We think this is a great overview and general summary of the challenges and process of making a new drug in relation to the current coronavirus crisis:
On 16 March, a needle was put in the arm of a Seattle woman who may change the world.
Jennifer Haller had a candidate vaccine against coronavirus injected into her bloodstream – the first human trial aimed at preventing the further spread of a disease that could still kill millions.
As her story hit the headlines, many celebrated: It appeared that perhaps Donald Trump had been right two weeks earlier when he said: “Very soon, we’re going to come up with a vaccine.”
Not so, says everyone who is involved in the most closely watched race since the one to reach the moon.
Developing a successful vaccine is complex, painstaking and difficult.
And it is expensive. The UK government, which has put in £250m so far, is just one of many administrations around the world spending billions.
But, while it will be too late for many of the people who have caught COVID-19 already, it is essential to help those who will need to remain free of the disease if they want to survive.
To get a vaccine to the people who need it, there are four main phases.
Phase 1: Conception
Vaccines have been used to prevent people catching viruses for hundreds of years.
During that time, the technology used to create them has become increasingly sophisticated.
To do so, researchers examine the qualities of the disease they are trying to prevent – often looking at the structure of the pathogen and how it operates inside the body – to work out how to boost the body’s defences against it.
Laboratories around the world will already have been working on vaccines to prevent coronaviruses before SARS-CoV-2, the one that causes COVID-19, was identified in China in January.
Two serious outbreaks of coronaviruses, MERS and SARS, occurred in the last 20 years, reinforcing the need for potential vaccines.
Vaccines were worked on for those two diseases, but what prevented them being brought forward was that the outbreaks were brought largely under control. Drug companies had little incentive to continue pressing on as they could not get the money back on their investments.
SARS-CoV-2 is different to MERS and SARS, and will need a different vaccine.
But some of those working on a solution have quickly been able to identify candidates they believe could be successful.
One of those is Moderna, the company whose vaccine candidate was injected into Jennifer Haller’s arm as part of the first human trial.
Others have been working frantically to advance research that was in an early stage, bringing forward other potentials in case they too might work.
All, some or none of these could end up being successful.
The Coalition for Epidemic Preparedness Innovations, or CEPI for short, is an international coalition that has been set up precisely to tackle outbreaks such as coronavirus, by developing new vaccines.
But it is in its infancy – having been set up just three years ago – and those in charge say it would have benefited from several more years of operation if it was to be considered ‘ready’.
Nevertheless, CEPI is trying to lead the effort to save millions of lives around the world and says it needs $2bn (£1.61bn) to do so.
It is just one of a number of organisations and countries trying to find a vaccine. The race is on to see which one can find the drug that will prevent people developing COVID-19.
When CEPI put out a call for proposals, it had 48 applications for funding from people proposing a candidate vaccine. This has been whittled down to eight.
Some of those it is funding, such as programmes by Moderna and Inovio, came forward precisely because of CEPI’s earlier investment to tackle MERS and SARS.
CEPI’s CEO Dr Richard Hatchett said this was precisely why companies like Moderna were able to begin human trials so quickly.
He said: “I’ve seen some reports that there were a few people in China who actually claimed that ‘the US must have known about the COVID-19 virus in advance, otherwise how else could they have got to clinical trials so quickly?’ In point of fact, the way they were able to get to clinical trials so quickly was because of this meeting of prior research on coronaviruses and coupling that with the power of rapid response technologies.”
Al Edwards, an associate professor of biomedical technology at Reading University who is one of those who is working on a candidate for the COVID-19 vaccine, admits the race is on, but says it is a race to find a vaccine for the world, not as a result of competition between researchers.
He told Sky News the industry is normally very competitive but is striving to work together in order to produce a solution.
“Six months ago, I’d be very competitive because I would tell you that mine was way much better than everyone else’s, because that’s how scientists work. But right now, everybody is hoping that everybody else’s is going to work.”
Phase 2: Development
Once scientists have created a potential vaccine, they have to work out whether it can be practically used in the real world.
That means getting it to the stage when it can actually go into a human, and assessing whether it can be mass produced.
What this involves is testing, in a way that does not involve people.
Ultimately, the drug has to be put into animals to see how they respond.
The choice of the animal is key: it has to be able to react in a sufficiently similar way to how a human would do to be relevant. It also has to be capable of being infected with the disease that is being vaccinated against.
Some of the tests may show that the vaccine is in fact toxic to animals, and will probably therefore be so in humans as well.
The use of animals in testing vaccines is controversial, and is highly regulated in the UK and many other countries.
Other vaccines may be able to largely skip the animal testing phase because they are a new version of a vaccine which is already widely used, and therefore its toxicity is well known.
The aim of the tests is to work out which candidates can go on to further trials.
Dr Hatchett told Sky News that if the eight chosen vaccine candidates run into problems, CEPI might choose to fund others.
He said: “All of these programmes have really just gotten started. None of them have run into insurmountable problems, but we fully anticipate that some will and we are currently internally thinking about how we would flip out programmes that did not succeed and potentially bring new promising candidates into the fold if we have the resources to do so.
