Since England’s third national lockdown began in January 2021, Jake Hopkins has been taking extra precautions when he goes to work as a customer assistant at a supermarket in Tamworth, Staffordshire. He’s nervous about catching Covid-19 – not so much because of the risk it may pose to his health, but because it would mean he would miss the opportunity to be deliberately infected with the virus as part of a world-first “human challenge” study that got the go-ahead this week.
During the first lockdown he wasn’t so bothered. “Obviously I was nervous about catching it, but working there was fine; it’s one of the hazards of the job,” he says. “You don’t want to catch it because you don’t want to catch it, but I wasn’t scared of catching it for any other reason. Whereas now, I’m hyper-conscious, I wear three masks, because obviously if I catch it then I can’t take part in the trial.”
Human challenge studies for Covid-19 will see participants purposefully infected with the Sars-CoV-2 coronavirus in the hope of discovering more about the virus, and helping to develop and test vaccines and treatments. Hopkins is one of thousands of volunteers to sign up for a UK study that will be the first Covid-19 human challenge study in the world. But if he already has antibodies to Covid-19, he won’t be eligible to take part – meaning that if he catches the virus before the study begins, he’s out.
Hopkins, who is 23, found out about the idea of human challenge studies last year. Before the pandemic came to the UK, he had been intending to take a gap year from university and go travelling. Deciding he’d rather not do his final year during the pandemic anyway, he took a position at the supermarket and continued to work through lockdowns. Like many people, he spent a lot of his free time looking up information about the novel coronavirus and the development of vaccines that might slow its progress. Around June 2020 he came across an organisation called 1Day Sooner. Set up a couple of months prior, the group advocates for human challenge studies for Covid-19, and allows prospective trial volunteers across the world to register their interest in taking part in such a trial. The idea is that human challenge studies could help test vaccines faster than conventional trials.
For Hopkins, it was a no-brainer. “Pretty much as soon as I clicked on it, really – obviously I read through what it was – I put my name down almost instantly.”
Through 1DaySooner, he later found out about plans for a Covid-19 challenge study in the UK, and immediately put his name down for that too. The UK initiative has received £33.6 million in government funding and is a collaboration between Imperial College London, the Royal Free London NHS Foundation Trust and clinical trial company hVIVO. The study was slated to start as early as January 2021, but eventually received ethics approval on February 17.
The study will kick off in March 2021 and will see up to 90 participants exposed to Covid-19 at a specialised research facility in London. But since Hopkins first heard about challenge studies, a lot has changed. The UK alone has approved three Covid-19 vaccines, with almost 16 million people having already received a first vaccine dose. What can challenge studies still tell us – and is it worth infecting people to find out?
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Before we can consider running challenge studies to test vaccines or treatments, we need to know how much of the virus each volunteer should be exposed to.
The first study that will take place – the one which has received ethical approval – is what’s known as a characterisation study: an initial study to determine the smallest amount of Sars-CoV-2 needed to cause infection. This could then be used to inform subsequent challenge studies designed to test vaccines or treatments, or answer other research questions. It’s a delicate balance: too little, and the participants may not actually contract Covid-19; too much, and they are put at unnecessary risk. Researchers will start by exposing a small group of participants to the tiniest amount of Sars-CoV-2, gradually increasing the dose with a fresh group of volunteers each time, until they find the smallest amount that triggers infection in the majority of people. This will be assessed by measuring the virus coming out of participants’ noses.
“What we’re aiming for is for the majority of people to develop an infection where they shed virus, and that would ideally be something like 70 per cent of people,” says Chris Chiu, a clinical reader in infectious diseases at Imperial College London and the lead researcher for the challenge studies project. “The balance to that is that we need to make sure that people don’t get more serious symptoms.”
This is the main point of contention around human challenge studies for Covid-19: we know that the virus can cause severe health risks. It can be fatal. And if someone does get seriously ill, we don’t have a failsafe cure.
Chiu says he initially thought a challenge study would not be possible for Covid-19. But when it became clearer that younger people tend to get milder symptoms, he and his colleagues began to think it may be possible to run challenge studies without too much risk of harm. “And so that’s when we started thinking about it,” he says, speaking from his home in South London in January.
The study only accepts volunteers at the lowest risk of developing severe symptoms: they must be aged 18-30, with no smoking history and a BMI of up to 28 (with potential exceptions if someone is, for instance, very muscular). There’s a long list of medical conditions that rule a participant out, and all must undergo medical screenings. Martin Johnson, hVIVO’s medical officer, says the criteria are stricter than challenge studies for other viruses; someone who has grown out of childhood asthma and now has normal lung function might be able to take part in an influenza study, for instance – “but we’re saying no, you can’t even have had a recurrent wheeze as a child.”
