August 28, 2020

Over the past few months there has been one central question on everyone’s mind — when will we have a vaccine for Covid-19?

Back in March, pundits and experts were not hopeful: some were confident that it would take over 18 months, some thought at least two years, and others predicted several years. Five months on, with over 165 vaccines in development, Dr Anthony Fauci, the American epidemiologist advisor to the White House, says that an effective vaccine will be available in the US early or midway next year. And superforecasters – the paid experts whose job it is to successfully predict events – tend to agree.

Are we really on the verge of achieving something that was previously inconceivable: a vaccine for an entirely new disease, developed within a year? And who can make that prediction? On the one hand, there are scientists, who have deep knowledge of viruses, infectious disease, immunology, epidemiology and biology — but they may be unfamiliar with the global economic and political events that could influence vaccine development in a time of crisis.

On the other, there are superforecasters, who have broad knowledge of global issues, and skills and experience in their approach to making forecasts — but they may be unaware of certain quirks of viruses or the immune system that influence how difficult or easy it may be to develop an effective vaccine.

When estimating a vaccine date, the best approach might be to combine the knowledge and skills of both groups. But before that, we need to define the question we want to answer precisely. Do we want to know how long it will be until a Covid-19 vaccine is approved (for anyone? for the general public?). What about the vaccines that have been authorised in other countries, such as China and Russia? Perhaps we want to know how long it will be until there are a certain number of doses of vaccines that have been approved in the US and the UK? All of these questions might be interesting, but for the purposes of this piece, the last one may be most relevant.

At this point, it’s important to find an accurate ballpark estimate to work from, and it’s easy to be swayed by the predictions of other experts and media reports. As Philip Tetlock and Dan Gardner explain in their book Superforecasting: “When we make estimates, we tend to start with some number and adjust. The number we start with is called the anchor. It is important because we typically underadjust, which means a bad anchor can easily produce a bad estimate.” This effect, called anchoring bias, has been demonstrated in many large experiments.

Vaccines normally take a long time to develop, usually between 12-15 years from research to trials to approval and to distribution, and at each stage, the probability that any given vaccine candidate will make it through drops until only a few candidates, if any, actually succeed.

But today things are moving faster than ever before. This is partly because of improvements in biotechnology (such as cheaper genome-sequencing), computational speed, open data sharing, and preprints. But more significantly, the gravity and urgency of the situation have put the pandemic at the centre of attention, and there is more money for Covid-19 vaccines than for any previous types.

On top of this, scientists already have research from other similar coronaviruses (MERS and SARS), and some pharmaceutical companies already work with animal models of the disease and have factories to produce vaccines for their trials. What’s more, researchers don’t have to go through each phase of trials one-by-one, as they would usually, but can start multiple phases simultaneously to speed up the process.

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Some pharmaceutical companies have even started manufacturing some vaccines at scale so that they can be distributed swiftly, anticipating that they might be approved. The approval process, during which regulators scrutinise the evidence and inspect factories to find out how safe and effective a vaccine actually is, typically takes an additional year, but regulators have said this will be fast-tracked and begin while trials are ongoing. This means that a timeline that would usually take 12 years could be accelerated to 18 months or less.

And some previous global pandemics offer hope. In the spring of 1957, an American microbiologist called Maurice Hilleman, after reading a story in the newspaper, concluded that a deadly influenza epidemic in Asia could become a global pandemic. He sought out samples of the virus, and found it was a strain that most Americans had not encountered before, and therefore had no immunity to. Hilleman worked personally with vaccine manufacturers to scale up production, so successfully that the vaccine was trialed in patients in July that year; by the autumn, factories were ready with 40 million doses. This whirlwind speed massively reduced the impact of the Asian flu pandemic in the US and abroad – a timeline of only 4 or 5 months.

With other pandemics, though, we have not been so fortunate. During the Spanish flu of 1918, researchers were unable to identify the pathogen that caused the disease, while doctors often misdiagnosed patients, all of which interfered with the development of a vaccine. More recently, the HIV pandemic remains without an effective vaccine, decades since the virus was discovered.

Clearly, not all vaccines have turned out the same way — so how do we know whether a vaccine for Covid-19 can be developed reliably or not at all?

Fundamentally, an effective vaccine is a faithful representation of a part or all of the natural virus. It is administered by an injection, for example, and is absorbed by immune cells, which transport it to lymph nodes around the body. Here, little bits of the absorbed vaccine are shown to many immune cells, such as T-cells and B-cells, and some of these will be activated (if they match those bits of absorbed virus carefully). These cells will quickly multiply, producing antibodies and “memory cells” that can linger in the body for many years.

Later on, if the person is infected by the natural virus, a similar procedure occurs. The virus is absorbed by immune cells and transported to the lymph nodes, where the old memory cells are reactivated. These can quickly multiply and produce antibodies again, to fight off the virus before it can cause disease. Effective vaccines typically do not stop a recipient from being infected altogether, but they prevent a recipient from developing the disease caused by the virus.