“We would develop as many candidates as we have of human resources to manage and financial resources to support.”
Phase 3: Testing
At some point, it won’t be enough just to test on animals – the testing has to move on to humans.
The first phase of testing for Moderna’s candidate vaccine has begun in Seattle.
In that case, one part of the animal testing phase was skipped – a move that has been questioned by ethicists.
In any case, extensive testing in humans is required to look at all the possible ways a vaccine might inadvertently harm people, when it is supposed to be protecting them.
Prof Edwards said: “What you’re expecting from a vaccine is that you can give it safely to millions and millions of healthy people and none of them are harmed and it protects almost all of them against the virus. That’s a difficult thing to achieve.
“Some of them will fail when they go into clinical trials.
“So it might be, for example, lots of the people who are given an experimental vaccine have quite a sore arm. On the global scale, if you have a hundred volunteers and 10 of them have a really sore arm, that’s not acceptable. Because if you scale it up to 100 million people, you’re talking about 10 million people having a sore arm.
“The reasoning for that is that if you’ve got 10 million people with a sore arm, you might have 1 million people with a really, really sore arm and 100,000 people with an arm that actually falls off, because it’s a probability game.”
Prof Edwards said there have been occasions when drug firms have had their reputations badly damaged by using vaccines on a large population which have turned out to have harmful effects that were not picked up during the testing phase.
A vaccine created by a UK team was due to start animal trials at Porton Down, Wiltshire, in late March, with human trials getting under way in April, Professor Adrian Hill, director of Oxford University’s Jenner Institute, told The Guardian.
It is the need to ensure adequate testing has taken place that makes the process to licence vaccines so long.
However, a possible model for this crisis was laid down in West Africa during the Ebola crisis when the process of vaccine testing and adoption was accelerated due to the urgent need for a drug to protect people.
Several were trialled in the field – while the outbreak was ravaging countries like Guinea, Sierra Leone and Liberia – and it led to several generating results. One of those vaccines has since been licensed and the other is undergoing further trials in the Democratic Republic of the Congo.
Prof Edwards says that ideally you would like to follow a person who has been part of a trial for months afterwards, if not years, to see if it continues to be effective.
If the world chooses a vaccine that appears at the outset to work against coronavirus, but because it hasn’t been tested over the usual time frame it later turns out not to be as effective as had been hoped, by then it will be too late.
Phase 4: Manufacture
Even if a candidate vaccine proves successful during trials, one of the reasons it may still not be adopted and rolled out widely is because it cannot be easily and quickly manufactured.
The biggest difficulty, says Prof Edwards, is making sure the vaccine that has been produced in relatively small amounts in the lab, can be mass produced so that millions of doses can be distributed easily in the field.
He told Sky News: “These vaccines, they’re brewed, they’re grown. They’re not manufactured by a factory.
“It’s very important that the vaccine that you test is identical to the vaccine that you manufacture.
“So, if you brew one litre of your vaccine then you have to then make sure that the vaccine you get off that one litre is exactly the same as a 1,000-litre brewing.
“There’s massive biohazard challenges and containment challenges to make sure that it’s kept super clean.
“You then need to get all of that liquid and put it through some kind of vaccine filter that purifies all of your vaccine and gets rid of all of the gunk you really don’t want to inject into the human.
“Then the easy bit at the end is putting it into syringes so you can distribute it and inject it.”
He said that, while pharmaceutical companies have extensive experience of this, the economics and practicality of vaccine development and large-scale manufacture have often prevented a number of potentially effective vaccines coming on stream.
Because this has proved such a stumbling block in the past, he said it was likely that any candidate coronavirus vaccine will have to prove at an early stage it can be mass produced easily.
Dr Hatchett told Sky News: “We certainly wanted technologies that have the potential both for, in their existing manufacturing facilities, being scaled up to the tens or hundreds of millions of doses, but also for technology transfer to move that manufacturing to multiple sites, and to increase the manufacturing not only by perfecting of production process, but also by being able to replicate that production process.”
Organisation & fundraising
The devastating Ebola crisis in West Africa, which left more than 11,000 people dead, focused minds on the development of vaccines in a way they had never been focused before.
It became apparent during the response to Ebola, that a number of vaccines had been created but due to the economics of vaccine development – with many said to cost up to $1bn to bring to the market – some good candidates never saw the light of day.
The job should have been coordinated by the World Health Organisation, the United Nations agency with responsibility for international public health.
But, as many commentators have suggested, WHO is mired in many of the problems affecting a number of UN agencies – with their behemothic size often preventing them acting as dynamically as required in a crisis.
CEPI was set up to make sure the world is prepared to deal with new diseases.
It was conceived in 2015 by a director of the UK-based Welcome Trust and two other vaccine creators, and was launched after Microsoft’s Bill Gates offered a substantial investment at the World Economic Forum at Davos in 2016.
