Gilbert, a professor at Oxford’s Jenner Institute & Nuffield Department of Clinical Medicine, estimates her team needs up to £100 million (US$123 million) by June to succeed in their goal of developing a proven vaccine and partnering with a drug maker to manufacture it on a mass scale by autumn – a time frame up to a year shorter than those set by major pharmaceutical companies such as GlaxoSmithKline.

Gilbert said she believed her team has made the most progress so far and is likely to be first to reach the crucial milestone of showing vaccine efficacy.

Despite this, she is only “optimistic, but not confident” the money she needs will arrive in time – or even at all.

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“I don’t think the people with the money have really quite adjusted yet to what the vaccine developers need,” said Gilbert, who kick-started work on a coronavirus vaccine with a sum of about £500,000.

The funds were provided by the British government-funded Engineering and Physical Sciences Research Council and originally intended for other vaccines.

“I think in the minds of governments and the layperson, that’s for later. Because there’s such a demand for ventilators and personal protective equipment, that’s all anybody can think about now.” Gilbert said.

In recent weeks, Gilbert, who previously has worked on vaccines for Mers, the Nipah virus and Lassa fever, has spent countless hours filling out grant applications, searching for new funding partners and seeking approval to repurpose research funding earmarked for other uses – time she would have rather spent at the lab utilising her scientific expertise.

“A lot of academic funding these days is very, very constrained in what it can be spent on,” said Gilbert, whose work so far has been supported by university funds and government grants.

“There’s a very precise and detailed plan. That’s fine if the plan is what’s required. But when you need a new plan, when something else has happened, you need the flexible funding to be able to respond to that,” she said.

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The financial and bureaucratic hurdles facing the Oxford team indicate a mismatch between resources and incentives at the heart of vaccine development that could complicate the global effort to resolve a crisis that has focused the world’s attention like few problems in living memory.

Put simply, pharmaceutical companies that possess the means to fund expensive new vaccines often lack the motivation, seeing greater returns in treatments for chronic conditions such as diabetes and high cholesterol.

On the flip side, universities, publicly funded institutes and biotech start-ups that have the inclination and ability to step into the gap often lack the means.

The sheer scale of the crisis wrought by Covid-19 has spurred major firms to get involved, but belatedly and only with heavy state backing.

Pharmaceutical giants Johnson & Johnson and French multinational Sanofi are both relying on taxpayer-funded work by the Biomedical Advanced Research and Development Authority, a division of the US Department of Health and Human Services, to underpin their work on a vaccine.

“Until this model is fixed at the economic level, development of infectious disease treatments and vaccines will continue to face uphill battles,” said Ooi Eng Oong, deputy director of the Emerging Infectious Diseases Programme at the Duke-NUS Medical School in Singapore.

TOO COSTLY, TOO RISKY

Vaccine development is extremely costly and, from a business perspective, risky work.

Once a potential vaccine is created in a lab, it must go through three stages of clinical trials involving human subjects, culminating in Phase III trials during which a target population is administered the vaccine to test its effectiveness.

Multinational pharmaceutical companies such as Pfizer, GSK and Johnson & Johnson claim to spend between US$1 billion and US$2 billion to take a vaccine from the lab to its roll-out among the general population, a process typically taking 5 to 10 years and sometimes longer.

Michael Kinch, director of the Centre for Research Innovation in Biotechnology and Drug Discovery at Washington University in St Louis, said the major drug companies generally viewed vaccine development as high in risk and low in reward.

“The technology for most vaccines is not as advanced as for other more sexy technologies that can garner higher prices and thus revenues,” Kinch said.

Balking at the cost of in-house research, major drug companies have slashed R&D budgets in recent years to focus on the late-stage development and manufacturing of treatments pioneered externally – often by publicly funded entities such as government institutes and universities.

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All 210 new drugs approved by the US Food and Drug Administration between 2010 and 2016 were developed with funding from the National Institutes of Health, which distributes about 80 per cent of its US$40 billion annual spend on medical research to more than 2,500 universities and research institutes worldwide.

Given the reliance of industry on publicly funded research, resource issues at the university or research-institute level have the potential to dramatically affect the range of treatments that ultimately come online.

“Big Pharma generally do not have research divisions anymore,­ they gave those away when they found their research was three times as expensive per drug developed than ones sourced from academia,” said Ian Frazer, a professor at the University of Queensland who co-invented the human papillomavirus vaccine. “Industry only gets involved in manufacturing and marketing a likely successful product.”

Frazer said that failing to address shortfalls in academic research funding would leave countries unprepared for future threats to the public health.

“We run the risk that our labs won’t be ready for the next pandemic with the latest technologies in protein chemistry, genomics, crystallography, etc,” he said, referring to scientific techniques with applications in vaccine development.

