Coronavirus vaccine must strike the right mix of efficacy and speed
At every turn the public has been assured no corners have been or will be cut on the safety of a Covid vaccine. But can this really be true?
It was always going to happen sometime, somewhere, that the seemingly unstoppable march to a COVID-19 vaccine hit a pothole. Wednesday’s suspension of human trials of the promising Oxford University-AstraZeneca offering was a timely reminder that it is still a matter of if, not when, the hope of a world gripped by coronavirus is realised.
AstraZeneca announced overnight the resumption of the trials, but it’s too early to say whether the setback to the Oxford vaccine is merely a temporary glitch or something more lasting. Usually, the travails of medical research play out in the privacy of the laboratory, documented in the impenetrable jargon of scientific reports and papers. Not with COVID. AstraZeneca, the multinational pharma company that wants to bring the Oxford jab to market, including here under a deal with the Australian government and local drugmaker CSL, immediately went public with news that the testing had been halted after a participant came down with transverse myelitis, an inflammatory condition of the spinal cord.
Chances are this will turn out to be unrelated to the candidate vaccine. Like the rest of us, people involved in clinical trials catch cold, accidentally break bones and have heart attacks – which is exactly the point of the exercise, to benchmark the performance of a new pharmaceutic in a lifelike setting. Thousands are recruited for a phase-3 study, the culminating step to licensing, all of whom are dosed and monitored to an exacting standard, often in multiple countries. Many candidate drugs come a cropper at this late hurdle.
Yet in the same way it has changed the way we live and work, COVID has fundamentally rewritten the playbook for vaccine development. Lab investigations that would in the past have taken years have been compressed into months, sometimes weeks, thanks in part to the billions poured into the R&D program globally, while regulators have changed the way they do business, streamlining and fast-tracking approval processes.
At every turn the public has been assured no corners have been or will be cut on safety and efficacy. Can this really hold at the breakneck pace vaccines are being progressed? The answer is more nuanced than you might think. The issue isn’t whether an eventual drug might do more harm than good. The real question is: Could the outcomes be better if things were slowed down?
Dale Fisher, a World Health Organisation adviser and infectious diseases professor at the National University Hospital of Singapore, says the process is being rushed and any vaccine that emerges will be open to doubt on efficacy, longevity and the risk of side effects down the track. “The whole point is, it is going to be a mess if we rush it and we shouldn’t rush it simply because we can’t manage the pandemic from a public health point of view,” he says.
An Australian, Fisher was sent to the presumed seat of the outbreak in the Chinese city of Wuhan by the WHO back in February, as the world geared up to confront the virus. He knows better than anyone the urgent need for a vaccine. His message, though, is it’s likely to be no silver bullet.
“There is not going to be a fairytale ending where everyone takes the vaccine and we all go back to normal,” he explains. “I am as hopeful as everyone else and I think it’s likely we will get a vaccine. But I certainly say it is not definite, and I do question … some of the timelines. Whatever happens, we will have to continue to live with the virus for some time to come — it’s not going to magically disappear with a vaccine.”
That’s not to gainsay the astonishing advances that have been made. Take the US Moderna vaccine. The Moderna technology deploys a novel delivery system targeting messenger RNA, the genetic mirror of DNA that travels through our cells giving final instructions on which proteins to build to form the body’s cellular architecture.
The theory is that the cells would take in the genetic snippets of the coronavirus, SARS-CoV2, make viral proteins and generate immunity. The advantage over traditional vaccines is that the mRNA version is simpler and quicker to make, courtesy of the time saving on growing or inactivating an entire pathogen for the vaccine. The downside is that it has never yet worked in practice: scientists have struggled since the 1990s with the stability of mRNA vaccines because once inside the body the active agent breaks down faster than DNA.
Still, the Moderna vaccine went into phase-1 human trials just 63 days after the sequence of the new coronavirus was published by Chinese scientists, a remarkable feat.
Other pacesetting vaccine platforms span protein-based applications, such as the cutting-edge molecular clamp technology developed by scientists at the University of Queensland in partnership with CSL, part of the $1.7bn production supply deal unveiled this week by the Prime Minister; a DNA vaccine from US biotech firm Inovio; the non-replicating viral vector vaccine by CanSino of China; and a more traditional inactivated vaccine from Sinovac, another Chinese contender.
This means the bases are covered to an unprecedented degree if one or more of the pathways is found to be a dead end. Ian Frazer, inventor of the world-first cervical cancer vaccine Gardasil and 2006 Australian of the Year, is confident a vaccine will come, though likely not before mid-2021. “I am pretty sure we will get a vaccine that reduces the risk of dying of infection,” he says. “I am perhaps less confident that it will be 100 per cent effective or a vaccine that will stop the spread of the infection.”
The Oxford prototype is a non-replicating viral vector vaccine that sailed through phase-1 human trials to establish its safety and capacity to generate a baseline immune response, and will be given to more than 50,000 volunteers in the US, UK, South Africa, Brazil and India in the decisive stage of testing. Under Donald Trump’s Operation Warp Speed, the vaccine rollout is supposed to start in the US from next month — not so coincidentally in time for the November presidential election.