Several national governments have chipped in since, including the UK’s £250m so far, but CEPI says it needs $2bn to develop a vaccine that will be able to be rolled out to beat COVID-19. CEPI is working with pharma giant GSK, and has also issued grants to groups around the world.
Meanwhile, in the US, the government’s public health and biomedicine research arm, the National Institutes for Health, has been co-ordinating America’s efforts.
NIH has put money into the vaccine that went into the arm of Jennifer Haller, as has CEPI.
If an arm of the US government successfully develops a vaccine, it could prove controversial.
In mid-March, Germany reacted with anger when it emerged the Trump administration had tried to buy a German firm that was developing a vaccine. Some experts fear that governments may move to take control of a vaccine if it appears that a manufacturer in their country has successfully developed one. The political pressure on that government may be too strong to prevent any other scenario.
Some analysts say China, which has its own branch of government carrying out vaccine research, is unlikely to share what it develops with the world before it has immunised its own people, unless it is in its strategic interest.
Dr Hatchett says the risk that governments may try to purloin vaccines currently in development for their own needs is already a factor in deciding who to fund – spreading the risk that CEPI will be denied access to a successful vaccine.
He told Sky News: “Because national governments are so distressed by the current events, we do think there is a risk that vaccine manufacturing could be nationalised in any particular country. So, we need a globally distributed manufacturing base to offset that risk, to the greatest extent possible.
“Countries do have the right to do things that they view as meeting the needs of national security. So we wanted technologies that had advantages of getting to the clinic really, really fast, but also had the potential for technology transfer to move that manufacturing to multiple sites.”
Who’s doing it?
As well as those funded and coordinated by CEPI, there are some other major pharmaceutical companies that are putting resources into the development of a vaccine around the world, as well as foreign governments.
Several of the firms have agreed to share resources and clinical trial data among themselves and with governments, in an as-yet unprecedented way but, despite that, there have been calls, from the European Medicines Agency among others, for a more joined up approach, due to the number of studies under way.
The vaccine candidate that went into the arm of Jennifer Haller was produced by a US company called Moderna. Its candidate uses a variation on an already existing vaccine for respiratory tract infections. Initial research was funded by CEPI and the trials are funded by the NIH.
A team has received funding from CEPI and £2.2m in funding from the UK government.
Prof Edwards and the team he works with are also seeking funding for a vaccine candidate, which he says has the advantage of being able to be mass produced easily.
Institute Pasteur and Hong Kong universities
Have also received CEPI funding.
Johnson & Johnson
The US pharmaceutical giant is using another type of virus as a host for the vaccine – an adenovirus – taking out a small piece of its genetic code to stop it replicating. Into that virus is inserted some of the DNA of the virus J&J wants to protect against. The technique has worked already and J&J is optimistic it can do so again. Chief Scientific Officer Paul Stoffels told Sky News: “We have used that vector, now, four times… an HIV vaccine… with Ebola… with RSV and also with Zika. So that gives us now the possibility.”
Once the vaccine has been developed and manufactured, it has to be delivered to the millions of people around the world who will need it.
While millions of people may have had the disease by that point, millions won’t.
And while Western countries’ healthcare systems may be set up to deliver millions of doses to their citizens, those in the developing world will be less so.
Seth Berkley, GAVI’s CEO, told Sky News: “GAVI provides vaccines to 60% of the world’s kids. And we are very good at new vaccine launches. We’ve launched now 433 new vaccines in some of the most difficult places in the world.
“Obviously, there may be special characteristics about this. We tend to mostly vaccinate kids, but in this case, you may want to start with health workers, so there’ll be some adjustments.
“That’ll be one clear role of GAVI. The second one, which gets into what’s different about this vaccine, is we will want to think about access issues. We work with manufacturers to make sure the poor have access to vaccines at reasonable prices and we’ll continue to want to do that, but there’s going to be huge demand for the vaccine.
“We need to make sure that any candidate that comes out is manufactured in adequate quantities that it’s made available to not just rich countries, but to poor countries as well.
“Because, you can imagine a situation where people say ‘gee, I’m worried about my country’, but, if there are other places in the world where there’s a raging outbreak that allows the virus to mutate and adapt itself and become more virulent, there are places where the virus can be reintroduced.
“So we need to have a view about this that is really global.”
All those involved say they doubt a vaccine can be brought to market any earlier than 12 to 18 months.
But, it is possible it could be. And even if China or the US get there first, CEPI hopes that it will not prevent people around the world being able to benefit from it.
Dr Hatchett said: “If they’re manufactured within China or the US, obviously the US and China based production will serve the needs of those countries. But the production can potentially be replicated. So, there is no need for the vaccine to be monopolised by any single organisation, including CEPI or single country. The world having multiple efforts under way at the same time increases the prospect of the world succeeding in developing a vaccine.”
He added: “Twelve to 18 months is our aspirational timeline, which is filtered through our experience over many years and our understanding of the timelines of the products that we’ve got. Is it possible that vaccines could be available sooner than 12 months? It’s possible.”