Inside the race for a vaccine

The urgency to find a coronavirus vaccine is compressing years of research into weeks for these life-saving projects. Rachael Pells goes behind the scenes to understand the superhuman effort and international collaboration to find humanity’s golden ticket out of the pandemic

As millions prepared to celebrate the dawn of a new decade on 31 December last year, world health authorities in China received reports of a worrying new illness spreading across Wuhan city. Over the coming days and weeks, this novel coronavirus – which causes the disease now known as COVID-19 – would dominate news stories across the globe.

The coronavirus pandemic has killed over 317,000 people at the time of writing; it respects no authority or border and has upturned every aspect of society in its contagion. Now, the planet’s sharpest minds are racing to find a vaccine, which experts agree is the only exit strategy from the current state of social and economic limbo.

But a clear road to a successful vaccine and treatment is not guaranteed. Scientists face huge time-scale pressures, and navigation is especially complicated when traditional planning strategies no longer apply. In April, it was revealed that Remdesivir, a highly anticipated drug developed by researchers in China in the hope of treating coronavirus patients, had failed its first round of trials – a major blow.

While terms like ‘unprecedented’ and ‘global crisis’ have become clichéd through overuse, it is clear that the unpredictable nature of this disease means project managers are unable to plan to the same measures they once might have. It begs the question: how do we go about achieving such a complex and high-stakes mission when the only deadline leaders have is ‘now’?

Vaccine projects at the cutting edge

During previous epidemics, vaccines would take years to develop, but COVID-19 has come at an auspicious moment: cutting-edge genetic sequencing technologies make it possible to crack a virus’s genetic code in no time at all, and scientists are no longer required to put themselves at risk by handling dangerous, live molecules of a disease in order to develop a vaccine response. Instead, they are able to design artificial copies of the offending virus’s DNA or RNA.

Thanks in part to Chinese researchers who were quick to crack the virus’s code and share its unique genetic sequence, testing of potential vaccine candidates is well underway. Research by Imperial College London into an RNA vaccine – which works by training the body to build up a defence mechanism of antibodies against specific, harmful cells – is due to be ready for human trials in June.

Another project, underway at Oxford University’s Jenner Institute, takes a different approach: immunologists are creating what is known as a recombinant vector vaccine, designed to work by embedding a string of genetic coding from the coronavirus into an existing chimpanzee virus that is harmless to humans. The theory goes that, when the doctored chimpanzee virus is introduced to the human body, it hijacks cells to generate molecules that match the same shape as the coronavirus. Once the body has these uniquely shaped cells in its recognition, it will be ready to attack the real thing later on.

The potential benefits of this relatively new type of vaccine development is that it uses an existing structure, and is believed by some experts to be safer – getting researchers to the point of human trials much faster. The first volunteers were given trial injections at the end of April, with tests on rhesus macaque monkeys in May showing good results, and a further 10,000 volunteers to be recruited. According to Jenner Institute senior immunologist Professor Katie Ewer, creating a vaccine this fast has never been done before – nor has a clinical trial been designed so quickly during an outbreak.

Around 80 further academic laboratories and private institutions are also hard at work on the task at hand, not including dozens of grassroots and under-the-radar initiatives taking place among so-called ‘DIY’ or ‘citizen’ scientists via online forums and hacker-spaces. And while criticisms grow over political leaders’ responses to the pandemic, even the world’s largest pharmaceutical companies are teaming up with would-be competitors: in April, GlaxoSmithKline and Sanofi announced a joint-initiative clinical vaccine trial later this year with the hope of having a product ready by the second half of 2021.

Project leaders need strong allies

“A public health crisis – especially one on global scale – is not ‘business as usual’,” says Tarja Huuskonen, CEO at life sciences project management consultancy Action for Results. Leadership, resilience and a “focused pursuit of the end goal” are crucial, but perhaps more so than ever, team leaders will need to build a strong network of partnerships and alliances – often with competitor groups and across boundaries, she advises. This means “deploying agile methods and ‘fail-fast’ principles”, with a primary focus on getting to the point of scientific and clinical proof-of-concept “as quickly as possible – with clear go/no-go criteria and understanding of risk”.

“The great news is that novel technologies are being pursued with considerable potential to accelerate clinical development,” says Huuskonen. “However, the novelty of DNA/RNA based approaches also carries an increased technical risk associated with development.”

The clinical ‘proof’ for a vaccine is generated through Phase 2 trials, which still have a high failure rate – only around 33 per cent make it through to the approval stages, Huuskonen notes.

“From a global perspective, having a prioritised pipeline of vaccine candidates is important,” she adds. “While several global collaborations are in place, questions about prioritisation and ability to refocus resources and funding quickly appear.” To this end, communication is key: “Daily huddles with teams to stay connected will be critical.” Given that social distancing measures are forcing office teams – not just those used to collaborating internationally – to fully coordinate work online, often for the first time, “another challenge is to quickly learn virtual facilitation of work – truly working virtually, and not just meeting virtually,” she explains.

