Coronavirus endgame: What will it take to bring COVID-19 under firm control?

Doug Hendrie

24/07/2020 3:58:08 PM

We wiped out smallpox and tamed polio. Now Australia’s experts tell newsGP how we can beat COVID-19.

COVID-19 road sign
What will it take to bring COVID-19 under firm control?

We’re six months into the new world created by the coronavirus pandemic. 
Australia is battling a new wave of community transmission after the virus slipped quarantine, while the global coronavirus cases continue to surge – especially in India, Brazil and the US.
The huge amounts invested in medical research and vaccine development may be starting to pay off, with promising news from the vaccines furthest through testing, as well as effective treatments for those badly affected by COVID-19.

But a vaccine – by itself – may not be the silver bullet we’ve all been hoping for.
What will it take to bring this virus under our control, once and for all, as we did for polio?
newsGP asked six Australian experts their views on the pandemic endgame, based on the scenarios below. 
The experts
Epidemiology  Professor Raina MacIntyre, head of the Biosecurity Research Program at the Kirby Institute.

Infectious disease and microbiology – Associate Professor Paul Griffin, of the University of Queensland, who is leading the trials of the Novavax coronavirus vaccine candidate.

Public policy – Professor John Daley, Senior Fellow at the Grattan Institute.
Virology – Associate Professor Ian Mackay, of the University of Queensland.
Evidence-based healthcare – Professor Paul Glasziou, Bond University.
Pharmacology – Emeritus Professor Richard Head, University of South Australia.
The scenarios
The great vaccine hope
Best-case scenario: A safe vaccine (or vaccines) arrives, proving 70–80% effective. The vaccine is given to most of the world's population in a matter of months.  
Medium-case scenario: Vaccines only provide partial protection, and the immune response does not last long.
Treatment option
Better treatments have begun emerging for the disease. If these dramatically improve survival rates, would we be better off allowing the virus to spread more rapidly and focus efforts on treating those who are becoming worse affected? 
Will the virus evolve to become more virulent, but less lethal, if it spreads widely?
Taiwan and New Zealand have been able to eliminate the virus. But Australian authorities have so far deemed it an unachievable goal. Is elimination possible in places other than small island nations? 
Patchwork quilt 
If the vaccine hopes do not pan out – or at least not as well as hoped – will we see a mix of public health measures for the medium term, alongside better treatments and further investment in critical care as well as post-viral rehabilitation?
‘There’s hope ahead of us’: Professor Raina MacIntyre
If we could eradicate this virus just by letting the population get infected, we wouldn’t have needed a vaccine for smallpox. If we don’t have a vaccine, we have to live with this virus, like we did with smallpox.
The reason this virus is such a problem is that there is substantial transmission that occurs without symptoms. That means you don’t know who’s infected, and it makes it almost impossible to control without a vaccine.
Compare that to SARS or smallpox; they were only infectious when people had symptoms, and usually when they were too sick to get out of bed. With this coronavirus, people can feel perfectly well and walk around, spreading it.
It is possible the virus will attenuate and become less severe, but at the moment that is only speculation and you can’t just assume it will.
With influenza, pandemic strains eventually become a seasonal flu. But this is a different virus. That means you can’t just assume it will attenuate itself [and become less dangerous]. Look at the coronavirus that causes MERS. It’s just as severe as ever. You can’t just extrapolate from the flu. This virus is more stable and has less mutation than influenza.
Better treatments will obviously help if they increase survival rates, but they won’t help control the disease spread. Some drugs may be beneficial as prophylaxis, but then you’d have to take it all the time, like [anti-HIV treatment] PReP. With PReP, you have at-risk groups who can take it long term, but to do that across the whole population is not feasible.
If we get a vaccine, healthcare workers would need to get it first. That won’t have any impact on the infection curve, because they’re a relatively small proportion of the population. We could look at an aged-based strategy that vaccinates older people first. That would reduce deaths. But if we wanted to reduce transmission the most, we would have to vaccinate people in their 20s.
On the vaccine front, there’s hope ahead of us now that we have more than one immunogenic vaccine candidate. I believe there’s a reasonable prospect of having a vaccine that’s good enough. It may not be perfect, it may not have high efficacy and may need booster doses, but that may still be good enough for us to control the disease and allow some kind of return to normal.
COVID may still exist as a very severe disease, and we may have to live with it with vaccination. If the vaccination reduces the severity of the disease, that’s good enough. If you just get a common cold instead of going to the ICU, that’s a good outcome.

