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New EU-funded research projects to protect Europeans from potential future pandemics have just been approved by the European Commission (EC). But the road to strengthening the EU's resilience to cross-border health threats is still long and steep.
The fragmented and underfunded system built around the nascent Health Emergency Response Authority (HERA), part of the Health Union package, suggests that the EU has not learnt the two key lessons from the Covid crisis: long-term planning and greater investments.
The voices of scientists across Europe seem to have fallen on deaf ears once again, as they did before the tragedy. Yet another may be just around the corner.
“The World is not ready for the next pandemic, in case a new virus emerges it would take at least one year to have the first vaccines; broader-acting drugs should be developed,” prophesied Johan Neyts, professor of virology at the Belgian University of Leuven, at the 8th international Symposium on Modern Virology in September 2019 in Wuhan, China. A couple of months later, in the very city which hosted the event his forward-looking speech would sadly turn into the global havoc we have all experienced.
“If you have an enemy attacking you, then you’d better have your weapons ahead of the attack, so you need to build them in peacetime,” said Neyts “Instead, what we did with SARS-CoV-2 (the virus causing Covid-19) is that we waited for the attack and then we started building our weapons.”
That's it. The European Union (EU) has spent billions of euros fighting the Covid crisis, but only a few million trying to prevent it, failing precisely because of a lack of funding for research. Far more lives and economic losses could have been saved if Brussels decision-makers had stuck to the drug development investment strategy they adopted after the first SARS outbreak in 2003, researchers say. Two decades later, such a short-sighted approach still prevails, leaving European citizens vulnerable to future epidemic threats.
Shortsighted politics does not help long-term research
In the period between the two outbreaks, not only in Europe but around the world, public coffers had invested taxpayers' money in several SARS research projects, including both drugs and vaccines, which ultimately never came to fruition due to funding cuts. When the pandemic began and public funding became available again, some of these promising projects were resumed and their inhibitors proved to be somewhat effective against Covid, showing that sustained research efforts could have made a difference.
“The EU and governments in general still prefer to finance reaction rather than preparation for pandemics and I think this is a mistake, especially when it comes to the development of broad-spectrum antivirals which could be manufactured beforehand and used from the start of any outbreak,” said Bruno Canard, Director at the French Scientific Research National Center and specialist of virus structure and drug-design at Marseille University.
The numbers seem to confirm this conclusion. In 2023, HERA’s budget is 1.267,6 million, including contributions from different programmes: 389 million from Horizon Europe 2023-24, 636 million from EU Civil Protection Mechanism (UCPM/rescEU) and 242,75 million from EU4Health which, with 5.1 billion over the period 2021-2027, will become the largest EU health programme ever in monetary terms (five times more than all the previous health programmes ran since 2003).
Only a third of HERA's budget, or €474.6 million, was spent on fighting infectious diseases through pathogen surveillance, pharmaceutical countermeasures and improving health systems. No more than €50 million was allocated to research and development of drugs. This figure is less than 2% of what the EC alone has paid to Big Pharma to cover part of the cost of developing covid vaccines, which amounts to €2.9 billion (including €350 million for the research phase). And it is ten times less than the 525 million spent by the US National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health (NIH), on its Antiviral Drug Discovery Centers programme, dedicated solely to pandemic antivirals.
“Investing in drugs that can neutralise potential infectious diseases as soon as they appear is like an insurance premium, a choice between how much risk we want to take by simply letting it go and see what happens or to try to be prepared,”said said Eric J. Snijder, head of molecular virology research at Leiden University Medical Center.
The EU has paid its lack of preparedness against SARS-2 with almost 439 000 deaths and GDP decline of 6.5% in 2020, the first year of the Covid surge, and €2.018 billion mobilised through the Recovery Plan to rebuild the economy ravaged by the lockdown. It is reasonable to assume that €30 billion, the amount that the 27 Member States eventually had to take out of their safes to buy vaccine doses, would have been a fair premium to pay up front in the form of drug development and procurement.
