What Are the Implications Of Pausing the Astra-Zeneca-Oxford Vaccine Test?

It appears that the test subject who had the 'adverse event,' was given the vaccine, not a placebo. If the clinical reaction was due to the vaccine, it will probably have to be taken out of trial and redesigned. If it was unrelated to the vaccine, it may still take several weeks to resume the trial.

Astra-Zeneca is generally believed to have acted responsibly in reporting the event and pausing the trial. That it may have released more information to investors than to the public, if true, will raise ethical concerns which could affect perceptions of the drug's efficacy. JL 

Nicky Phillips and colleagues report in Nature:

Enrollment in global trials of a leading coronavirus-vaccine candidate are on hold after a ‘suspected adverse event’ in a person who received the vaccine in the UK. Many countries, including the US, have pre-ordered millions of doses of the Oxford vaccine in the hope that it will be successful. “The clinical hold shows that there are functioning checks and balances, in spite of political pressure. “If the event is linked definitively, or even probably, to the vaccine, it could be a definitive blow to this particular vaccine candidate. If unrelated, the hold might be lifted in a matter of weeks.”

Enrollment in global trials of a leading coronavirus-vaccine candidate are on hold after a ‘suspected adverse event’ in a person who received the vaccine in the United Kingdom. Scientists say that it’s too soon to say what impact this might have on the global push to develop a vaccine, but that the news highlights the importance of waiting for the results of large, properly designed trials to assess safety before approving a vaccine for widespread use.

Researchers at the University of Oxford, UK, in collaboration with the pharmaceutical company AstraZeneca, are developing the vaccine, which is one of nine coronavirus vaccines in the final, ‘phase III’ stage of being tested.

Details of the adverse event, including how serious it is and when it happened, have not been reported by Oxford or AstraZeneca. But the trial’s pause comes amid concerns that US drug agencies might face political pressure to approve a vaccine before trials are completed, ahead of the US presidential election in November.

“The clinical hold shows that there are functioning checks and balances, in spite of political pressure,” says Marie-Paule Kieny, a vaccine researcher at INSERM, the French national health-research institute in Paris. “It might indeed remind everybody—even presidents—that for vaccines, safety is paramount,” she says.

“I do hope that the adverse event is unrelated to the vaccine, since Oxford’s candidate seems quite promising so far,” says Florian Krammer, a virologist at the Icahn School of Medicine at Mount Sinai in New York City. The decision to halt the trial shows that the process to evaluate vaccines works, and ensures that only safe and effective therapies make it to the market, he says.

On Tuesday, health-news website STAT reported that the US phase III trial of the coronavirus-vaccine candidate had been paused. On Wednesday, the University of Oxford confirmed to Nature that enrolment in trials of the vaccine in Brazil, South Africa and the United Kingdom will also be paused.

“As part of the ongoing randomized, controlled global trials of the Oxford coronavirus vaccine, our standard review process was triggered and we voluntarily paused vaccination to allow review of safety data by an independent committee,” AstraZeneca said in a statement.

“This is a routine action which has to happen whenever there is a potentially unexplained illness in one of the trials, while it is investigated. We are working to expedite the review of the single event to minimize any potential impact on the trial timeline. We are committed to the safety of our participants and the highest standards of conduct in our trials,” the statement notes.

“If the event is linked definitively, or even probably, to the vaccine, it could be a definitive blow to this particular vaccine candidate. If unrelated, the hold might be lifted in a matter of weeks,” says Kieny.

But without more details of the adverse event, including how serious it is and when it happened, it is difficult to assess the impact it will have on the trials and the timeline for the vaccine’s approval, say scientists.

It is the second time that administration of the vaccine has been paused in the UK, according to two people who took part in the study and to information sheets uploaded to a clinical trial registry. Previously, a participant developed symptoms of transverse myelitis, an inflammation of the spinal cord which is often sparked by viral infections, according to an information sheet given to trial participants dated 12 July. After a safety review, the trial resumed. The individual was diagnosed with an “unrelated neurological illness”.

CROSS-COUNTRY TRIAL

AstraZeneca started the trial of its vaccine candidate AZD1222 in the United States last month, with plans to enrol 30,000 adults at about 80 sites across the country. Efficacy trials in the United Kingdom, Brazil and South Africa involving a total of around 17,000 people are also under way. In a double-blind trial, roughly 20,000 of the US trial participants were to be given two doses of the vaccine, while the other 10,000 would receive a placebo. Such large-scale testing in people is needed before regulators, such as the US Food and Drug Administration, will approve a vaccine for widespread use.

Many countries, including the United States, have pre-ordered millions of doses of the Oxford vaccine in the hope that it will be successful. By late last month, countries had ordered at least 2.94 billion doses — more than any other coronavirus-vaccine candidate. More than a third of those doses have been bought by the United Kingdom and other European nations, Japan and the United States. The US Biomedical Advanced Research and Development Authority has given AstraZeneca more than US$1 billion to develop the Oxford vaccine.

Adverse events are not uncommon in clinical trials, and are often unrelated to the treatment being tested, says Paul Griffin, an infectious-disease researcher at University of Queensland in Brisbane, Australia, who has conducted large clinical trials. For instance, an adverse event would include a participant being admitted to hospital for any reason, and might automatically trigger the pausing of the trial even if the admission was unrelated to the vaccine. Studies have protocols that specify what type of events trigger a pause, after which there is a process for investigating whether the event is related to the vaccine, he says. AstraZeneca study protocols have not been made public.

That is not unusual, but given the stakes involved in the development of a safe, effective vaccine, all of the study’s details should be made public, says Paul Komesaroff, a physician and bioethicist at Monash University in Melbourne, Australia. “The trials are all publicly supported, the disease is posing the greatest threat to humanity in a hundred years, the drug-development processes are highly politicized, and the outcome will only be a successful one if public trust can be secured and maintained,” he says.

WHAT NEXT?

The independent committee that will now review the AstraZeneca data will probably be working out whether the participant who experienced the adverse event received the vaccine or a placebo, say researchers. If the person received the vaccine, the investigators then have to try to work out whether it caused the adverse event. “That can be tough to sleuth out,” says Jonathan Kimmelman, a bioethicist who studies clinical trials at McGill University in Montreal, Canada.

If the event is significant and found to be related to the vaccine, that might have a significant impact on the study, says Griffin. “But I think it is too soon to assume that that is the case,” he says. The first priority is making sure that the volunteer is safe and getting the best medical care, he says.

“I have every confidence that this group will very quickly assess this adverse event and make the results of that investigation known,” says Griffin.

Researchers have been especially worried that COVID-19 vaccines could cause an ‘enhanced disease’ when people who receive the vaccine are exposed to the virus subsequently. Animal studies and early-phase human trials of COVID-19 vaccines, including the Oxford/AstraZeneca candidate, have so far reported no signs of enhanced disease.

The Oxford vaccine is a viral-vector vaccine that harnesses a cold-causing ‘adenovirus’ isolated from chimpanzees. The chimpanzee adenovirus has been modified such that it can no longer replicate in cells, and it expresses the ‘spike’ protein that the coronavirus uses to infect human cells. Dozens of groups say they are working on viral-vector vaccines for coronavirus, including a candidate developed by US drug maker Johnson & Johnson, and another co-developed by the Chinese military and CanSino Biologics, based in Tianjin, China.