Bengaluru: The Jenner Institute, which is working collaboratively on developing the promising vaccine candidate from University of Oxford, is considering human challenge trials to expedite results, according to a report in The Guardian Thursday.
Human challenge trials (HCTs) are those where participants are exposed to the virus on purpose, which is normally not allowed for ethical reasons.
Exposure occurs in controlled laboratory settings, which would mean that the trials could potentially be completed in just a few weeks and require fewer people.
Adrian Hill, director of Oxford Jenner Institute, said the team were working on the technical side of the preparation for a human challenge trial, and it hoped to recruit volunteers within months.
“We’re hoping to be doing challenge trials by the end of the year,” he said. “This might be in parallel or might be after the phase three trial is completed. They’re not competing options, they’re complementary.”
The statement follows an open letter written by 125 academics, doctors, epidemiologists, scientists, and professors, including 15 Nobel laureates, asking for human challenge trials to address the urgent need for a vaccine to curb the pandemic.
“If challenge trials can safely and effectively speed the vaccine development process, there is a formidable presumption in favour of their use, which would require a very compelling ethical justification to overcome,” they wrote.
The World Health Organization, in May, had released detailed guidelines for human challenge studies for Covid-19 and how to mitigate their risks.
Advantages of human challenge trials
Vaccine development is a long and laborious process, where after the establishment of safety, comes the establishment of efficacy. These trials take place in phases, where first safety is established in Phase I trials over a few months, followed by Phase II and III trials on hundreds to thousands of people to monitor their efficacy and side effects.
The Oxford vaccine, called ChAdOx1 nCoV-19, is currently undergoing Phase II/III trials in multiple countries, where thousands have been given the vaccine and are being followed up with — a process that consumes time, but is standard.
The vaccine’s Phase I safety results are expected Monday, and the ongoing trials are based on established safety from past work with the adenovirus used in the vaccine.
It is because pathogens can have dangerous effects on the body and because we now have even less information about novel pathogens, it is not a standard practice to infect humans with a pathogen to test the efficacy of a drug or vaccine.
Instead, volunteers are administered the vaccine and are monitored. The control group, which isn’t given the vaccine, is usually given a placebo vaccine and wouldn’t know it. The researchers then wait to see if the vaccinated group contracts the virus, especially whenever the control group does.
The trial is made hard by physical distancing measures, preventing participants from getting infected.
This is why standard vaccine development takes 10-15 years. By skipping multiple standard early steps, Covid vaccine is expected to be rolled out in 2 years.
The intensively long time period can somewhat be mitigated by enrolling a higher number of patients. Phase II studies typically have only a few hundreds of patients and Phase III a few thousand. However, the Oxford vaccine is undergoing a combined Phase II/III trial involving over 10,000 participants already in the UK, Brazil, and South Africa.
But human challenge trials can greatly speed up the process.
Under extremely precautious laboratory conditions, with measured viral loads and a whole host of other restrictions, the virus is exposed to young, healthy adults who don’t have pre-existing conditions and have developed antibodies since vaccination.
This removes the wait for a real-world situation to play out and directly tells us whether the vaccine works or not.
Many virologists, immunologists, ethicists, and other experts have asked for replacing Phase III trials with HCT.
Dangers and WHO guidelines
Supporters of HCT do not discount the risks associated with such studies.
“Obviously”, wrote epidemiologists Nir Eyal, Marc Lipsitch, and Peter G. Smith in a paper earlier this year, “challenging volunteers with this live virus risks inducing severe disease and possibly even death. However, we argue that such studies, by accelerating vaccine evaluation, could reduce the global burden of coronavirus-related mortality and morbidity.”
Volunteers must ethically give informed consent to HCTs (and any clinical trial), and should be fully informed of the risks, monitored closely, and should they contract an infection, be given the best possible care.
After the Nazi regime’s unlawful and unethical experiments on humans, the Nuremberg Code was instituted in 1946, consisting of 10 principles of an ethical framework for research involving humans. It puts extreme restrictions on risks involved even if participants have given informed consent to them, mandates autonomy of participants (including them dropping out midway), and stresses on high value from the output of the studies.
Experts argue that the loss of few in the worst case, painful as it might be, would be worth saving the lives of billions more. And volunteers should agree too. However, HCTs have been conducted regularly, with no negative effects so far, because such trials are designed with the farthest extreme levels of safety.
“It introduces risks, it also removes risks,” said Eyal about HCT study designs. “And the net risks, while unclear, are not clearly extremely high.”
And a big risk also includes litigation by participants and families.
“Any harm resulting from [normal] research is foreseen but not intended. On the other hand, harm resulting from deliberately infecting an individual with a disease cannot plausibly be described as unintended,” argue bioethicists T. Hope and J. McMillan.
History and future
HCTs are not without precedent.
The very first vaccine, the smallpox vaccine developed by Edward Jenner in 1796, was conceptualised and tested by inoculating willing people with material from the pus or wound of an infected person. And there too, safety was demonstrated.
Jenner didn’t start using smallpox inoculation, he used material from cowpox, which belonged to the same family, so humans produced antibodies to it, but it caused a mild, non-threatening illness.
HCTs have contributed to the development of vaccines for yellow fever, influenza, typhoid, cholera, and malaria (ongoing), with no real risks or dangers of any sort so far. Vaccine candidates are tested for safety on many different animals before being administered to humans, and participants are monitored every day with extreme thoroughness. Experts say the risk is equivalent to that of a kidney donation.
Strict guidelines have also been issued by WHO earlier this year, pointing out that most other HCTs have been for a disease that is curable.
Covid-19 doesn’t have a cure. Further, it warns of loss in trust in vaccination in the face of an already growing anti-vaccine sentiment based on pseudoscience.
However, it is precisely in situations like this where HCTs are most warranted, ethicists around the world have agreed, and have thus issued multiple guidelines.
The WHO guidelines outline eight key criteria for SARS-CoV-2 challenge studies. These include strong scientific justification after risk assessments and study design in consultation with experts from various backgrounds. Every participant must provide fully informed consent, and studies have to undergo rigorous peer review.
The Oxford study and any other vaccine HCT will have to follow such guidelines strictly. Volunteers for such trials have already expressed willingness.
A global initiative called 1DaySooner, where the scientists and Nobel laureates had published their open letter, has already registered over 32,000 volunteers in over 140 countries.
The Oxford vaccine undertaking HCTs would, in the worst case scenario, take just as much time as non-HCTs. In the best case scenario, it could shorten the time taken to roll out a reasonably effective vaccine to mere weeks.