“We cannot blame Pharma companies for not developing drugs against coronaviruses because there was no market for them back then since SARS-CoV-1 waned after a few months,” Neyts said. “I think the rich countries are to be blamed, that they did not create the necessary incentives for companies to develop drugs that can be stockpiled.”
“To stockpile ahead of future outbreaks, a drug has to go through clinical studies to show that it is safe (phase 1) and to demonstrate that it is active (phase 2) against at least a virus of the same family, for example another coronavirus,” said Snijder. “Only big companies have the capacity and funding to run such clinical studies, so they need to be involved.”
“The problem is that the most boring pandemic is the one we will have prevented from happening, because nobody will know about it. And those in power will not get any credit for countering it, let alone that they do not consider it attractive to invest a lot of public funds in things that may stop something at some point, but nobody knows when and if it's going to work 100%,” Snijder said. “Politicians tend to look 3-5 years ahead because it’s just the time for which they have been appointed or elected, while a long-term and broad antiviral drug development plan takes 10 to 20 years.”
Canard agreed: “We cannot achieve long-term tangible results with projects that usually the EU funds for up to 5 years, but I understand that scientific anticipation, which takes time, is perceived as less visible for the taxpayers than reaction.”
Promising efforts which could have mitigated the pandemic
According to the prominent researchers we interviewed, the 18 years that elapsed between SARS-1 and SARS-2 was enough time to develop a number of good inhibitor prototypes, and Pfizer has shown with its Paxlovid that it can be done in just two years if there is sufficient investment. Research literature shows that other scientists would agree with Snijder, Canard and Neyts that we might have had a chance to contain SARS-2 locally by distributing and using multi-spectrum drugs in Wuhan, and that while one can never promise that the virus would not have spread around the world anyway, at least we would have bought a lot more time for vaccine development.
Snjider, Canard and Neyts, along with Rolf Hilgenfeld, head of the coronavirus team at the Institute of Molecular Medicine at the University of Lübeck in Germany, are key pioneers in the trans-European network of scientists working on coronaviruses since the first SARS outbreak. They were part of three promising cross-border projects co-funded by the EU with a total of €30 million with the 6th and 7th Framework Programs, which could have paved the way to an effective response to Covid and changed our fate for the better. Each of them was the logical continuation of the previous one: SARS-DTV (2004-2007), Vizier (2004-2009) and Silver (2010-2015).
“The overarching principle underlying these past projects is that in peace time we cannot predict which pathogen will emerge, but we can anticipate that it will belong to one of the families of viruses we have already identified as having epidemic and pandemic potential, such as the coronaviruses (also responsible for human flu), for which we had a second warning with MERS-CoV in 2012 in Middle East,” said Neyts. “So, our objective was to develop for each of these families a broad set of potent antivirals (multi-spectrum drugs), after studying their biological structure and finding their weak points, and I am sure this was and it is still possible.”
“First with Vizier we characterised the target molecules of different virus families, then with Silver we intended to create inhibitors that could precisely hit such targets,” said Hilgenfeld.
“The big advantage of antivirals is that they inhibit the virus enzymes and other key elements which do not mutate as quickly as the Spike protein targeted by vaccines, which always need to be developed tailored to the exact virus that comes out and we can see how long it took to adapt them to Omicron,” said Snjider.
“The probability that an antiviral which works on SARS-CoV-1 may have worked on SARS-CoV-2 was very high,” Canard said. “Had we had at least the possibility to test the safety of our molecules for SARS-CoV-1 through phase 1 of clinical trials (the stage proving that a medicine is safe for humans), as soon as SARS-CoV-2 emerged we could have moved directly to phase 2 (the stage proving that a medicine is effective against a virus), instead of starting from scratch and we could have had inhibitors in six months after coding the virus sequence.”
The shared dream of Snijder, Neyts and Canard did not last long. There were other crises, such as Ebola in 2014 and Zika in 2015, and the EU shifted money away from coronavirus research to respond to these other viruses. The EC's website proudly claims that over €4 billion has been invested in the fight against infectious diseases from 2007 to 2020. In particular, before the pandemic, under the entire Horizon 2020 (2014-2020), €178 million and €650 million respectively were mobilised for vaccine and antiviral R&D, according to the EC spokesperson. This money was not enough to avert the disaster.
