Shi Zhengli, a top virologist nicknamed China’s “bat woman” for her pioneering research on bat viruses, has spent much of 2020 answering controversial questions thanks to US President Donald Trump’s disputed coronavirus origin theory targeting her lab.
But when she joined a World Health Organisation (WHO) advisory group in April, she was tasked with weighing one of the most pressing ethical dilemmas in humanity’s fight against the Covid-19 pandemic: is it justifiable to deliberately infect healthy young people with the disease if it helps scientists discover a vaccine?
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The process is called a “human challenge trial” (HCT), and Shi was among a group of scientists gathered by the WHO to look into the feasibility, and pros and cons, amid mounting advocacy from volunteers, politicians and scientists.
The global acceleration of the Covid-19 pandemic, which has infected nearly 17 million people and killed over 666,000, has prompted some scientists, ethicists and volunteers to challenge the traditional views about HCTs – but they all agree that such trials must be done ethically and with the free consent of volunteers.
The WHO advisory group, comprising more than two dozen scientists from different countries and disciplines, discussed technical issues about how to design and implement human challenge trials, should the green light be given by a future ethics committee and health authorities.
Among the questions the team grappled with, three were particularly contentious.
First, should such trials be carried out even if there is no cure for Covid-19?
Second, the most probable HCT trial would recruit young, healthy volunteers to minimise the chance that they might die or become seriously ill after infection. But studies have found that elderly people, the group most vulnerable to the disease, are less responsive to vaccines. So, would it be worth the potential risks to find a vaccine that may not work for those who need it most?
Third, would human challenge trials shorten the time to discover a vaccine? Would scientists gain any distinct advantage by exposing volunteers to the risks?
The experts in the WHO advisory group were split on the first and third questions, while the majority thought elderly people might not benefit from the findings of the trials. How Shi voted on these questions was not known. She did not reply to an email query from the South China Morning Post.
Human challenge trials are not unprecedented and have helped scientists learn how to treat other infectious diseases such as cholera, malaria and influenza.
For years, there has been a consensus among medical ethicists and scientists that deliberately infecting volunteers can only be justified if there is an effective treatment for the disease and that it will not cause death.
A weakened form of the virus is typically used to minimise harm to volunteers and there should be ample evidence that these trials could accelerate the development of a vaccine.
But the divisive views on these questions show how discussions about HCTs have entered uncharted territory.
For example, a previous proposal to use the human challenge model to test a Zika vaccine was rejected by an ethics committee in 2016 due to the risks it would pose to the volunteers and their sexual partners.
Nir Eyal, a biomedical ethicist at Rutgers Global Health Institute, argued in a peer-reviewed paper published in Ethics and Human Research in May that the lack of proven treatment, plus the likelihood of deaths or other severe adverse events, are not the most crucial questions when debating the ethics of HCTs.
“The right question is whether challenge trials would increase study participants’ likelihood of similar bad outcomes, compared to two alternative scenarios: non-participation in any trial and participation in standard efficacy trials for the same vaccines,” he wrote.
He argued that a volunteer might face lower risks when intentionally infected than in a conventional clinical trial because the volunteer’s condition would be monitored at an HCT facility and they would be treated as soon as possible.
Some scientists are also challenging the conventional argument that HCTs are justifiable only when it can expedite phase-three clinical trials. They argue that HCTs can be used to compare the efficacy of different vaccines, even if they cannot accelerate or replace phase-three trials.
A number of the vaccine front runners – including those developed by Oxford, Moderna, BioNTech/Pfizer and Chinese firms like Sinopharm and Sinovac Biotech – have already started phase-three clinical trials or will begin soon. They expect results by the end of the year or early next year.
Professor Adrian Hill, director of Oxford University’s Jenner Institute, announced earlier this month that he would collaborate with the volunteer group 1Day Sooner to prepare for possible HCTs in addition to phase-three clinical trials.
“We see considerable potential in the use of human challenge studies to accelerate Covid-19 vaccine development, [to help filter] and validate the best candidate vaccines, and optimise vaccination approaches,” he was quoted as saying in a statement issued by 1Day Sooner.