Still, the risk is not zero. While Covid-19 death rates for young, healthy people are much lower than other demographics (one Public Health England report found that someone aged over 80 is 70 times more likely to die after testing positive than someone under 40), we still don’t know exactly why some people are affected worse than others. Participants may also be at risk of severe symptoms or “long Covid”, whereby symptoms persist weeks or months after initially contracting the virus.
On the other side of the risk-benefit equation are the advantages that challenge studies could bring. But these are also constantly changing. Initially, challenge studies were primarily touted as a way to get a safe and effective Covid-19 vaccine sooner. Challenge studies could streamline or reduce the time taken to run conventional phase three trials, hopefully leading to a successful first-generation vaccine becoming available earlier, and thus saving lives. If Covid-19 transmission levels had decreased significantly, for example due to lockdowns, then challenge studies may have been the only real way to test vaccines; conventional vaccine studies require people to have some community exposure to the virus, in order to see if the vaccinated group proves less likely to be infected than the control group.
But as the pandemic has progressed, things have changed. In December, the UK approved its first Covid-19 vaccine, developed by Pfizer and BioNTech. A second, by AstraZeneca, was approved the same month, followed in January by the Moderna vaccine. China and Russia are among countries to have already approved other vaccines, and vaccine candidates in development by the likes of Novavax and Johnson & Johnson have reported promising results. None of these required human challenge studies.
Even with a first generation of vaccines, however, challenge studies could still help us fill in gaps in our knowledge and understand how better to manage the pandemic. We don’t know much, for instance, about why some people are asymptomatic, and what this means for transmission. When it comes to vaccines, we don’t know how long people will remain protected, nor whether vaccines stop transmission. Challenge studies could help test and compare new vaccine candidates, such as those developed to be stored or distributed more easily, or produced in response to changing variants (challenge studies could be particularly helpful here as you could control which variant study participants are exposed to). They could also help us test antivirals and other treatments.
But while the UK study has received ethical approval, some argue that the potential benefits are not enough to justify a challenge study. “I don’t think human challenge studies involving Sars-CoV-2 are ethical at this point,” says Charles Weijer, a professor of bioethics and research ethics at Western University, Canada. Weijer was part of a World Health Organisation working group for guidance on Covid-19 challenge studies in 2020 and says that he does not believe challenge studies currently meet that guidance. “It’s quite plain that, at present, these challenge studies do not fulfil the ethical criteria set out by the WHO in May of 2020,” he says. (For his part, Chiu says he believes the study does fulfil the WHO criteria, and states that the scientific justification, risks and benefits have been assessed and accepted by the independent ethics committee.)
For Weijer, a human challenge study would need to answer questions that could not be obtained using less risky study designs. While this may be the case for some questions, he believes that, now we have vaccines, they are unlikely to be of sufficient importance to justify the risk to participants – at least as long as we don’t have a cure. “Last March, it was a reasonable thing to say, ‘let’s think about human challenge studies,’” he says. “But a year later, I think it’s no longer reasonable to say that human challenge studies are still somehow part of the solution here.”
He accuses some challenge study advocates of “moving the goalposts” when it comes to the benefits, switching their focus from the need to get an initial vaccine faster to the desire to develop more vaccines. He rejects the idea that challenge studies could play a major role in solving the issue of global access to vaccines, which he says is as much an issue of manufacturing and distribution as vaccine development. “What are challenge studies going to do to address those problems? Well, I can tell you: exactly nothing.”
But Julian Savulescu, director of the Oxford Uehiro Centre for Practical Ethics, thinks that the risk posed by challenge studies is in the same realm as that posed by activities such as driving or donating a kidney, and that individuals should therefore be allowed to volunteer. He argues that challenge studies could reduce the time needed to develop and test a nasal vaccine, for instance, which could be easier to roll out in countries where access to medical equipment such as needles is not a given. If the virus mutates such that it is not responsive to current vaccines, challenge studies could also help to develop new ones faster. “Although it is different now to how it was in March , the value of this research tool is still significant,” he says.
He also thinks that human challenge studies could play into what he sees as a broader human rights issue. At the moment, many countries have restrictions such as lockdowns, which are usually justified on the basis that people may pose a risk to others. But if we know more about the transmissibility of the virus – for example, whether you can still transmit it after being vaccinated or recovering from an infection – then he believes it may not be acceptable to restrict people’s liberties. “I put a lot more significance on that issue, and I think it’s been convenient for us not to know, because everyone can be treated equally,” he says. “But that might not be justified.”
