this years ago. It doesn’t matter if you explain that after clean water and sanitation, nothing in human history has saved more lives than vaccinations. They will tell you a scary story about someone’s cousin who once got a vaccine and is now in a wheelchair, even if they can’t name that person, or prove it was caused by a vaccine.”
Winning people over to the vaccine will be essential to allowing normal life to return. “It’s a big job to persuade 90 per cent of the population to get a vaccine like this,” says Scally.
The signs are very promising <br/>
The recent new strain associated with mink in Denmark shows “this virus will shift and change in terms of its genetic makeup. We don’t know whether it’ll become a seasonal virus like influenza. But we know enough to know that is an extraordinarily versatile virus, very dangerous and very infectious.
“It would be wrong to think that we’re going to create this fantasy of herd immunity, and then we’ll all be fine. Because all you need is one arriving traveller from the other side of the world with a different strain encountering a parcel of people who haven’t been immunised.”
Does the speed mean safety has been compromised? Absolutely not, says Butler. The speed has been “amazing . . . But a lot of that has been due to the additional resources that have been put in, and the speed of handling a lot of the bureaucracy, without compromising moving through the three phases, or the safety monitoring throughout. It has been very fast, but it has been about developing efficiencies rather than any kind of sloppiness.”
Amidst all the optimism, Grimes does offer a final note of caution. Science can be unpredictable, and all we have from Pfizer at this point is a very promising press release. “This will be the most pored-over data probably in the history of medical research. Every eye in the world of medicine and science will be looking at these results and insights.
“At the same time, we have to wait until all the research is out and independent experts, other scientists and doctors have been able to analyse the data. But the signs are very promising.”