‘Playing Roulette’

Even with the best of intentions, there can be no doubt that these teams, alongside their ruling governments and policymakers, will succeed better with help from coordinating bodies. “While it is good to have multiple efforts under way, given high failure rates, if these efforts are driven independently, the overall probability of success – defined by having a safe and effective vaccine out in record time, in the right quantity to address global needs – decreases,” Huuskonen explains. With this in mind, “the end goal” should be “to have a platform for ongoing preparedness in the long term”.

The Coalition for Epidemic Preparedness Innovations (CEPI) was set up to respond to exactly this eventuality. Launched at Davos in 2017 as a joint initiative by the Norwegian and Indian governments, the Bill and Melinda Gates Foundation, Wellcome Trust and the World Economic Forum, CEPI was born out of a consensus that a coordinated international and intergovernmental plan was needed to develop and deploy new vaccines to prevent future epidemic crises.

The timing of epidemics is unpredictable, but that’s not to say that some degree of forward planning is impossible. Within the first six months of operation, CEPI had negotiated partnerships with vaccine developers to offer financial and advisory support for work on nine vaccines, which may or may not be needed. CEPI may not be able to develop vaccines for every known virus, but it can make educated predictions as to which diseases are likely to cause problems in the near future.

“We are playing roulette,” Richard Hatchett, CEPI’s CEO, told Margaret Heffernan, author of Unchartered, in late 2017, adding with acute foresight: “We have to deal with beta coronaviruses, like MERS and SARS, because they have pandemic potential.”

A race against the virus

Today the organisation has an 80-strong staff body working on the international COVID-19 response, including researchers from a variety of backgrounds in industry and academia, as well as project managers, contract managers, lawyers, and communications, financial and administrative staff. When the World Health Organisation declared COVID-19 an international public emergency in January 2020, CEPI moved to set up eight new partnerships with promising vaccine programmes around the world, backed by $23.7m in funding. “This virus can only be beaten with international cooperation, and we are seeing unprecedented levels of global scientific collaboration,” says Mike Whelan, project leader for CEPI. “There is certainly a race to find the vaccine right now, but it’s a race against the virus and not against each other.”

As with any project of this scale, a timeline was set: in this case, 16 weeks, something leaders acknowledge is “extremely ambitious and unprecedented”. Agreed vaccine projects are broken down into defined work packages, “each with pre-agreed milestones, and transfer between work packages is controlled by a pre-defined review procedure”, Whelan explains. Partners are allocated a dedicated CEPI project lead, each with extensive experience in vaccine development to provide real-time support and guidance.

Oxford’s Jenner Institute: a pioneer

The Oxford vaccine trials are also partially funded under CEPI. Sarah Gilbert, the recombinant vector vaccine programme’s leader, first came across the new virus in early January – weeks before UK ministers met to declare the contagion of COVID-19 a threat to national health. While many took time off to celebrate seasonal holidays, Gilbert and fellow scientists remained clued up on the crisis taking place on the other side of the world through group email conversations within the medical community. It was not long before she began to consider the potential impact of this new disease: “It looked like it might be something interesting, but we didn’t know if it had spread very far,” Gilbert recalls.

Gilbert’s research group were already busy working on vaccines for diseases including Lassa fever, MERS and ‘disease X’, the name given to the unknown threat “that we knew was going to come and cause a pandemic at some time in the future”. Given their available resources, she and colleagues decided to get started on a vaccine, just in case.

The Jenner Institute is unique in that it has its own manufacturing facility for Phase 1 and 2 clinical trials, and has previously conducted 12 clinical trials against similar diseases, giving Gilbert’s team a head-start. Now, more than ever, organisation is key: the vaccine centre currently has around 200 people on rotas to manage the set-up of human trials, screening volunteers ready to take part as soon as vaccines are available.

“In the context of social distancing this is a huge logistical challenge,” notes Andrew Pollard, chief investigator on the study. To speed the process up, the team must effectively build the train while on the track: researchers would ordinarily wait more than a year after the first phase of trials has finished before moving on, “but here in a pandemic we have to manage things differently,” he explains. “Trials are organised to run in quick succession, so there’s no change overall in procedures, just the urgency to try and move rapidly through the testing.”

Manufacturing the vaccine, adds institute director Adrian Hill, is “one of the biggest challenges faced. It’s no good telling you the vaccine works but we don’t have any ready,” he says. As such, “risk manufacturing” of the most promising vaccine candidate has already begun in that partnerships are being set up with a network of seven manufacturing companies around the world. “We’re now moving to the point where, instead of doing maybe three-litre manufacturing runs, we’re up to 50 litres. We’ll go to 200, maybe even 2,000 litres. The aim is to have at least a million doses by around September once we’ve got the vaccine efficacy result, and then move even faster from there – it’s pretty clear the world is going to need hundreds of millions of doses by the end of this year.”