“To be effective, budgets need to be made sustainable, meaning that public tenders have to ensure continuity to research efforts through funding projects which can evolve into other ones, precisely like Vizier and Silver”, Canard said. “But when Silver funding period was over, the EC told us it was not worth going further, there's a lot of science lobbying both at national and EU level and apparently it's not the structural biology for antivirals that won the race.”
“We informally recommended to the EC to have Silver 2, but they did not agree,” said Hilgenfeld. “I think that we would have been much better prepared for Covid, if they had given us money to continue our project.”
“But by then, there was no more tender which could have matched our research area, but I understand there are other interests as well, it is inevitable that the next crisis will always push away the funding for the previous one,” Snijder said. “It is almost like policymakers have a guilty conscience, they realise they did not invest enough to limit a particular disease, so there's a huge amount of money made available for a few years, and then it goes away again and there are other crises.”
The post-Covid EU wake-up
As the crisis escalated in 2020, the EC doubled its total R&D spending compared to the previous six years and immediately provided emergency funding of around €23 million for several covide-response projects: two targeting vaccines and seven focusing on drugs. "All these projects run for two or three years, and then they have to find a way to continue, and that's going to be hard," said Snjider, who, together with Neyts, Canard and Hilgenfeld, coordinated one of these EU-funded efforts, called Score, which built on the experience he and his colleagues had gained from previous EU-funded research that had been interrupted years before SARS-2 emerged.
The four “drug paladins” are also part of Care, a larger consortium to develop covidalene antivirals supported by the Innovative Medicines Initiative (IMI). The latter is a public-private partnership between the EU through Horizon 2022 and the European Federation of Pharmaceutical Industries and Associations (EFPIA).
"Both Score and Care include most of the groups that were part of Score, and we have continued to collaborate on certain issues since then, although it is more difficult to continue without external funding," says Snjider. "I would like to prevent this from happening again by finding new resources for the goals we have set for Score and even broadening them beyond just coronaviruses by going back to the Silver concept.
The inhibitors developed in Score are based in part on those identified over the last two decades, particularly in studies of SARS-1 and MERS coronavirus, and on the general knowledge gained about coronaviruses over this period, which has been essential in defining suitable viral drug targets. "This shows how investment in basic research pays off in the end, but it's easy to forget because EU programmes often focus on short-term rather than long-term research investment," said Snijder.
"When SARS-2 started, everyone said: 'Oh, we didn't learn the lessons from SARS-1'. Now the question is: do we really learn the lessons from SARS-2 and build a prevention strategy for SARS-3 and other groups of high-risk viruses?" Snijder said. "The panic is over now, but then we can react by relaxing and saying: 'OK, this is over and we'll just wait and see if the next crisis is around the corner' or we can assume that it is likely to happen and use all the capacity that has now become available with a clearly defined roadmap and dedicated funding to work through to the end, including the necessary trials, to have drugs that we can use immediately when they are needed and then of course extending this beyond coronaviruses should be an additional step".
This is precisely the direction the EU has recently taken, at least on paper. The final report of the workshop co-organised by HERA in November 2022 acknowledges that "the development of broad-spectrum antivirals for the major virus families of concern is no longer out of reach and there is no doubt that their availability will make the difference when the next pandemic hits". The document also highlights the need for sustained efforts by industry, even in the absence of a guaranteed market, clarification of the regulatory pathway and rapid approval of multinational clinical trial protocols, similar to the joint EC/European Medicines Agency (EMA) action on Covid therapeutics launched in January 2022.
Research consortia, including academic institutions from several European countries, responded to Horizon Europe's first call for proposals, which was launched last January. Snjider, Neyts and their colleagues rushed to meet the April deadline by submitting their new collaborative project, called PanViPrep. It was funded, and their successful application gives them the opportunity to continue their work. Indeed, in line with the goals that inspired Vizier and Silver many years ago, the EC has prioritised projects focusing on broad-spectrum antivirals, including the repurposing of already approved or pipeline drugs, targeting viruses with high epidemic potential.
