Noam Ross, a virus hotspot modeller for EcoHealth Alliance
Covid-19 has reminded the world of the ever-present threat posed by viruses. From universal vaccines to miniature organs that can assess the lethality of a virus, scientists are racing to find new solutions that can prevent future disasters from happening. Here we look at three of the most innovative ideas for stopping the next pandemic before it begins.
A universal coronavirus vaccine
In May 2020, Matthew Memoli, director of the US National Institutes of Health’s (NIH) Laboratory of Infectious Diseases, published a comment piece in the journal Nature in which he urged the scientific community not to repeat the mistakes of the past.
While vaccine developers across the globe were racing to develop a vaccine for Covid-19 – as of August 2020, there were more than 170 such vaccines in development – Memoli argued this was not enough. Instead, he outlined a more ambitious target. “We must go further,” he wrote. “We must work towards a universal coronavirus vaccine with broad protection against a diverse number of coronaviruses.”
Memoli’s reasoning is that history has a habit of repeating itself. From SARS to MERS to the SARS-CoV-2 virus behind Covid-19, the world has now been rocked by three major coronavirus outbreaks of increasing severity. Each time, scientists and policymakers have tended to focus entirely on the problem at hand, at the expense of planning for the future.
Speaking from his office in Bethesda, Maryland, Memoli says we need to keep the bigger picture in mind. As devastating as Covid-19 has been, future coronaviruses may pose far greater threats. “Just focusing on this individual virus to me is a mistake,” he says. “At the same time we need to be thinking about the future. Even if we come up with a great vaccine for this virus, that doesn’t necessarily mean we’re going to be ready for the next one.”
The concept of a universal vaccine – one which can protect against many different coronavirus strains – may seem far-fetched, but it isn’t a completely new idea. In the early 1990s, a group of scientists at Norden Laboratories – the Pennsylvania-based animal health division of pharma company SmithKline Beecham, now GSK – came up with the ambitious plan of developing a vaccine that could protect cats from multiple coronaviruses. Back then, the commercial interest in coronaviruses came not from their threat to humans but to animals, as there are various strains which can be harmful to household pets.
Norden’s team, which dubbed themselves “gene jockeys” due to their expertise in cloning genes from various pathogenic viruses, got as far as filing a patent for the proposed vaccine, but the project nosedived in clinical trials with the vaccine failing to demonstrate any protective ability. However, it left in its wake a key lesson. Achieving effective protection against more than one strain of coronavirus – whether in animals or humans – would be a complex task, likely requiring inducing an immune response broader than neutralising antibodies.
“We thought we could stimulate an antibody response to a spike protein [a common target of coronavirus vaccines] that would protect against different feline coronaviruses,” says Elaine Jones, one of the original Norden scientists and now an executive who sits on the boards of multiple biotech companies. “But this approach alone was not sufficient to get the right long-lived immunity.”
Two decades on, the first hints that a universal coronavirus vaccine might be viable came from scientists studying the MERS coronavirus, shortly after it had caused a large outbreak in the Middle East in 2012. Keith Grehan, then a PhD candidate at the University of Kent and now a researcher in molecular biology at the University of Leeds, was intrigued to know whether blood samples taken from survivors of the SARS coronavirus outbreak in the early 2000s exhibited any kind of immune response to this new virus.
To his surprise, Grehan discovered that approximately a quarter of SARS patients had neutralising antibodies in their blood against MERS. When he compared the protein sequences of the two viruses, he found that there was some overlap. In one particular region of the spike protein, 40 per cent of amino acids were conserved between SARS and MERS. Grehan was even more intrigued when he discovered a further overlap across SARS, MERS and the OC43 and HKU1 coronaviruses which are linked to common colds.
To him, this suggested that it might be possible to develop a vaccine which could induce an immune response across many coronavirus strains. But by 2016, fears of MERS had waned, and funding for the project had all but disappeared. As he puts it: “Going to a pharma company saying ‘We have a vaccine that potentially protects against some colds, plus if people happen to be near a camel and catch MERS, they’ll also be protected’ wasn’t really a great commercial proposition back then.”
Four years later, the landscape for such vaccines could not be more different.