In fact, Cambridge-based pharmaceutical giant AstraZeneca signed a deal at the end of April with the Jenner Institute to team up to manufacture and distribute the prospective vaccine, with the capacity to supply up to 100 million doses by the end of the year, and then expand from there. Gilbert has given the project an 80 per cent chance of success, possibly as early as September.

The financial cost of a global vaccine

Biomedical testing is a costly business – CEPI estimates the cost of developing a single epidemic infectious disease vaccine at between $31–68m, assuming no risk of product failure, during ordinary times. Since the COVID–19 outbreak, the foundation has received over $765m from the UN, Canadian and European governments, and some private-sector donations, but much more will be needed to ensure fair distribution of the products across continents.

The ideal situation, according to Whelan, will be to have multiple licensed vaccines ready for distribution, not just one “winning” formula. But project managers’ work will continue far beyond that initial eureka moment. “Ultimately, when a vaccine becomes available there will be global demand, so it is vital that a system is in place to ensure that those who most need it get priority access.”

Jenny Ottenhoff is a project leader for health and education programmes at the ONE campaign. A major part of her role is to drive routine and targeted fundraising on a global scale to support charity and research bodies, including CEPI. “Whenever we are working on projects that are as key as this one, they’re always mission-driven and we need an objective,” she says. “One of the challenging things about COVID-19 is that the objective is clear but how to get there is murkier than ever.

“Making decisions when you aren’t positive that you have the right information is challenging in itself. So keeping a resilient attitude and making it clear to partners that you might be taking some risks is really key in this time of uncertainty,” she says, adding that a “big tent attitude” is required. “We’re drawing on expertise and resources, talking to every partner we can to share ideas, lock intel and try to connect dots. Right now, I think the biggest lesson from this outbreak is that we’re all in this together and the solidarity message is really key. It absolutely cannot be done in a silo.”

This global connectedness is an ambition shared by researchers in Gilbert’s lab, too. “We would be really keen to work with other vaccine developers, either sending them samples from our clinical trials or receiving samples from theirs so we can start to compare the immune responses,” she says. “With the 2014 Ebola outbreak, this didn’t happen. Different groups were using different ways of measuring the immune responses so it wasn’t possible to compare like with like until after one of the vaccines had been through an efficacy study – when it should really be the other way round.”

This would not only help experts to prioritise the vaccines that work, but would give researchers a greater understanding of RNA and DNA vaccines in general, she explains. “We don’t think ours is the only vaccine that’s going to work, but we don’t think all of those out there are going to be useful.”

Gilbert’s team was awarded a further £2.2m by UK public funding bodies in March, and she is confident a vaccine will be ready for manufacturing by autumn 2020. If so, they will have achieved an extraordinary feat in a marginal time frame thanks to their ability to prepare for virus response ahead of time. Once this crisis is over, there will nonetheless be lessons to learn for next time around.

“We are seeing significant positive movement: public-private partnerships, sharing of information across traditional boundaries, funding from government and philanthropic sources, vocal demand for vaccines,” Huuskonen reflects, “[and yet] from a programme management perspective there isn’t a clear global or national plan, nor a clear definition of roles and responsibilities. Still a siloed approach rules more than not – and, unfortunately, political and personal agendas get in the way.”

‘We’re all at risk’

“I am very optimistic that we will learn from this and continue to improve the global response to these types of things. We already have,” Ottenhoff adds. “But it’s imperative that preparedness stays at the forefront of policymakers’ minds once this is over.” Ultimately, project leaders need to be willing to make risk management a regular feature in their month-to-month planning, not just after a crisis has hit. “But I would say it really happens at a government level,” Ottenhoff concludes, “every country on earth needs to be prepared for an epidemic, and until all of us are prepared and our systems are functioning well, we’re all at risk.”

Lessons learned from Ebola

The global need for an organisation like the Coalition for Epidemic Preparedness Innovations (CEPI) was recognised after the devastating Ebola epidemic hit West Africa in 2014. “The world’s response to this crisis fell tragically short,” CEPI’s Mike Whelan reflects. “A vaccine that had been under development for more than a decade was not deployed until over a year into the epidemic. That vaccine was shown to be 100 per cent effective, suggesting that much of the epidemic could have been prevented. It was evident we needed a better system to speed development.”

One positive lesson learned from the epidemic is that delegation and outsourcing of project management in large-scale vaccine trials is proven to have a significant impact on the speed with which immunisation – from laboratory testing all the way through to distribution of the drug – can be implemented in a community in times of crisis.

With the Ebola outbreak already underway, action was required to push vaccine trials through at a faster rate than laboratories were previously found capable of. To this end, help was sought from big pharmaceutical companies such as GlaxoSmithKline in the development, testing and licensing of a vaccine, and the task of project managing such a feat was awarded to Quintiles (now rebranded as Iqvia), a US multinational company responsible for outsourcing services for pharmaceuticals. Quintiles oversaw the recruitment of 3,000 adults and 600 children required for Phase 2 trials of the most promising vaccine, and managed the task three weeks ahead of schedule.