Understanding the immune response to a virus can help direct development of the vaccine. In the case of Covid-19, there are several pieces of information we can make use of.

First, the way the virus mutates can tell us whether a vaccine will activate the same memory cells that can destroy the natural virus. If there are many strains of the natural virus, which appear very different to the immune system, the possibility that memory cells from the vaccine can recognise and destroy the virus becomes less likely. Effective vaccines for the coronavirus may be easier to develop than vaccines for many other viruses, because its mutation rate is fairly slow – thanks to special enzymes in coronaviruses (called exoribonucleases), which most viruses don’t have, and which proofread new mutations and fix most of them.

Second, the way the immune system usually responds to the virus can tell us whether the virus can be cleared from the body at all. A pessimistic scenario is one where the virus infects humans, finds cells to target quickly, and uses them to multiply very rapidly in the body, accumulating countless new mutations before immune cells can absorb it and take it to the lymph nodes. That is the case for HIV, which patients cannot clear from their own bodies, and for which a safe and effective vaccine has eluded scientists for decades. Even though there is still a great deal we are learning about the disease, this pessimistic scenario is less likely for Covid-19 because most patients do seem to be able to clear the virus from their body and recover from the disease.

These factors bode well for the prospects of an effective vaccine, but they are not all. We knew much of this in March, so why was it that even in late April, forecasters said there was only a 5% probability that a vaccine would be approved in the US before April 2021, with enough doses to vaccinate 25 million people, but they now believe that probability is 49%?

The fact that forecasts can shift so much so soon is more of a feature of forecasting than a bug. Many events that we forecast depend on whether other events happen, so just as my chances of being hospitalised are far greater if I’ve just fallen off a tree than if it was any random day, the approval of a vaccine becomes more and more likely if the vaccine succeeds in each phase of trials. When unlikely events come true, they make other events that are tied to them more likely.

Happily, the events of the last few months mean we can predict with some more confidence whether the trials will pan out as planned, and if the vaccines will be effective and safe.

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Often, large obstacles in vaccine development have come during the undertaking of trials. During phase III trials, participants are randomly given a vaccine or placebo, and researchers note the difference in the chances of disease between the two groups. But that difference would be undetectable if the outbreak was contained or sporadic, because few participants would be exposed to the virus at all.

We now know that is unlikely to be a problem for Covid-19, since the pandemic is still pervasive and participants are being recruited in hotspots around the world as they develop. Many thousands of people have already joined for the phase III trials of many frontrunning vaccines and recruitment is almost complete for Astrazeneca’s trial.

Even if a trial were feasible, though, it’s not guaranteed that a vaccine candidate would be effective or safe. It will be months until we know if the frontrunner vaccines will actually prevent the disease, when results from phase III trials become available. So far, we can only base our predictions on the data that is available from animal research and some phase I and II trials, which tell us whether the vaccines have triggered some immune response and what their side effects were, for a limited demographic.

When it comes to Covid-19 vaccines, some reviewers and experts (such as Hilda Bastian, Florian Krammer and Derek Lowe) have written detailed summaries of the data from phase I and II trials so far, and the results are broadly encouraging. The frontrunner vaccines trigger an immune response, people produce working antibodies and T-cells to them, and don’t exhibit major side effects.

But there are still caveats: these trials were very small, most vaccines required boosters, and mild side effects were common. Since the participants were mostly young and healthy, that could become a problem when the vaccine is then tested in a wider demographic. Fortunately, some vaccines, such as by Pfizer and Moderna, have been tested in elderly people, and they did not show significant side effects. Still, it is difficult to compare the results of phase I and II trials between different vaccines, because the numbers of participants were low and the doses of each vaccine varied in each trial.

But, judging from the results so far, we can rule out some worst-case scenarios: that vaccines wouldn’t trigger any immune response at all, or that they would frequently cause serious side effects. The results so far provide some cautious optimism about the prospects of these vaccines; but squeezing much further interpretation out of this data, which is limited and preliminary, is probably premature.

Having examined all this evidence, how do we put it together to answer the original question: how long will it be until there are enough doses of an approved vaccine for Covid-19 for 25 million people (in the US)?

Useful forecasts tend to not give single specific estimates of when events might occur (such as simply saying they will happen in December), but give a series of predictions. Even though some time periods will be most likely, we would also want to find out when things will occur if not then. So a useful exercise may be to imagine three forecasts – an optimistic timeline, a pessimistic timeline, and in-between “Goldilocks” timeline.

Here’s how those might play out.

In an optimistic timeline, a majority (say 60%) of the early vaccine candidates are on track to succeed. Even though this likelihood is far higher than the average proportion of all trialled drugs that are approved over all phases of trials (around 10%), the biology of the virus and promising results so far suggest that this anchor should be updated. Moreover, the pandemic continues to be pervasive, so a smaller number of participants need to be recruited to detect the effect of a vaccine, and phase III trials take much less time than usual.