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The streets around hVIVO’s Whitechapel quarantine facility are quiet in November 2020. Cafes have drawn down their graffitied shutters and the bike racks lining the street are empty. A sandwich board outside the facility, located inside the Queen Mary Bioenterprises Innovation Centre, advertises “FluCamp” – the catchy name for hVIVO’s residential clinical trials covering influenza, cold viruses and respiratory syncytial virus (RSV). Inside, a receptionist sits behind a plastic screen and arrows on the floor indicate a one-way system. Seats in the lobby are pushed together, with a sign asking visitors not to sit on them.
Upstairs, Andrew Catchpole, hVIVO’s chief scientific officer, gives a tour. In one room is a screening area, with four hospital beds with curtains. Here, volunteers for challenge studies are given a medical exam to make sure they are healthy enough to participate, and to run blood tests to check that they haven’t already got antibodies to the virus in question. “Obviously, we’re intending to make them sick to an extent,” Catchpole says from behind his face mask. “If they’ve already got enough antibodies that there’s no chance that they’re going to get ill, then they’re not going to be much use to the trial.”
All the viruses the facility uses are naturally occurring in the community, which means volunteers may have antibodies without knowing. For flu studies, as many as 85 per cent of people may be screened out at this stage. For RSV it can be around two thirds. “Covid is a bit more unknown, because it’s a changing number every day,” Catchpole says.
Behind two sets of double-doors, forming a kind of airlock, is the quarantine area. Anyone and anything entering or leaving the quarantine area comes through here, including samples taken from volunteers and sent to the lab on the same floor. Usually, we would not be permitted to enter, at least not without donning a lot of PPE, but when I visit the quarantine area it is not being used. Staff members have set up laptops in one or two of the quarantine rooms, using them as temporary offices.
The first Covid-19 challenge study will take place in a similar facility at the Royal Free Hospital in Hampstead, but volunteers may go through the health screening process at hVIVO’s centre (some already have) and future Covid-19 studies may happen here.
A central nurses’ station looks over the 24 rooms in the Whitechapel facility. Each participant has their own room, with an en-suite bathroom, which they have to stay in for the duration of the study. For Covid-19 studies, this will be around 17 days: participants will spend two days completing a final medical screening before being exposed to the virus; they will then stay for 14 days, after which they will be able to leave if they are shown no longer to be shedding the virus.
The virus used in the first study will be a version of that which has been circulating in the UK since March 2020 – not one of the newer variants which we have less information about and which may be more harmful. This has been developed to a medical grade by collecting samples from patients in UK hospitals and growing the virus in a cell line. Participants will be given the virus in the form of nasal drops via a pipette. Then, they wait. “What we expect to happen is that probably at least half the people will have no symptoms at all, because that’s what we see in natural infection,” Chiu says. Those that do have symptoms will likely start experiencing these four or five days after exposure.
As most participants should not feel too unwell, boredom can become the main challenge – although many find interesting ways to pass the time. In the Whitechapel facility, each room is equipped with a hospital-style bed with table, a desk area, TV, coffee machine and PlayStation. “You name it, they’ve done it,” Catchpole says. Some have brought in guitars with the aim of teaching themselves to play; students have written theses; people have used the time to get started on writing a book. “People come in with these little projects that in normal life you never get a chance to do.” Participants are paid for their time by an amount approved by the ethics committee, which is intended to be sufficient compensation without acting as an incentive for people to take a risk they otherwise wouldn’t. For the Covid-19 challenge study, including screenings and follow-ups, this is around £4,500.
In a separate small kitchen area, trays of food are prepared. Volunteers get a choice of meals, but their diet is controlled – some drug products tested in challenge trials may have interactions with specific ingredients, so participants aren’t allowed to bring their own snacks. Alcohol and cigarettes are also banned.
A day in the life of a challenge study is quite monotonous. As researchers want to track the development of a virus over time, routine is key: three times a day – typically around 6AM, 2PM and 10PM – participants will undergo a nasopharyngeal swab. This involves pushing an extra-long cotton swab through a nostril and up the nose, right to the back of the nose and throat. Catchpole says that it’s similar to a Covid PCR test – except that it goes in deeper. “They’re not painful, but they make little odd sensations,” he says. “They would make your eyes water, yeah.” Volunteers have a nasopharyngeal swab as part of the screening process, to make sure they can tolerate it.
Blood samples are also taken, and participants fill out symptom diary cards several times a day, rating how affected they feel by different symptoms – say a runny nose, or a headache – from zero to three. In the Covid-19 study, they will be given scratch-and-sniff cards to test their sense of smell, and cognitive tests aiming to pick up on even light symptoms. Nurses and doctors also make regular health-check visits.