The focus will be on diseases on the World Health Organisation (WHO) and HERA lists. Last December, the two organisations signed a new partnership with a €15 million allocation under the EU4Health programme 2021-27 to strengthen capacities at national, regional and global levels to better prepare for and respond to health emergencies.
Uncertain sustainability for pharmaceutical R&D and production
"Our new PanViPrep project will use the toolbox developed by Score, Vizier and Silver to further our research to identify compounds targeting both coronaviruses and other virus families with epidemic and pandemic potential, and to take some of these compounds to an advanced pre-clinical stage," said Neyts. "We hope that if we achieve promising results within the four-year funding period, the EC will provide follow-on funding to take these molecules into clinical trials."
"The role of antivirals, which could really be the first line of defence, still seems to be underestimated," said Snjider. "Historically, the structural proteins of the virus, which are targeted by vaccines, have been prioritised by funding agencies compared to the viral enzymes (non-structural proteins that are often absent in the virus particle and only appear in the infected cell), which are targeted by antivirals instead, meaning that the targets of antiviral drugs are less studied and understood."
There are concerns that the limitations of the current EU funding scheme could jeopardise the financial sustainability of winning projects.
"Horizon Europe is limited in time and funding and therefore cannot ensure the sustainability of funded projects after the funding period; projects are encouraged to explore ways to ensure their sustainability during their lifetime," the European Commission spokesperson admitted. "Preparations for the second part of Horizon Europe (2025-2027) are underway in coordination with the Member States, but at this stage it is not possible for us to comment on this point."
In particular, the call for proposals on which the PanViPrep team has relied only supports pre-clinical work, proof-of-concept studies and early safety studies. Phase IIb/III trials, which are crucial to determine the potential success of an antiviral therapeutic, are beyond the scope of the programme, both in terms of time and budget. While Phase IIa trials are an extension of Phase I, focusing on dose finding and safety profile, Phase IIb already includes efficacy trials to determine if the drug has the desired activity.
"Efficacy trials, which are the most expensive part of drug development and approval, are rarely covered by EU calls for proposals because the general line today is that they should be done by industry," says Ed Schmidt, Senior Project Manager Pandemic Preparedness at Leiden University Medical Center, who works with Snijder on a number of cross-border projects. "However, at least phase IIb could easily be done within an EU grant, as it has a relatively low cost of around €1 million (covering patient recruitment, sample collection and analysis, storage, handling and characterisation), provided that the trial centre agrees to work on a not-for-profit basis (paying the salaries of the trial staff out of its own pocket)."
"SCORE ended in September 2022, so even if our new project proposal was successful, we had a funding gap of at least one year," says Snjider. "And after securing additional funding, we need to take our compounds to a pharmaceutical company that, if interested, will invest in further development and testing, as there is no university that can afford to do these things."
"We could still have tried to transfer some of our Score activities to Care, which lasts five years and is coordinated by the pharmaceutical industry, which hopefully has an interest in further extending the short funding period offered by the EU," says Snjider. Within Care, phases I and II of clinical trials are co-funded by companies.
So far, the EU has provided funding for Phase IIb of clinical trials only of Covid vaccines already approved by EMA through the Vaccelerate programme.
To help companies that have difficulty accessing sufficient public and private funding for research and development (R&D), the EC announced the creation of HERA Invest in July 2023. This initiative, funded by the EU4Health programme, adds €100 million to the InvestEU programme (supported by the European Investment Bank). In addition, €80 million has been released to support particularly promising Covid vaccines. These amounts, like those invested through Horizon Europe, are still a relatively small fraction of the total cost of bringing a new product to market, which is estimated to be over €2 billion in 2013.
Besides R&D, another bottleneck is production capacity for future threats. So far, HERA has reserved production capacity for vaccines through the FAB network of industrial facilities, with contracts signed in June at a cost of €160 million in 2023.