Matthew Memoli, director of the Clinical Studies Unit at the US NIH’s Laboratory of Infectious Diseases
The second wave of coronavirus vaccines
In July 2020, French biotech Osivax secured more than 32 million euros in funding from the European Innovation Council and investment bank Bpifrance to develop a universal coronavirus vaccine. It was just one of a series of announcements relating to a new class of coronavirus vaccines which have a broader vision in mind.
A second wave of coronavirus vaccines, aimed at more than just Covid-19, are in the pipeline, including from Belgian startup myNEO, Canadian pharma company VBI, an initiative led by the Chinese Center for Disease Control and Prevention and an NIH-funded program led by Memoli.
These will take a little longer to hit the market – all are still in preclinical development with human testing planned for early 2021, while some Covid-19 vaccines are already at the final stage of trials before clinical approval – but, if successful, their broader applicability could make them more useful in the long run.
“We hope these vaccines will offer added value by protecting against more coronaviruses, including if the current strain causing Covid-19 mutates,and by offering longer-term immunity,” says Cedric Bogaert, co-founder and CEO of myNEO.
All these programmes are looking to build on what Grehan discovered with SARS and MERS, namely that when you probe the protein sequences of the coronaviruses known to infect humans, there are a number of similarities. The main question is how best to exploit them.
When Memoli penned his paper in May, he already had an idea in mind, having devoted more than a decade to the ongoing search for a universal influenza vaccine. As the Norden scientists had found in the early 90s, he had learnt that making a successful broad spectrum vaccine likely requires inducing different aspects of immunity, such as training T cells to recognise tell-tale indicators of these viral strains.
T cells are thought to be particularly vital, as once they have learned to recognise a virus, they generate copies of themselves which remember the pathogen and remain dormant until a future encounter. A vaccine that stimulates this part of the immune system, as well as trying to induce an antibody response, is more likely to offer protection across different coronavirus strains, and in different age groups and populations around the world. Such is the importance of T cell responses that several Covid-19 specific vaccines in development stimulate them.
“The beauty of the T cell response is that it tends to have benefits in the elderly where their antibody responses and antibody immune memory isn’t as strong,” explains Memoli. “We want to use as many aspects of immunity as we can, so there are lots of ways the virus could be attacked to reduce disease.”
T cells can be trained to recognise internal components of coronaviruses which mutate less and so are more likely to be similar between different strains. These internal proteins are notoriously more difficult to target, but in recent years scientists working on flu vaccines have figured out ways to reach them by injecting parts of a virus’ RNA or DNA into bodily cells, causing them to expose these proteins at their surface where they can be recognised by the immune system.
Osivax’s vaccine aims to use T cells in this way to target the nucleocapsid – an internal protein which is thought to be highly conserved between all known human coronaviruses – while Memoli’s group and myNEO have an even more ambitious plan. Through utilising computational algorithms to sift through all available coronavirus sequences, they intend to identify cocktails of targets across all the viral proteins which appear to be essential for coronaviruses to survive.
Similar approaches are also being trialled for universal influenza vaccines, but there is hope that it may be more straightforward for coronaviruses, as there is less diversity within their genetics.
“You can take the sequences of these viruses and determine how related they are,” says Memoli. “And through this you can group all the coronaviruses that have infected humans into four families. Influenza is much harder from a genetic standpoint because there are broader numbers of subtypes and strains.”
But while such programmes offer optimism that the world will be more prepared for future coronavirus outbreaks, coronaviruses are far from the only pathogenic species lurking amongst wildlife which could pose a threat to humans.
Keith Grehan, a researcher in molecular biology at the University of Leeds
A lab of mini organs
At Fudan University in Shanghai, plans are afoot to design a high-level containment laboratory with the specific intention of helping predict the next pandemic. Known as a biosafety level 4 (BSL-4) facility, there are only a few dozen such places on the planet.
Inside BSL-4 labs, conditions are more akin to exploring outer space than conducting scientific experiments. Workers wear space suits with their own air supply systems, and the entire area must be secured by airlocks.