Some academics see pitfalls, too, in collaborating with powerful industry players.

“The biggest challenge with such studies is that the research question and protocol are developed by industry and brought to academia for implementation,” said Keymanthri Moodley, director of the Centre for Medical Ethics at Stellenbosch University in South Africa. “It is not an authentic collaboration from the start, with sharing of ideas and equal partnership.”

The technical demands of producing a vaccine on a mass scale mean that research institutes and smaller start-ups will eventually need to partner with bigger players if they have not already to bring their creations to the public.

Despite the declining focus of major drug companies on innovation, there are potential advantages to such a division between the research and late-stage development process.

“I think the system works fairly well in the sense that primary research should be done at the academia level because it’s much more varied,” said Paul Offit, director of the Vaccine Education Centre at the Children’s Hospital of Philadelphia and the co-inventor of the rotavirus vaccine.

“You want hundreds of scientists working on this – all of them have different ideas. Then you want industry to step in and do the hard part, which is the research of development.”

Other major drug companies have eyed collaboration with biotech start-ups – which are often seen as being more innovative and agile than their Big Pharma counterparts – such as in the case of Pfizer’s partnership to develop a vaccine with German company BioNTech.

“Fortunately there are many biotechnology companies but unless they have adequate funding they cannot develop a vaccine beyond Phase I, after which they also need pharmaceutical money,” said Stanley Plotkin, an emeritus professor at the Wistar Institute and University of Pennsylvania who invented the rubella vaccine in the late 1960s.

INNOVATIVE, BUT POOR

It is such concerns about the most innovative players not receiving adequate funding that spurred the establishment of the Coalition for Epidemic Preparedness Innovations (CEPI), following the lacklustre global response to the 2014-2016 Ebola outbreak in West Africa, which killed more than 11,000 people.

Even though Ebola had been known about since the late 1970s, there was no vaccine available at the height of the crisis.

Because outbreaks of infectious disease often subside over time or are contained before infecting huge numbers of people, the financial incentive to develop a vaccine can be weak until a major public health crisis is under way – particularly in poorer regions where the prospects of reaping large profits are slim.

In an echo of that slow response in West Africa, Dr Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases, lamented as late as mid-February that major pharmaceutical companies had yet to “step up” and commit to manufacturing a vaccine.

“Companies that have the skill to be able to do it are not going to just sit around and have a warm facility, ready to go for when you need it,” Fauci said.

Publicly funded institutes that are not driven by profit similarly struggle to attract support once a disease drops out of the public consciousness.

In 2016, researchers at Baylor College of Medicine in Houston, Texas, developed a vaccine for severe acute respiratory syndrome (Sars), but could not attract funding for human trials because by that point there had not been any new cases for more than a decade.

Those researchers are now again seeking funding to resume work on their vaccine out of a conviction it could be effective against the novel coronavirus, also known as SARS-CoV-2.

“For vaccine development, the greatest threat is the episodic nature of pandemics,” said Jerome Kim, director general of the International Vaccine Institute (IVI), a South Korea-based non-profit organisation set up as an initiative of the United Nations Development Programme.

“Often by the time a vaccine reaches tests in humans, the epidemic has abated. Funding goes away, even though the threat of future epidemics by the same pathogen continues.”

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REASONS FOR HOPE

Established by the government of Norway, the Bill & Melinda Gates Foundation, the Wellcome Trust, the World Economic Forum, and India’s Department of Biotechnology in 2016, CEPI raises money from governments and philanthropic sources to quickly fund the development and manufacture of vaccines for emerging infectious diseases that struggle to attract private investment.

Already, the organisation has been credited with getting the development of a number of potential vaccines for SARS-CoV-2 under way at an unprecedented pace.

The Oslo-based group has so far committed funding to eight vaccine-related projects involving partners including the University of Queensland, the University of Hong Kong and US biotech firm Inovio Pharmaceuticals.

With the ultimate success of any one initiative impossible to determine at this stage, CEPI is aiming to produce at least three viable vaccine candidates that can be licensed for use among the public.

One candidate developed by Moderna, a Cambridge, Massachusetts, biotech firm that is yet to commercialise any products, and the NIH is already a month into Phase I clinical trials.

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The company, which previously worked on a Mers vaccine and is using a new development platform called messenger RNA, believes its vaccine could be ready for emergency use by health care workers before the end of this year, although a version for general use is still not expected for 12-18 months.

“Every one of the major companies has a SARS-2 project, so they are not slacking,” said Plotkin. “However, the most inventive projects are being done by biotechs which will need to convince major companies to produce large quantities. There could be more collaboration between the two, and for that matter a central body to enhance collaboration. CEPI fulfils that role in part, but not sufficiently.”