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So perhaps one or two of the vaccines that started phase III trials very early (Astrazeneca, Pfizer or Moderna) are demonstrated to be safe and effective in key arms of the trials. And owing to demand and perhaps political pressure, they are authorised for emergency use soon after the companies stated they would submit applications (between September and December). Vaccine manufacturers quickly manage to produce tens to hundreds of millions of doses of these vaccines as they have claimed they will have by the end of the year. And the approvals process takes only weeks to a couple of months, because of rolling reviews.

This would place the date that 25 million doses of approved vaccines are available in the US sometime around January 2021. Although not everything went perfectly in this timeline and lots of vaccines failed, most things went well for at least one or two early vaccines. What would happen if they didn’t?

In a pessimistic timeline, only a minority (say 10%) of early vaccine candidates will succeed. It turns out that several of the vaccine candidates show severe side effects in the elderly in phase III trials. A few of the vaccines, alarmingly, also cause rare side effects (in trials or after emergency use authorisation). Pharmaceutical companies and regulators decide to scrutinise vaccine applications for much longer than in the optimistic timeline, and err far more on the side of caution until they are unequivocally shown to be safe.

Simultaneously, there are geopolitical setbacks or disasters that affect manufacturing and transport, or perhaps far larger doses are required than anticipated. Even more unluckily, the vaccines that do eventually get approved turn out to be the ones that are more difficult to manufacture at scale.

This would place the 25 million doses date sometime around June 2021, if not later. Distressingly, lots of things went wrong in this timeline, but they were still somewhat realistic. Fortunately, because so many vaccines were in trials and vaccine funding was at its highest level ever, at least some vaccines succeeded less than two years after the disease was identified, but this was still much later than people had hoped.

Now we should synthesise the two scenarios, but striking a balance between them could be difficult. Perhaps we can pick apart the chances of each of the events in both scenarios to try to figure out the most likely timeline. Here is my thinking:

So far, the speed of trials and dose manufacturing has been much faster than anticipated, the preliminary results are quite promising, there are very many different types of vaccines in trials, and the ongoing pandemic means it will be unusually easy to recruit enough participants into trials. The biology suggests that an effective vaccine is very achievable, the worst-case side effects are likely to be rare, and the urgency has already sped up the approvals procedure. At the same time, low efficacy and mild-to-moderate side effects could be a problem for several of the vaccines in trials, and unforeseen setbacks in manufacturing or approvals will probably occur for some of the vaccines.

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My view, then, is somewhere between these scenarios, with the most likely outcome being that vaccines will be approved and available in that quantity around February 2021, given what we know or can estimate so far.

Note that this doesn’t mean it would take until then for the public to receive Covid-19 vaccines. If a vaccine is cleared for emergency use authorisation, it could be prescribed to treat or prevent infections as a sort of experimental drug, before it might be approved.

The chances that no vaccine is approved before 2022 is probably fairly low, given the large number of vaccines in trials, but it also includes scenarios where vaccines would take many years to be approved, because of unforeseen or rare events. All in all, these are the chances that I would place on vaccines becoming approved and available in those large quantities in each time period: before 1 October 2020 (1%), between 1 October 2020 and 31 March 2021 (58%), between 1 April 2021 and 30 September 2021 (32%), between 1 October 2021 and 31 March 2022 (6%), not before 1 April 2022 (3%).

With a concrete set of predictions, then, this finally brings us to the end of the forecast, for the time-being. Events of the coming months, including results from phase III trials, will mean we can revise and refine our predictions; but many questions will remain.

How many vaccines will be approved? How effective will the first-approved vaccines be? Will people need to take boosters or combinations of vaccines? How will the vaccines be distributed? How long will it take to achieve herd immunity with vaccination? How long will it take for the disease to be eradicated globally; and is that even possible in our lifetimes?

The momentous day a vaccine arrives will feel revolutionary – a triumph of modern science over suffering. But with all the questions that remain and all that remains to be done, history suggests that it will be just one more hard-won battle in humanity’s long war against infectious disease.

 

 

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  • August 31, 2020
    No, I said the coronavirus vaccine, that is, the vaccine under discussion, was only justified as a placebo. I didn't even mention other vaccines, which are generally well-researched, only allowed into circulation after extensive testing, and targeted at serious diseases that merit vaccination. I... Read more

  • August 31, 2020
    Nobody talks about Uruguay, never in lockdown, dry border with brasil, 13 Deaths/1M pop. Simple because it doesn’t much the official narrative and proves that the governments were embarrassingly wrong. Lockdown does NOT make the difference Read more

  • August 30, 2020
    No I can't clarify anything for you, I'm not qualified. Particularly as regards Australian law. Maybe you need a different government - but it's not my call. Time was, we Brits would tell you what you should do, and some still would, but those times are gone and I'm not one of those.... Read more

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