This is what it takes to work with potentially lethal viruses, and in the eyes of Hans Clevers, a 63-year-old Dutch professor who is one of the driving forces behind these plans, such a facility is a necessary investment if we are to catch future pandemics before they even begin.
A pioneer in developing organoids – miniature, simplified versions of organs created from stem cells – for more than two decades, Clevers is something of a father figure in the field. His vision for the Fudan lab, of which he is honorary director, is to create a dedicated centre where scientists can cultivate organoids from the cells of bats, pangolins, civets, and other indigenous species across China and East Asia. One idea is to create gut organoids from the intestinal cells of these animals, as many viruses live in the intestinal tract. This would allow scientists to use these organoids to assess the danger levels of the unknown pathogens lurking within.
This centre would be the culmination of a new dimension of virology which Clevers and others have ushered in over the past ten years. Since 2012, they have created numerous organoids, as a way of gathering data on everything from the norovirus (which causes stomach flu) to Ebola.
Most organoids make an inauspicious sight to the naked eye. At first glance they look like little more than a series of pale blobs floating in their petri dishes. But under a microscope they can be revealed in their full glory: these curious structures are around a million times smaller than those in our bodies, yet complex enough to provide a realistic model for understanding how viruses invade cells.
The first time organoids really captured the imagination came during the Zika epidemic of 2016. Three years earlier, a German molecular biologist named Jürgen Knoblich had created a stir by deriving cerebral organoids – dubbed “mini brains” in the media – from pluripotent stem cells, a breakthrough which was named one of the top ten discoveries of 2013 by Science. As Zika spread across Brazil, Knoblich’s organoids gave some of the first clues as to why the virus was causing an outbreak of children born with small brains.
“It was the first time anybody had been able to show that Zika could lead to this neurodevelopmental disease,” Knoblich says. “This made organoids primetime as a way of studying viruses.”
Amid the current Covid-19 pandemic, organoids have played a key role in understanding the diverse range of symptoms that patients can experience. Through infecting intestinal organoids with SARS-CoV-2, Clevers showed that the virus can easily infect the gut, causing nausea and diarrhoea, while others have created replicas of the vascular system to demonstrate how it can use the human ACE2 protein to spread through the blood.
Now, increased investment is being devoted to using organoids as a way of assessing problematic viruses. A major area of concern, particularly in Asia, is the threat posed by hybrid influenza viruses which have arisen from pigs or birds and exchanged genes with human strains. Earlier this year, a case of hybrid influenza was identified in Idaho, USA, which contained genetic material from both seasonal influenza and the H1N1 virus which caused the 2009 swine flu outbreak.
In partnership with scientists at Hong Kong University, Clevers has set up a system for predicting how deadly these new viruses are, through ascertaining the amount of damage they cause to the respiratory system when allowed to infect lung organoids. “Sooner or later a new dangerous influenza will emerge in East Asia,” he warns. “It’s a constant worry. But this allows scientists out there to take any new strain and quickly assess how contagious it is, and what it’s likely to do to the body.”
Hans Clevers has pioneered the use of organoids created from stem cells as a way to study viruses
Cultivating unknown viruses
There are many viruses out there in bats and other species in hotspots around the globe which are not yet capable of infecting human cells, but only need minor mutations to be able to do so. This makes it likely that they will develop this ability in the near future.
Clevers is keen to cultivate these viruses in the lab, and test potential drugs and vaccines so we can deal with them, should they jump to humans. The only way of doing this, is to cultivate organoids from the animals themselves.
For a long time it wasn’t possible to do this, but Clevers and his team have figured out a way. “We found that by taking stem cells from any organ, and sticking them in a mix of stem cell growth factors, they keep on making the organ where they came from,” he explains. “This allows us to create organoids for any mammalian species. We’ve even made snake venom organoids.”
Such work, however, involves an element of risk. Creatures like bats have a sturdy immune system to keep viruses within them at bay, but when growing their organoids in a dish, such protections are no longer there. Unless extreme precautions are taken, such research could allow potentially dangerous pathogens to escape, which is why the highest levels of biosecurity are required.“You need very special training and equipment to do this,” Clevers says. “Bats carry a lot of dormant viruses that are kept in check by their own immune system, but the moment you put them in culture, the viruses can now propagate. This has to be done extremely carefully so we don’t have an escaping virus.”But while Clevers is screening viruses which have yet to infect humans, another organoid scientist is monitoring pathogens which are already known to be dangerous, and are spreading to more populated parts of the world due to factors such as climate change.
