It’s widely believed that the best way of ending the COVID-19 pandemic is a vaccine. One of the most scientifically powerful ways of testing a vaccine involves administering it to people and then exposing them to the virus.
Zeb Jamrozik is a medical doctor and bioethicist who recently completed a PhD at the Monash Bioethics Centre focusing on infectious disease ethics. He was also lead researcher on a Wellcome Trust-funded project, led by Professor Michael Selgelid, on the ethics of human challenge studies in endemic settings.
“Many people don’t realise that to test vaccines, people have to get infected one way or another,” Dr Jamrozik says. The COVID-19 vaccines in development are considered promising when they trigger an immune response – but whether that immune response is protective against COVID-19 cannot be known until it’s tested in humans who are then exposed to the virus.
In May 1796, Edward Jenner inoculated eight-year-old James Phipps with the cowpox virus, using fresh lesions from a dairy maid’s hands. Phipps became ill, but soon recovered, as Jenner hoped he would. He wanted to test if exposure to cowpox would protect Phipps from smallpox. In July of that year, he inoculated the boy again, this time with smallpox. The boy developed no illness, and the world’s first vaccine was created.
“So, that’s a success story,” says bioethicist Professor Selgelid, from the Monash Bioethics Centre. “But it’s also a controversial case, because Jenner experimented on a child who couldn’t give proper informed consent. Later on, Jenner rewarded Phipps with the gift of a house.”
In the past 50 years, challenge studies have also been used to accelerate vaccine development for strains of cholera and typhoid.
During WWII, the Japanese deliberately infected prisoners of war with bubonic plague as part of their biological weapons program, while Nazis infected concentration camp prisoners with tuberculosis. Professor Selgelid says these experiments were barbarous and cruel – but a consensus of bioethicists deny that it was intentional infection with pathogens, per se, that made them immoral.
“The purpose of some challenge studies is to learn how to infect people, to develop what they call a model of infection,” he says, “and these models can then be used in other challenge studies that involve the testing of vaccines or treatments.
“Challenge studies are really powerful scientifically. Quickly, with a small number of people, 20 to 100, you can get an indicator of effectiveness.”
At present, more than 200 possible COVID-19 vaccine candidates are being considered. A human challenge study would allow scientists to assess which of these are most worthy of further development, he says.
But he’s also aware of the many risks involved – including the risk that the wider community would disapprove of the experiment.
“If you do things that the community doesn’t accept, then that can have adverse effects with regard to trust,” he says.
In turn, that could compromise a community’s willingness to accept a future vaccine. Clearly, these work best when they’re widely administered.
In May this year, Professor Selgelid led a working group for the World Health Organisation setting out the key criteria for the ethical acceptability of COVID-19 human challenge studies – and Dr Jamrozik was lead author of the WHO guidance document that resulted.
This guidance document outlines eight conditions that need to be met for an ethical human challenge trial.
It suggests that an ethical COVID-19 challenge trial would be conducted on healthy young people. At present, in the 18 to 30 age group (whether healthy or not), up to 1% of people infected with the virus causing COVID-19 require hospitalisation, and up to 0.03% develop fatal disease – so the risks might not be unreasonable.
But a difficulty with conducting a COVID-19 trial is that the disease is not fully understood, adding to the potential uncertainty.
Nevertheless, Dr Jamrozik says that finding trial volunteers for a COVID-19 trial “doesn’t look like it’s going to be a problem”.
“Lots of young healthy people, including myself, want to volunteer to be infected,” he says. “Now, I’m too old. I’m 36, and the people who’ve thought about this, including me, have said that we should probably start with the lowest-risk adults, so that means people who are 18 to 25 (or 30).”
The ethics regarding recruiting volunteers have improved hugely since Edward Jenner’s time. Dr Jamrozik says volunteers are not only required to sign a consent form, but must also pass a test demonstrating they’ve understood the possible risks involved.
The volunteers would also need to be quarantined in a state-of-the-art facility where they can be monitored and treated, Dr Jamrozik says. At present, no such facilities exist in Australia.
But is a human challenge trial the only way of testing a COVID-19 vaccine? An arguably safer method is through a field trial.
Existing COVID-19 field trials involve injecting 15,000 people with a vaccine candidate, another 15,000 with a placebo, and then monitoring what happens to them when they’re let out into the community.
“Then we can work out whether the vaccine is protecting them relative to the placebo by observing who gets infected and how severe it is,” Dr Jamrozik says.
In places where stringent physical distancing and lockdown measures are in place, a field trial to assess a COVID-19 vaccine could take years. “The harder the lockdown, the less feasible a field trial is to conduct,” he says.
“Unless there’s an out-of-control epidemic, it takes a lot of time for a large enough proportion of those people to get infected, to test the effectiveness of the vaccine,” he says.
Another problem is the large number who must be recruited for a field trial. For example, testing five vaccines by field trials would involve monitoring 150,000 people in total.
Challenge studies, on the other hand, require fewer people (less than 100 typically) and less time (maybe three months, if the humans are infected in stages). Three elements are needed: “a virus prepared in the laboratory to give to people”, a facility “in which you can do it safely”, and volunteers.
Dr Jamrozik suggests a basic payment to compensate people for their time in quarantine could be offered, if the community agrees that a payment is acceptable (as we do for jury duty, for instance).
“The risks of research have to be justified by the scientific or public health benefit,” he says. “We can’t justify more risk by paying people more money. It’s important to emphasise that we’re not talking about paying people for risk here.”
Ideally, a successful challenge trial would be followed by a field trial to monitor how the vaccine is tolerated in a larger population, Professor Selgelid says.
If it’s ultimately found to be safe and effective, the vaccine should then be widely and equitably distributed.
Asked why he studied bioethics after medicine, Dr Jamrozik says: “I was always interested in both medicine and philosophy – and the Monash Bioethics Centre is one of the best places to study philosophical bioethics.
“In medicine, I was most interested in the health conditions that affect the worst-off people in the world. Infectious diseases in general harm people who are poor, vulnerable, and living in countries that are less resource-rich.
“Infectious disease research can produce huge benefits. And not just for COVID. Think about malaria. I don’t know how many COVID deaths we’re up to now – more than half a million worldwide. Malaria kills half a million people every year, mostly children under five in Africa. From my point of view, it’s as urgent that we get a malaria vaccine as it is that we get a COVID vaccine.”
A human challenge trial for a malaria vaccine was conducted in north Queensland earlier this year.
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