As well as answering the main question about the minimum level of virus required to cause infection, researchers will analyse data to see how the virus progresses, swab surfaces and take air samples to see how it spreads, and monitor the immune response. “Because it’s such a commitment from these volunteers to come and stay with us for 16 days and have all this stuff done to them, it’s really important for us to get as much information out of each study as possible.”
After the study is complete, participants will be followed up for 12 months to take extra samples and make sure they have no lingering symptoms.
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Some participants have already gone through the initial screening process to take part in the study. One is 18-year-old Alastair Fraser-Urquhart, who is based in Stoke-on-Trent in the West Midlands. Like Hopkins, Fraser-Urquhart learned about the idea of Covid-19 challenge studies through 1Day Sooner. “I just found them and it was like, oh, this is just so intuitive – challenge trials, yeah, sign me up,” he says. He had intended to start university in September 2020 to study cancer biomedicine but got caught up in the UK exam grades fiasco; he hopes to start his course this autumn instead. He initially joined 1Day Sooner as a volunteer, and later took on a paid role as UK chapter manager, leading the organisation’s advocacy work in the UK.
When the government announced that it was funding work on human challenge studies in October 2020, Fraser-Urquhart was caught by surprise. Although he had hoped that challenge studies would happen, he’d considered it as a largely theoretical debate at that point; now the government was putting £33.6 million behind them. “This was wild,” he says.
After learning more about the study from hVIVO, he put his name down as a volunteer. He recognises the risks, and says for him the scariest may be the ones we may not yet know about, such as potential long-term effects. “But the concern is not high enough for me to not want to do a challenge trial,” he says.
His main motivation for wanting to take part is to help get vaccines to the rest of the world. Some of the most widely-used vaccines currently approved need to be stored at very low temperatures or require two doses, which makes global access tricky. He is concerned that, without challenge studies, it may become difficult to test other vaccine candidates if infection rates fall, or if people are less willing to take part in phase 3 studies when there are approved vaccines available. “In terms of [global] distribution, there’s so much more that vaccines could do but without challenge trials might fail to do, and that’s really scary,” he says.
Fraser-Urquhart also thinks that running a challenge study now could set a precedent for future pandemics, laying the groundwork for starting a challenge study earlier. “Right now, for this pandemic, I will admit that the benefits have been somewhat diluted,” he says. “But for the next pandemic, that could be a really, really impactful thing we could do, because maybe the norm then will be to run challenge trials, and the next time around when we have another virus – which is likely to even be in my lifetime – maybe we’ll have a vaccine a lot more quickly.”
Hopkins says that he was initially motivated by the idea of developing a vaccine – any vaccine – sooner, but has only become more steadfast in his decision now that some vaccines are available. He too wants to see more vaccines developed that are easier and cheaper to distribute globally, and believes that the scientific data that could be collected from a human challenge study justifies the risk. “Realistically, even if no vaccine comes from this, there’s still massive other benefits that can come from taking part in a trial like this,” he says.
Hopkins went to hVIVO’s facility for a fitness screening in January, which included blood tests, a lung capacity test and an ECG. The worst bit, he says, was the urine test; he’d drunk a lot of water in preparation but then ended up having to wait a while. “I was like crossing my legs for ages,” he says. He also found one of the tests of lung function nerve-wracking, as you only get so many attempts to do it correctly. He failed his first try, and was worried that he might not be able to do it. “I was getting proper nervous, like ‘god am I not gonna be able to take part in this?’” he says. “I think that sent home how much I really do want to take part in this.”
Now that the characterisation study has ethics approval to go ahead, Hopkins and Fraser-Urquhart are waiting to hear if they have been accepted to take part. Hopkins says the news of the approval was “very exciting”. He’d been getting disheartened by the delays to the study and was concerned it wouldn’t happen, so was delighted to wake up and see the news on Wednesday. (Some of his friends and family, he says, were less happy – “I think some of them maybe were hoping it wouldn’t be approved,” he says.) Fraser-Urquhart says that, given the delays, he’d thought the study was going to be rejected. He was shocked by the news, and immediately went into “work mode”, fielding press requests on behalf of 1Day Sooner. “It’s incredible,” he says. “Really cool. Wow, it’s going ahead.”
Now that ethics approval for the first study has been granted, Catchpole says, the next step is to contact volunteers that meet the pre-screening criteria and undergo the informed consent process, and then start to actually inoculate participants with the virus. This study, he emphasises, is very much the first stepping stone into human challenge studies – an “enabling study” which will then make it possible to run further trials. The ideal outcome at this point would be to find the smallest amount of virus to cause infection, with no safety indications. “That will be our ideal outcome, and it will enable us then to move forward with very quickly using the model to test vaccines.”
Vicki Turk is WIRED’s features editor. She tweets from @VickiTurk
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