Josef Penninger, an Austrian molecular biologist, is leading a new initiative called MAD-CoV 2 – one of eight projects selected by the European Union’s Innovative Medicines Initiative to share a funding pot of 72 million euros – which launched in August 2020.
The idea behind MAD-CoV 2 is to use organoids to identify potential drug targets for a whole range of different viruses. By taking human lung organoids covered in thousands and thousands of cells, exposing them to a virus, and then studying the cells which survive, Penninger believes they can identify mutations capable of blocking that particular strain.
He is looking to apply this both to new coronaviruses being discovered in Asia, and also hantaviruses. This family of viruses, which can be deadly to humans, are usually found in remote tropical regions, but are now becoming increasingly common in parts of Europe. “Climate pockets are now developing all over the world, which is causing some viruses to move in these geographical regions, which have not been seen for centuries,” he says.
It is a project Penninger has been waiting to launch for several years, but until now, he says, no one was willing to fund it. The impact of Covid-19 has been such that both governments and the corporate world have changed their minds.
“This technology has been available but nobody really cared,” he says. “A year ago I would go to investors and tell them, ‘We have this cool new way to study viruses which could lead to new drug targets,’ and I was basically shown out of the office. Instead they were investing in their 120th company on cancer. We all knew there might be a pandemic, but nobody believed it.”
For Clevers, more than anything, the sheer economic impact of the crisis has forced policymakers to reconsider. “I think it’s now not so difficult to make the calculation of how much a pandemic costs, versus how much it costs to set up a facility like the one we’re discussing in Shanghai. There’s no comparison,” he says. “And this is not a freak incident – we’ve had SARS, MERS, and now Covid-19. You can either just wait for the next virus or try to do something about it.”
Noam Ross has modelled how biodiversity and land use affects animal-to-human viruses
An atlas of viruses
Of all biological entities on Earth, viruses are by far the most numerous. To put things into perspective, there are more individual viruses coexisting with us on the planet – an estimated 10 nonillion (10 to the power of 30) – than there are stars in the Universe. A single teaspoon of seawater contains roughly ten million of them.
Given such numbers, tracking down every single viral species with zoonotic potential – meaning it can jump from animals to humans – may seem like an impossible task. But a global consortium of scientists have a plan to do just that.
Jonna Mazet makes it sound so simple. “There are around 500,000 viruses out there which could infect us,” explains the wildlife epidemiologist and director of the University of California, Davis One Health Institute. “We know that for just over a billion dollars we can find the majority of them, and for close to four billion we can find just about everything.”
Mazet has a track record in this area. Over the past decade she has served as director of PREDICT, a US government-funded initiative to detect viruses capable of causing emerging pandemics. Armed with the latest next-generation sequencing technology, the project discovered and sequenced more than 1,000 viruses between 2009 and 2019, found everywhere from rice fields in Nepal to the urban slums of Sierra Leone. Impressive numbers, but still nowhere near enough.
For all the team’s efforts, they missed SARS-CoV-2. But Mazet had forewarned of this possibility. In a 2018 World Health Organization bulletin, co-written with other scientists involved in PREDICT, she wrote that “the world is not well enough prepared for the next emerging viral outbreak.”
Now, in the wake of the Covid-19 pandemic, she is reinforcing this message. While PREDICT will soon be replaced by a new US-led five-year initiative called STOP Spillover – which focuses on identifying further coronaviruses as well as Ebola and Nipah viruses – she is urging political leaders to get behind a far more ambitious prevention programme.
The Global Virome Project (GVP) – a global consortium of pandemic prevention experts, of which Mazet is one of the seven-member leadership team – aims to carry out PREDICT’s goals on a far larger scale. Over the course of a decade it intends to create an atlas of every potentially zoonotic virus out there, through collecting samples from between 1,000 and 2,000 individuals of every mammal and water bird species thought to be capable of carrying viruses which could spill over to humans.
