Vaccine trials and tribulations
It’s being called a blip. As Oxford University and pharmaceutical giant AstraZeneca announced they were pausing the promising trial of Covid-19 vaccine candidate AZD1222 to investigate a serious adverse event involving one recipient, politicians and officials purred public reassurance. This was routine, they said. It demonstrated safety and transparency. Things would likely be back on track, maybe even within days.
Experts agree, notwithstanding the very optimistic time line. But from within the vaccine research world, there’s another key message: the pause in phase three of human trials in the most advanced of the would-be vaccines must serve as a reality check.
“It should be a reminder that this is not a game,” says Jane Halton, the Australian chair of the global non-government Coalition for Epidemic Preparedness Innovations, which is funding nine candidate vaccine trials, including AZD1222. “This is a proper scientific process.”
Less than 24 hours before the pause was announced, the Australian government revealed its updated plans for buying doses – including from AstraZeneca – if the selected vaccine candidates are proved to be safe and effective and can be manufactured.
Prime Minister Scott Morrison and Health Minister Greg Hunt outlined agreements worth $1.7 billion for the supply and production of 84 million doses of two vaccines – the Oxford–AstraZeneca candidate and another promising prospect being trialled by the University of Queensland.
The money is only payable once the vaccines are approved for production. Australian manufacturer CSL would produce both onshore, if they are approved by Australia’s Therapeutic Goods Administration.
The Oxford vaccine is in phase-three human trials, involving up to 50,000 participants worldwide, and is ahead of UQ’s version, which is still in phase one.
The stakes could not be higher: scientists around the world are seeking an elusive shot in the arm to prevent untold deaths, curtail economic ruin and return daily life to normal.
Jane Halton’s comments are aimed at those in government, media and elsewhere who might seek to exploit the search, raise public expectations to unrealistic levels or pressure scientists to cut corners.
The pressure is already so great – not least from United States President Donald Trump, who faces an election in November – that the chief executives of nine global pharmaceutical companies, including AstraZeneca, took the extraordinary step this week of pushing back.
“We, the undersigned biopharmaceutical companies, want to make clear our on-going commitment to developing and testing potential vaccines for COVID-19 in accordance with high ethical standards and sound scientific principles,” they wrote in a statement issued on Tuesday. The statement underscores the careful steps that must be followed in seeking a vaccine.
“You have to have the right design to make sure that you are testing widely and you’re testing on a variety of populations. That’s absolutely imperative,” Halton says. “The regulators’ job is to assure themselves that before they let something loose in the population, it is safe to do so. And the biopharma companies are basically saying the same thing.
“They’re saying: ‘Look, we’ve got the same interests as everyone else here. We have an interest in getting this out to customers as fast as we can, but it will not help us or anybody else if it’s not done properly.’ ”
The executives’ statement came just a day before British–Swedish AstraZeneca and its Oxford University research partners announced the pause in their trial.
According to The New York Times, the adverse event involved a British recipient who developed transverse myelitis, an inflammatory condition that affects the spinal cord. The condition can have a range of causes, including viral infections, but may be unrelated to the vaccine.
Health Minister Hunt said on Thursday there was “no change to the timetable for the delivery of the vaccine in Australia”, which he previously indicated could be as early as January or February, assuming the vaccine was approved.
Hunt was insistent the researchers had “no belief that it will be changed in terms of its nature, form or delivery, but they are always subject to the medical advice”.
One vaccine specialist cast doubt this week on the suggested time lines, insisting it was impossible to say any vaccine would be available in January or June next year.
On Thursday it emerged the person with the adverse event was a vaccine recipient and had not received a placebo.
Earlier the specialist had told The Saturday Paper if that was the case, the event would need to be investigated thoroughly to see if it was connected or just a random unrelated serious event – something that was more likely the larger a trial group became. In that case, there would likely be “a few weeks, a month’s delay while they make this assessment”.
Australia’s purchasing agreements to date cover 33.8 million doses of the Oxford vaccine, 3.8 million of which would be imported initially, with the rest produced at CSL’s Melbourne plant, along with 51 million doses of the UQ vaccine.
The government has provided $300 million to CSL to fund its research capabilities and modify its existing production plant to manufacture the Covid-19 vaccines. It has also contributed $5 million towards the research and development of the UQ vaccine candidate.
If approved, both vaccines are expected to require two doses to be effective, meaning Australia’s purchase would cover 42 million people – its own population plus 17 million more. Excess may be made available to neighbouring countries in Asia and the Pacific. The government has already announced $80 million to enable regional vaccine access. However, whether there are doses left over after vaccinating the Australian population may depend on how long the vaccines offer immunity. Hunt said lead researchers on both had told him they were likely to offer “multi-year protection”.