L–R: Professor Raina MacIntyre, head of the Biosecurity Research Program at the Kirby Institute; Associate Professor Paul Griffin of the University of Queensland.

‘This is our moonshot’: Associate Professor Paul Griffin
Is this our generation’s moonshot moment? I think so.
The research into coronavirus vaccines and treatments is an incredible example of what we can achieve when we do devote our time, effort and resources. It’s no mean feat to achieve what we have already achieved. We have a large number of vaccine candidates, and many with great phase 1 results. It’s a huge step forward.
What we need to see – that people are protected when they get the vaccine – is hopefully only a few weeks away.
Some people say that we will never have a vaccine for the SARS-CoV-2 coronavirus, but all the reasons they give are not valid.
When people say we’ve never had a vaccine for other coronaviruses – well, we never had this level of funding, research and devotion to it by leading scientists. Lots of people draw parallels with the SARS-CoV-1 virus that caused SARS and say there was no vaccine for that one, but that threat was eliminated with infection control before vaccine trials were completed in people. There were lots of promising vaccine candidates, but we controlled it first. So that parallel is not valid.
Others say that we have never got rid of any coronavirus that causes mild illness like the flu. But you’d never get funding for that work, because they’re so mild. We haven’t put the time and effort into doing that.
So these reasons are not valid.
We are now seeing many candidates passing their first trials and very quickly progressing to later trials. If the results support it, we could soon see millions if not billions of vaccines ready for widespread use. That’s why I believe we will be able to vaccinate a significant proportion of people worldwide next year.
Before that, we need to see good efficacy data from later trials. We have seen really good laboratory data, but it doesn’t necessarily translate to an effect in later stage trials.
What we want to see in later trials is that significantly fewer people who have been vaccinated get the virus compared to those that haven’t. That’s when you know it’s worth it. So far, we haven’t seen that data for any candidate.
It is almost certain some vaccine candidates won’t make it over the final hurdle, but with so many looking good I am confident that some will.
The candidate vaccine I’m overseeing [Novavax’s NVX-CoV2373] entered human trials last week and is progressing as well as can be hoped for. Our pre-clinical data was very impressive and up there with some of the best.
So the Novavax one is progressing well, and the UK and Chinese candidates reported on in The Lancet look promising as well. I’m optimistic we will have more than one reasonable vaccine.
All of the frontrunners are looking to manufacture the vaccines in parallel with the late trials, which would give us the capacity to produce millions of doses by the end of the year and billions next year. That’s a testament to the time, effort and finances devoted to this project.
If I look at your scenarios, I think we’re likely to evolve through all of those. Even if we have a great vaccine, it’s not as if the whole world will get vaccinated the day after. It will take time. Uptake will be a key factor. That means we’ll still need complementary interventions for some time, such as restrictions, controls on travel, infection control practices, social distancing, hand hygiene and therapies so fewer people actually succumb to the disease.
There has been research suggesting that people may gain some immunity from exposure to other coronaviruses. There is an element of cross-reactivity. But if [other coronavirus antibodies] offered partially protective immunity to lots of people, we wouldn’t be in the situation we are in, given how ubiquitous other coronaviruses are.
People are worried about the news that antibodies for SARS-CoV-2 do tend to wane quickly, but that doesn’t really correlate with the protective effect of vaccines. That’s why we have vaccines – to produce a better lasting immune response that’s likely to be protective.
I’d anticipate that an effective vaccine with the right adjuvants will protect people longer than the antibody work would suggest. Antibodies are a really crude measure of protection that doesn’t correlate with actual protection. They’re easy to measure, so that’s why people do it. But the crudeness is why we don’t just measure antibodies, but other parts of the immune system as well.
You need a broad immune response to protect against a lot of these viruses, and lots of candidates suggest they can do that.  
Any protection will be useful. There’s lots of talk about aiming for an 80% efficacy rate of protection, and the more the better. But efficacy is only part of it. If you had a vaccine that was only 50% effective but we rolled it out with excellent coverage alongside infection control, we could get the virus under control really well.
So having a vaccine with sub-optimal efficacy could still be useful to complement our existing strategies.
Aim for ‘tight border control and free movement of travel inside Australia’: Professor John Daley
In our March article in The Conversation on the coronavirus endgame, we pushed for a significant lockdown to be maintained until we got to zero cases – or at least so few that our track and trace systems could work to kill off the rest.