Such an atlas could hold a range of benefits. Doctors in at-risk nations could be primed to keep a lookout for symptoms of these diseases, and the viruses could be ranked for pre-emptive vaccine development based on how likely they are to reach us in the near future.
Mazet admits the scope of the project may sound daunting, but there is a complex strategy behind the GVP’s plans. For each continent, they plan to sample regions based on mathematical models of where viral hotspots are likely to be, and how they are evolving over time.
Computer scientist Noam Ross works for New York-based non-profit EcoHealth Alliance, one of the driving forces behind the GVP, and is one of the world’s leading hotspot modellers. He explains that there are three main drivers which make a particular region a hub for zoonotic viruses: high biodiversity in the mammalian population; patterns of climate change; and active land use change.
“Firstly, animal biodiversity leads to viral biodiversity,” he explains. “If you have a lot of different species with overlapping habitats, they will share viruses, and when viruses are already jumping a lot between species, it makes it easier for them to jump to humans. Climate changes cause animal populations to shift their habitats towards regions which suit them more, and in regions where there’s a lot of land use changes through industry and agriculture, that brings humans closer to these biodiverse areas.”
Because this is constantly evolving over time as both humans and animals move, modellers like Ross use satellite and climate data to make predictions of areas likely to become viral hotspots. This is then combined with information from scientists on the ground conducting serological surveys, taking blood samples across populations to look for antibodies which show that humans are repeatedly coming into contact with new viruses. Ross says EcoHealth Alliance has just begun a new survey looking for viral antibodies in rural communities in Malaysia, with plans to expand this across multiple countries in Southeast Asia.
Gaining political willpower
While PREDICT was bankrolled by a United States Agency for International Development grant, the funding required for the GVP to commence has yet to be secured – although Mazet says that there have been verbal signs of interest from political leaders in China, UK and the US, among other countries. While the price tag – estimated to be between $1.7 billion and $3.7 billion to accomplish the GVP’s major goals – may have made politicians balk in the past, the hope is that the fallout from Covid-19 will make policymakers more attuned to the potential cost-saving benefits of investing in the project. Some estimates of the global economic cost of Covid-19 have been in excess of £7 trillion.
“The total price tag of the Global Virome Project is minuscule compared to what Covid-19 has cost the world,” says Mazet. “I see this pandemic as a clarion call to say ‘OK, we’ve all lived through something horrible, we never want this to happen again, so let’s get prepared.’ We have all the technology, the scientific momentum to find these viruses, we just need the political will.”
In the meantime, various national initiatives are already underway, with individual countries carrying out other virus mapping projects, albeit on a much narrower scale, focusing on particular species. One of these projects is in Beijing, where scientists at China Agricultural University are constantly on the lookout for new strains of swine or bird flu, monitoring tens of thousands of swabs from slaughterhouses across the country to detect the emergence of new strains with pandemic potential.
Other ventures are looking to complement the planned aims of the GVP by trying to identify warning signs in wildlife which can be used to alert nearby communities of potential new viruses, and to find ways of reducing the risk of infections being passed on from animals to humans.
From studying bat populations in Bangladesh and Ghana, Raina Plowright, an infectious disease ecologist at Montana State University, knows that at certain times, species tend to shed viruses in particularly large quantities or “pulses”. This typically occurs because the bats are under stress, meaning their immune system is weaker than it otherwise would be. Plowright is currently running a project which hopes to be able to detect changes in bat behaviour, for example in their nutritional intake or reproductive success, which indicates they are likely to shed more viruses.
“These trigger points could be used as an early warning system,” she says. “For example in places like Bangladesh, that data could be used to warn people not to consume date palm sap during those months, which is often contaminated by bats, because it’s likely to have a higher viral load.”
For Mazet, the importance of such projects cannot be underestimated because as devastating as Covid-19 has been, future pandemics could be far worse. “Researchers in this field are thankful it’s not worse, because it could have been so much more deadly,” she says. “The main problem with Covid-19 is that we let the genie out of the bottle. What projects like the GVP can do is give people the ability to mitigate the risk of these events at a much earlier stage.”