Although there is potential overlap in the work of so many different groups across academia and industry, experts say there is a strong case for funding multiple approaches. For every 10 vaccines created in a lab, nine fail to make it to the approval stage.

“I don’t think we know enough about SARS-CoV-2 to be able to predict which vaccine candidate would work,” said Ooi. “But I think it is very important for us to take multiple shots at goal to make sure that at least one vaccine candidate would cross the line and work to prevent Covid-19. That there are many groups working on vaccines, to me, is a very good thing.”

CEPI has funding challenges of its own, even after receiving large sums in recent weeks from donors including Britain, Germany, Canada, Denmark and Norway.

So far, it has been able to raise only a little over one-third of the US$2 billion it asked for in an urgent call for funding on March 14.

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For researchers, accessing what money is available from the organisation, which did not respond to requests for comment, comes with a considerable amount of red tape.

“The T&Cs CEPI has accepted from their funders mean that it is a complex process for them to award funding to anyone,” said Gilbert, who has received some funding from the organisation.

Other entities besides CEPI, both public and private, have also turned to approaches outside the traditional vaccine funding and development process.

Microsoft founder-turned-philanthropist Bill Gates has announced plans to preemptively fund the construction of manufacturing plants for seven of the most promising vaccine candidates before it becomes clear which vaccine or vaccines are safe and effective.

The move, which will see billions of dollars effectively wasted to create manufacturing capacity that will never get used, aims to save valuable months that would otherwise be spent waiting for the most promising vaccine to emerge.

The US government has sealed deals with Johnson & Johnson and Moderna to produce large quantities of vaccines before any candidate is shown to work.

“The Covid-19 outbreak is obviously unlike anything we have encountered in living memory and efforts are now galvanising to pursue promising vaccine candidates,” said Robin May, director of the Institute of Microbiology and Infection at the University of Birmingham.

SAFETY LIMITS

Underscoring the urgency for a vaccine, the pandemic has controversially spurred the use of countless experimental treatments to try to treat Covid-19.

But even with an unprecedented focusing of attention and resources, there are limits to the extent to which vaccine development can be fast-tracked.

“Under the pressure of the pandemic, we have to carefully consider the balance of safety and speed,” said Kim of the IVI, which is working with a number of firms and public bodies on a vaccine.

“Vaccines are given to healthy people to keep them healthy, and vaccine developers must ensure that safety is not compromised. The absence of information on SARS-CoV-2 or Covid-19 itself further highlights this responsibility.”

Such safety considerations are not an abstract concern. In the late 1970s, the US government’s rushed roll-out of a vaccination programme to immunise the population against a novel strain of swine flu resulted in more than 450 people developing Guillain-Barré syndrome, a rare disorder that causes paralysis.

One scientist at a multinational vaccine institute said the SARS-CoV-2 vaccine would face a “safety hurdle” because of how the virus affects older people more severely than the young.

“A new virus in a population typically causes more severe disease in individuals with natural prior exposure to something similar,” said the scientist.

“[This is] one hypothesis as to why older people have [been more severely hit]. This occurs when someone has prior exposure to a similar virus – there are other common coronaviruses – and the resulting immune response causes the next encounter with a similar virus to be more severe. This phenomenon has been seen with other diseases such as dengue.”

The scientist added: “Because of this possibility, any vaccine will be scrutinised to be certain it will not cause more severe disease.”

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Unanswered questions about the nature of the virus – including definitive proof that those who are infected gain immunity – could also complicate development.

“Upper respiratory tract viruses without a blood-borne infection phase have not to date been successfully targeted by vaccines,” said Frazer. “On the plus side, this appears to be a relatively stable virus, not like flu or HIV where the virus changes quickly.”

In a possible breakthrough, a team of South Korean scientists announced on Friday they had successfully mapped out the architecture of the virus’ RNA genome for the first time, potentially aiding vaccine development.

Even so, most experts believe that a usable vaccine is at least 12 to 18 months away, with many arguing that even that time frame is wildly optimistic and unrealistic.

Offit said many people underestimated the enormous challenge of producing a vaccine on a mass scale.

“The research is the easy part,” said Offit, who is sceptical any vaccine can be rolled out within 18 months. “The hard part is the research of development because you have to do proof-of-concept studies. You have to have the right buffering agent, the right stabilising agent.

“The flaw in the system is that far fewer companies are doing it. In 1955, there were 27 companies that made vaccines. By 1980, there were 18, today there are four.”

Gilbert said she believed her team can best expectations – their “highly ambitious” goal relies on adapting a previously used vaccine delivery system and manufacturing vaccines concurrently with clinical trials – but only with a major rethink of research funding that offers quick and flexible support for work such as hers.

“We don’t have an organisation that is ready to deal with the pandemic,” Gilbert said. “We now need to be thinking about flexibility of funding on a much larger scale because we need to be able to go fast.” ■