We argued that elimination was worth a try. Many said then it was not possible and some still say it’s a mirage, but we have four states and New Zealand that show it’s not a mirage. In fact, one of the things we underestimated in that March article was in a sense that it could be easier to get to zero new cases than we thought it could be. Once you get down to low numbers, track and trace systems do work really quickly.
But we also underestimated how hard it would be to get quarantine right. It’s not impossible, but clearly Victoria did not get there. If I had a magic wand to rewrite that article on the endgame, I would say: put serious resources into quarantine, given estimates show Victoria’s outbreak can be traced back entirely to the quarantine breach.
We also glided over how hard contact tracing is. We’re pretty good at testing, but tracing has proved rather harder. It appears the system New South Wales is running, with a more dispersed public health system, has worked better than the system Victoria has, where it is centralised.
The reason we said elimination was a better strategy than suppression was that if you simply go into suppression, you get the ‘yo-yo’ effect – which of course is now what Victoria is seeing. We said that the yo-yo would be expensive, but we now know it’s really, really expensive.
So however expensive it might seem to put a lockdown to get down to zero new cases – or so close that track and trace get you there – it seems cheap relative to what Victoria’s seeing now. The estimate is that the new lockdown is costing around $1 billion a week.
The final thing we guessed at back in March, but that we now know, is that everyone thinks lockdowns are expensive, but people largely change their own behaviour anyway when you get an outbreak like Victoria has.
So yes, the virus costs you lots of money in any scenario. Government restrictions add to that, but not very much. We know that because we have a lot of data from Australia showing that behaviour changes well in advance of restrictions.
We also have the live experiment of Sweden versus Denmark. Sweden had very few formal restrictions and the virus ran its course. But people changed their behaviour so much in Sweden that their economic downturn was almost as big as Denmark’s.
Weird politics have emerged around elimination versus suppression. Some state governments nailed their colours to the mast, saying we’re not going to go to elimination. New South Wales is now aiming for zero cases of community transmission, but not elimination. What I’d say is that if it quacks like elimination, it is in effect elimination. All they’re doing is saying they can’t guarantee quarantine is safe.
No one is arguing that people shouldn’t be allowed into Australia. You don’t have to stop people coming in to stop community transmission, you just have to have a quarantine system that works.
We also know there’s a huge difference between self-isolation and proper quarantine. Self-isolation leaks like a sieve. Quarantine has to mean what it says on the tin: a physical space isolated from the rest of the world that is in some way enforced. That was the original idea – quarante is Italian for 40, the 40 days you had to spend on the island outside of Venice to stop disease.
We had quarantine stations at Point Nepean in Victoria and at North Head in Sydney; these were a big deal, to keep out tuberculosis, polio and yellow fever. In fact, the anomaly is the last 30 years where we have not had quarantine stations. Until recently, it was standard.
Looking forward, we’ll be getting constant cases coming in, so we need effective quarantine. We’re looking at a world in which trade in goods continues much as it has – that’s been the evidence so far – and quarantine breaches through trade in goods has been minimal, as it doesn’t involve a lot of people.
But international movement of people has more or less ground to a halt and it will stay there as a trickle until a cure or a vaccine for the disease emerges. Australia is now down to 350 people coming in a day. Compare that to what we used to see, it’s tiny.
The public response to tightening of quarantine has been very accepting. You can enter Australia if you are prepared to be quarantined and pay for it – and that’s how it is.
When we were writing our endgame article, people were saying, can you possibly imagine constricting passenger travel that much with a strict lockdown? But look at it now; you have Western Australia, which is reopening internally, or you can have a bunch of tourists. WA looks pretty attractive now.
Tight border control and free movement of travel inside Australia is a way better answer than anything anyone else has come up with. The irony is that the whole country almost got there.
In terms of the economy, if we shut down to the world but reopen internally, the economy would recover reasonably well. Look at New Zealand and China, and the short answer is you get back to 80% functioning pretty quickly. The remainder takes longer and we’re not going back to the November 2019 position any time soon.
It can get rather better than 80% recovery, but the best estimates – which have the economy contracting 6–7% – suggest we won’t get that last part back until the virus really has been eliminated. The infection rate is high enough that once it starts to circulate, it’s very hard to shut it down short of a significant lockdown.
It’s worth remembering that the virus took off when there were still plenty of restrictions in Victoria and when many people were still working from home, many restaurants were restricted and public events were not really a thing. Even with that, we still had an R0 [reproduction number] of 2, or even 3. This thing is so infectious.