“We’re hoping to be doing challenge trials by the end of the year,” he told The Guardian. “This might be in parallel or might be after the phase-three trial is completed. They’re not competing options, they’re complementary.”
This week, a total of 32,665 people from 140 countries have signed up as volunteers for a potential HCT organised by 1Day Sooner.
Abie Rohrig, a spokesman for 1Day Sooner, said no volunteers had asked to withdraw, despite some new findings pointing to possible long-term damage to organs such as the kidneys, heart and nerves, although they were rare among young adults.
“I have not heard from any volunteers about withdrawing because of these risks. Every volunteer I have personally spoken with understands that there is a large degree of uncertainty with respect to Covid-19, and they are willing to take on that uncertain risk in a challenge trial,” Rohrig said.
Advocacy for HCTs received another important boost after over 150 scientists and academics, including 15 Nobel laureates, signed an open letter to Francis Collins, director of the US National Institutes of Health, asking the US government to work with world bodies to make immediate preparations for HCTs. But they also said a high-quality ethical review was required before HCTs could start.
Seema Shah, a bioethicist at Northwestern University who was the main author of the ethics panel report on Zika, said that the advocacy was unprecedented.
“HCTs for Covid-19 have a tremendous amount of advocacy behind them that is unprecedented, for two main reasons. First, the advocacy group 1Day Sooner has been working hard to keep media attention focused on HCTs. Second, the widespread damage that has already been done by Covid-19 leaves the public grasping for any way to speed up vaccine development,” she said.
Some scientists have questioned whether the risks for volunteers are justifiable.
In an opinion piece published on the US medical website STAT, Michael Rosenblatt, chief medical officer of Flagship Pioneering and former chief medical officer of pharmaceutical giant Merck, wrote: “These authors, like 1Day Sooner’s volunteers, are well-intentioned but wrong.”
Rosenblatt, who is also an adviser to Moderna, said HCTs took months to prepare and Covid-19 vaccine development would not be accelerated by testing young volunteers.
“The volunteers might end up having risked their own health without truly helping those who are in greatest need of vaccine protection,” he said, referring to the elderly.
“An equally disturbing scenario is what if one of the first volunteers dies, either due to the play of chance, a problem with the vaccine, or the individual’s genetic make-up? This is unlikely to happen, but it can, and did, in another setting with consequences that stretched far beyond the single tragic death,” he wrote. He was referring to the death of an 18-year-old volunteer in the first gene therapy trials in 1999. The death put similar research on hold for years.
Shah said that HCTs could be considered when treatment was found in the future and may be used for vaccine comparison, but not right now.
“In the short term, HCTs may not be needed and should not be approved if they are not needed,” she said. “However, HCTs may be worth doing in the longer term if we have more knowledge about how to decrease risks and treatments for people with Covid-19, and there are other reasons to do them.”
Chinese virologist Shi is in a subgroup advising on which virus could be used in HCTs, especially because scientists have not manufactured a weaker version of Sars-CoV-2, the clinical name of the coronavirus. Rohrig said volunteers wanted to use wild strains as the data was more robust.
Shah said an active HCT would widen the Overton window about when it was acceptable to pursue trials.
“If HCTs are green-lighted now, when there is substantial uncertainty about the risks, they could set a new precedent for the level of risk and uncertainty that is tolerated in research,” Shah said. “If there are bad outcomes in these trials, or if the vaccines tested in them have safety issues when given to the general public, HCTs could hurt public trust in vaccines in the longer term.”
Owen Schaefer, a bioethicist at NUS Yong Loo Lin School of Medicine in Singapore, opposes HCTs but said that, even if the trials were given the go-ahead, they should not set a precedent for future trials.
“These are exceptional times, with perhaps the most rapid, well-funded, internationally coordinated effort to eradicate a particular disease in human history … Our approach to challenge studies would likely remain the same as before.”
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This article Vaccine race: ‘unprecedented’ momentum and questions for deliberately infecting volunteers with Covid-19 first appeared on South China Morning Post