The government’s advice on vaccine candidates is coming from a new taskforce established last month and chaired by the Health Department secretary, Dr Brendan Murphy.
“We are engaging widely with a range of the potential vaccine candidates at the moment,” Murphy said. “There are detailed discussions, but these two are very exciting.”
He emphasised the importance of being able to produce any vaccine locally – a core requirement given supply chain vulnerabilities revealed by the pandemic.
“A home-grown sovereign plan for vaccines is the hope I bring to Australians today,” Scott Morrison said.
Jane Halton says the prime minister has “a pretty good handle” on the vaccine challenge. “Everything going well, that is possible particularly if they can import some vaccines … It’s ambitious but it is not unrealistic and it’s good to be ambitious.”
As of last week, there were 321 vaccine candidates in development worldwide; 32 undergoing human trials and six at phase three. Halton acknowledges researchers are under pressure to reach a successful conclusion as fast as possible. “The truth of the matter is we all want it to be quick. That’s unambiguous,” she says. “But we also want it to be safe.”
But Halton also warns it’s still possible there won’t be a vaccine soon and people need to step up the social distancing and handwashing and maintain it. “You might as well get good at this now because we cannot keep the whole country in hibernation for an indefinite period,” she says.
Australia is among 80 countries taking out insurance with other vaccine candidates in addition to the two the government has announced so far. On September 2, it confirmed it intends to also buy into what is known as the Covax facility, a joint venture of CEPI and GAVI, the Vaccine Alliance. Covax was set up to fund a range of possible vaccines through development and ensure successful ones are made available to countries equitably, regardless of income.
Australia’s buy-in through Covax – not yet finalised – would entitle access to successful vaccines. Confirmation is required by September 18.
Beyond the $80 million already committed to the region, the Morrison government has not yet indicated if it will contribute further to the other side of the Covax initiative – providing funding to subsidise at least 92 registered countries with less ability to pay to vaccinate their populations.
Countries may buy enough to cover between 10 and 50 per cent of their own populations, depending on how much they pay and the eventual price per dose. But allocations above 20 per cent will not be made until all countries in the group being financed have received 20 per cent coverage.
The principle behind the two-part facility is that “no one is safe” from the virus “until everyone is safe”.
“To my mind, it’s very difficult for countries to say, ‘Well I’m happy to buy for me but I’m not happy to purchase for anyone else,’ ” Halton says. She is urging the US to be involved as a donor.
The US has set up its own funding facility, Operation Warp Speed, investing $US10 billion to fund the development of vaccine candidates to enable access to the vaccine for its citizens. It has taken the highly unusual step of also funding the production of certain vaccine candidates before they have been approved or even completed their trials. The stock of unsuccessful candidates will have to be destroyed.
All of this is predicated on the belief a vaccine can be found. Tempering that is the fact that no vaccine has been produced for any other kind of coronavirus.
Deakin University professor of epidemiology Catherine Bennett says pharmaceutical companies weigh the upfront cost – vaccine production is hugely expensive – against both the need and the likely return. A paradox of the Covid-19 pandemic is that the very reasons a vaccine is required so urgently – its virulence and spread – may make finding one easier.
The virus’s high community saturation in certain parts of the world helps shorten the time lines normally required for trials.
“You get people volunteering and you know that you’re going to have a high rate of exposure to the virus,” Bennett says.
Researchers and regulators have two considerations in deciding which, if any, vaccine candidates can be approved: are they safe and are they effective?
The ideal vaccine would be a single dose, safe for the whole population and 100 per cent effective for life. Achieving that is rare. But even partial effectiveness can provide a level of protection. The usual effectiveness benchmarks – the level of protection it offers to each individual recipient, expressed as a percentage – may be lowered because of the scale and urgency of this crisis.
Regulators may determine that lower effectiveness is acceptable if it provides some protection and buys time while better options are developed. But safety is less negotiable.
Once a vaccine is found – if it is – then comes the challenge of mass vaccination. This will be the first time an immunisation program has been carried out on this global scale.
But as the news from the Oxford–AstraZeneca trial this week demonstrated, nothing is guaranteed.
“We still don’t know if we can do it,” Catherine Bennett says. “And we won’t until we get there.”
This article was first published in the print edition of The Saturday Paper on Sep 12, 2020 as "Trials and tribulations".
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