L–R: Professor John Daley, Senior Fellow at the Grattan Institute; Associate Professor Ian Mackay, of the University of Queensland.

Test, trace and quarantine while we wait for a vaccine: Associate Professor Ian Mackay
While it is possible the virus could evolve to become less virulent over time, we can’t rely on that to happen. It isn’t a predictable path or a sure thing.
Australia is very far from anything like widespread immunity to this virus. But with a vaccine, that will change. For now, we know that even the hottest of global hotspots have seen only a quarter of their population generate a basic immune response. We haven’t qualified the nature nor quantified the long-term effectiveness of that response in those places yet.
A vaccine accompanied by effective antivirals and anti-inflammatory treatments would be essential components of a scenario with the most benefit to human health.
The likelihood of useful vaccines is growing. Treatments need to improve survival rates and improve quality of life in the years that follow the initial infection.
There is a real need to try and head off long-term consequences from severe, but perhaps also moderate and mild cases of COVID-19.
In this space, we still have much to learn. At the same time – not in serial, but in parallel – we need to better support the mental health of those in need of help during lockdowns and quarantines and isolations.
Part of that is to continue to provide all the incentives required to safely keep people in frontline work but also to permit them time off to avoid work when necessary. These are not ‘business as usual’ times. This is a pandemic. It’s a historic event. Responses must be historically different. Economics must be considered in the context of the health of the society it supports. The long-term cost of getting our response wrong could be worse than the short-term costs. 
In terms of elimination versus suppression, Australia could – and mostly did – eliminate COVID-19 transmission and then reduce restrictions while retaining the capacity to respond to future mistakes.
Yes, we will still receive cases via travel, but in most jurisdictions, quarantine has been well managed and has not led to new cases. Perhaps we’re getting bogged down in the terminology instead of the goals we’d like to achieve.
Principal among these goals is to return to having a healthy, mobile working and spending society within our borders, while we await ways to better manage this scourge.
We can and have effectively kept SARS-CoV-2 at or beyond our borders, apart from mistakes in Victoria that we must learn from. Anywhere in Australia can, has and will make mistakes. These are things we can do and have done.
The concept of ‘living with the virus’ is dangerously unexplored and unexplained. Accepting that the virus is here to stay in the world – it is – need not mean it’s here to stay in Australia.
There are countries now living with the virus who still see hundreds of cases a day, any one of which could cause a new period of exponential growth. There are others who have eliminated it and successfully manage intermittent arrivals of SARS-CoV-2 via border control and quarantine.
‘Living with it’ suggests that we are cohabiting with circulating SARS-CoV-2, and it would be harder for us to eliminate transmission if we later decide to.
Elimination means stopping transmission within our own borders. As opposed to eradication, which is global elimination. I don’t think we can eradicate SARS-CoV-2.
We’ve seen again and again, all over the world, that the more widespread the virus is, the harder the fight to rein it back in becomes.
Rapidly making hard, complex decisions has always been paramount in reducing the risks from COVID-19.
Delays and obfuscation are repaid in deaths and in greater economic losses and mental and other health costs, according to the expert-backed Roadmap to Recovery published in April.
For those more focused on economics or on balancing economics and health, the question becomes one around risk versus benefit.
Would elimination of the virus from within our borders actually be less costly than ongoing flare-ups that can easily occur at the same scale as in Melbourne, but in other populated parts of Australia?
Given we respond dramatically to each of these with lockdown measures anyway, and given evidence for its ongoing health and unequal economic hardship, it’s hard to see how ‘living with the virus’ provides any sensible future strategy for all.
So while we wait for a vaccine, the future holds continued testing, tracing, quarantine, isolation and international border controls.
We need to be very aware of the public in all of this. Their tolerance for ongoing surges of cases and rolling lockdowns is not without limit.
I think we are already seeing those limits being reached along the east coast of Australia. I hope we also see enhanced communication campaigns with a view to building public trust through explanations, justification and education.
From there, what happens next will come down to the decisions by a few, hopefully based upon the expertise of a consensus of the many.