In Australia, AstraZeneca is due to deliver 3.8m doses of the Oxford vaccine early next year, contingent on regulatory approval from the Therapeutic Goods Administration. CSL’s vaccine arm, Seqirus, will then produce another 30m vials of the drug under licence while ramping up manufacturing for 50m doses of the UQ vaccine from mid-2021, enough with plenty to spare to give every Australian the required two-shot course.
The nuts and bolts of how to make this happen are now being hammered out by CSL and the federal government. CSL will seek provisional approval to set the wheels in motion early in the 12-month combined phase-2/3 testing, assuming this starts late this year.
Seqirus senior vice president Russell Basser says the pathway is similar to emergency use provisions employed by US regulator the Food and Drug Administration to speed up licensing.
Until now, drug development has mostly been done sequentially through the various clinical trial phases to regulatory approval and, only then, production. This time, the TGA will be asked to consider “indicative results” of the phase-3 testing as part of a rolling submission by CSL. AstraZeneca will push through the Oxford vaccine separately.
“When we have finished chunks of investigation and document writing, instead of it all going into one big dossier when we have finished phase-3, we will agree on which documents we sent them at what points in time so they … finish off the review process along the way,” Basser says.
The problem, as Fisher sees it, is that the regulators will be operating in the blind. The UQ phase-3 trial by necessity will be staged offshore, in countries with a much higher rate of COVID-infection than Australia. The anticipated cohort of 30,000 will be divided between those who get the control agent, a placebo such as saline or a neutral drug, the meningitis vaccine in the case of the Oxford trial, and people injected with the candidate vaccine. The researchers then sit back and wait to see who contracts COVID; only those who become sick enough to be hospitalised are supposed to be counted in the study.
“Maybe in the placebo arm 1000 people get the virus and in the non-placebo arm, the vaccine arm, only 500 get it,” Fisher says. “So you say, OK, the vaccine is 50 per cent effective at three months. Now what happens if over the next six months everyone gets sick with COVID … the vaccine is wearing off. This you don’t know if you use indicative indicators, you don’t know how long it will last.”
Aware of this pitfall, the co-ordinators of most of the 20 phase-3 studies under way internationally have beefed up the size of their studies. But Jim Buttery, the professor of medicine who heads Monash Immunisation and sits on the Advisory Committee on Vaccines to the TGA describes the target of early next year to begin the rollout in Australia as “very ambitious”.
“The thing that will influence that is … if they are recruiting faster and there is a higher rate of disease in the community they may get a lot of safety and efficacy information earlier than expected, even though they have to finish following the patients for 12 months,” he says. “It is conceivably possible but it’s ambitious.”
Dale Godfrey, professor of microbiology and immunisation at Melbourne University’s Peter Doherty Institute, insists there is protection in the numbers involved in the registration trials, ranged between 30,000 in the UQ program and the monster enrolment of 50,000 for Oxford-AstraZeneca’s study. “That allows you to some extent to base the safety on a larger group in a shorter time frame,” he says. “It’s not ideal but there are no ideal scenarios in this situation.”
Another expert member of the VAC, Kristine Macartney, director of the National Centre for Immunisation Research and professor of paediatrics at the University of Sydney, says the process, though accelerated, is based on tried and true methods dating back more than 70 years to the drug trials for penicillin. “We have been practising this for a long time … and what we are talking about here is making that process rigorous as part of a rolling review.”
Fisher, though, has more questions. What if the two vaccines Australia has signed up for, sight unseen, turn out to be less effective than those that follow? Could people who have already been inoculated go again? Would that be safe?
And let’s not forget the anti-vaxxers hovering in the wings, ready to call just about anything that can go awry with a person’s health the complication of a vaccine, potentially eroding public confidence when it is needed most to ensure strong take up.
“We know from experience with other vaccines that as soon as things are seen to be going wrong they blame the vaccine even though it’s got nothing to do with it,” Fisher says. “This is going to be food for the anti-vaccine movement and, of course, I am not an anti-vaccinator but I would have a lot of sympathy for them if things are rushed through.
“I … would rather wait for the vaccine that is 80 per cent effective and lasts at least five years than have the one that is 50 per cent effective and needs a booster at six months.”
Buttery agrees on the need to build and maintain community trust, quoting legendary US immunisation advocate Walter Orenstein’s maxim: “Vaccines don’t save lives. Vaccinations save lives.” Buttery adds: “We can have a brilliant vaccine but if no one takes it, it’s not going to do anything.”
Godfrey has a question of his own: What if we did wait, until all the possible long-term side effects of a vaccine were apparent? “A company could say, ‘we’ll get you a vaccine in 2030 and it will be perfect, no worry’. But there would be uproar about the cost to human life, the economy, everything else,” he says.
“This really boils down to a risk-benefit analysis, because no one wants to wait five or 10 years for a vaccine, but nobody wants to rush a vaccine through to the point where we have no idea whether it is safe or not. It’s a balance and so far, I think, it has been struck fairly well.”
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