Every system has holes – we need different layers of protection: Professor Paul Glasziou
The Oxford vaccine study is very promising but there’s a long way to go yet. Treatments won’t be enough as even mild cases can get prolonged illness. Elimination is a good aim, but you would have to maintain vigilance until you get a vaccine, as even Taiwan gets occasional cases. Contact tracing doesn’t catch every case. People don’t present for testing. Vaccines may be only partially effective.
So what we need is a Swiss cheese model. That’s a metaphor for the combination approach emerging from work on errors in medicine. The idea is that every system has holes, but adding different layers of protection can give overall protection.
With this model, even if we had a partially effective vaccine, similar to the flu vaccine, that improves community protection and makes things easier to manage. Imagine that Victoria had a 50% effective vaccine in use. That would make the spread much slower, and enable contact tracing to contain the whole outbreak. So even an imperfect vaccine adds a layer.
But we also need to work on our other layers. We could improve the contact-tracing component. New South Wales was able to reduce their test turnaround from five days to one day, on average. That four-day reduction is very important because it means contacts that could have been transmitting the virus are contacted earlier to go into quarantine. That reduces their exposure time. Test turnaround time is a key factor in containing things.
It may also be we have to maintain appropriate distancing at big indoor public events that pose the highest risk, such as restaurants or weddings, as well as workplaces like meatworks.
What we need to know now about the top vaccine candidates, such as the Oxford one, is how long the very good immune response will be maintained, and if it actually provides protection from SARS-CoV-2.
The best-case scenario for a vaccine is that there are reasonable results by the end of the year, which could enable ramp up of an effective vaccine early next year. Worst case is we have a partially effective vaccine available towards the end of 2021.
My guess is we will have an at least partially effective vaccine available by the middle of next year, but with wide confidence intervals around that.
In combatting this, it’s almost certain vaccines will play some role. But when they will do that and how effective they will be is not clear. That means we can’t dispense with any other process.
This is true of other disease as well. We’ve only ever eliminated one disease – smallpox. What we’ve done with all the others, such as polio and measles, is to vaccinate and then contain any outbreaks. Measles used to be more common until we increased our booster dosing in early adolescence. Booster doses may be necessary with COVID – the Oxford trial found those with booster doses got better responses.
In short, we need enough layers to protect the population and keep the R0 below 1.

L–R: Professor Paul Glasziou, Bond University; Emeritus Professor Richard Head, University of South Australia.

Repurpose existing pharmaceuticals to buy us time: Emeritus Professor Richard Head
We would urge attention be given immediately to coordinated clinical evaluation of existing pharmaceuticals in an international repurposing program targeted toward managing the host. Such a program can provide adequate time for the development of vaccines, serum‐based approaches or antiviral drugs, and separately will provide a therapeutic insurance with the inevitable easing of social isolation.
Our focus in our recent journal commentary was due to the possibility that the global roll out of a vaccine may not develop as planned or take longer to complete.
In the immediate absence of a vaccine, a portfolio of approaches is required. One component which we would argue for is the repurposing of clinically tested existing therapeutics for use in COVID-19 disease.
Our focus has been on strategies for bridging the gap between the here and now (often co-existing with the virus) and the subsequent employment of treatments such as effective vaccines.
We would see repurposing existing drugs once they have been shown to be effective and safe in COVID-19 as being important in this scenario. In other words, pharmacologically-based approaches to treating the host and not necessarily the virus in this setting.
In this scenario, the easing of social isolation will require some form of therapeutic-based insurance.
The most obvious initial target is to correct the virus-induced dysregulation of the inflammatory response in the lung and the vasculature. This is an area we believe should be further developed and a target for investment.
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Dr Julian Padraic Collins   26/07/2020 12:05:42 PM

Thanks for very informative ,up to date information and reasoning.