This effort is considered insufficient by McKinsey. In a study paid for by the EC and published in March 2023, the global consultancy recommends higher annual investments in capacity reservation, with a range of 560 million euros for vaccines and €100 million for antivirals. Despite the suggestion that vaccines should be prioritised, the study points out that "broad-spectrum antivirals, defined as antivirals that inhibit the replication of viruses belonging to one or more viral families, represent one of the most important areas of innovation in therapeutics from a pandemic preparedness and response perspective." Unlike most approved antivirals, which are virus-specific, broad-spectrum antivirals can be developed before specific viruses emerge, including new viral strains or variants.
In addition to testing and manufacturing problems, the EU has not set up a common mechanism for mandatory stockpiling of drugs. "We fund the procurement, management and hosting of stockpiles proposed by member states, but we do not provide further financial incentives," the European Commission spokesperson said. In 2023, €636 million will be spent on stockpiling through the UCPM/rescEU.
The EU's approach to R&D, manufacturing and stockpiling still appears to be market-driven. The revision of the pharmaceutical legislation, proposed by the EC in April, aims to ensure the supply of safe and affordable medicines by supporting the innovation efforts of the European pharmaceutical industry. "Our proposal incentivises investment in areas of unmet medical need and orphan drugs through market access rewards and guaranteed revenue schemes," said the EC spokesperson.
| Former EU-funded projects on broad-spectrum antivirals Comparative Structural Genomics of Viral Enzymes Involved in Replication (VIZIER) The project aimed to identify potential new drug targets against RNA viruses through comprehensive structural characterisation of the replicative machinery of RNA viruses, including coronaviruses. Replicative machinery are the most conserved and essential viral components, thus are attractive targets for antiviral therapy. The core enzymes/proteins of the replication machinery were characterised and compared to design strategies for virus inhibition. More than 2000 genomic sequences were resolved, hundreds of relevant recombinant proteins were synthesised, and more than eighty crystal structures of viral replicative enzyme domains, i.e. potential antiviral drug targets, were discovered. VIZIER therefore served as the ideal platform for a dedicated viral drug discovery programme. Small molecule Inhibitor Leads Versus Emerging and neglected RNA viruses (SILVER) The project focused on selected medically important RNA viruses for which the development of drugs is considered essential, including coronaviruses. It has completed a major research initiative on screening for molecular inhibitors. SILVER recognised that the discovery programme could not realistically proceed beyond the stage of Proof of Concept (PoC) through demonstrating that identified viral inhibitors were effective in vitro tests, did not induce genetic resistance readily and were effective in vivo laboratory models. Thus, any effective, non-toxic inhibitors which satisfied the criteria for PoC, would have to be patented and then licensed to pharmaceutical or other relevant companies with adequate funds to take them through the clinical trials and then to market. Swift Coronavirus Therapeutics Response project (SCORE) The project, building on the experience gained with VIZIER and SILVER, aimed to fight the rapidly spreading SARS-CoV-2. Its objective was to understand and inhibit coronavirus replication through using five independent approaches: FDA-approved drugs, targeting viral RNA synthesis, inhibiting coronavirus proteases, blocking virus entry, discovery and development of new antivirals using a medicinal chemistry approach. The project provided detailed information of the efficacy of 9500 drugs considered for drug repurposing, in-depth characterization of the structure and function of the coronavirus RNA polymerase complex, in-depth characterization of SARS-CoV-2 main protease structure and function, characterization of inhibitory properties and antiviral activity of existing and novel α-ketoamide inhibitors of the coronavirus main protease, design and antiviral activity inhibiting the SARS-CoV-2 Spike protein. |
| Who are the researchers in EU-funded projects Rolf Hilgenfeld, researcher at University of Lübeck in Germany, started working on coronaviruses in 1998, well before the first SARS outbreak. He has tried to develop inhibitors against coronaviruses (SARS-CoV-1, MERS-CoV and SARS-CoV-2) through taking part in all major EU-funded projects. His first research on coronaviruses was funded by the German Research Foundation, but was not supported by the Scientific Advisory Board of the Institute of Biotechnology in Jena where he worked back then. In the early stages of his inhibitor-discovery project his research group synthesised a potential inhibitor of SARS virus and compared it with all of the cysteine protease inhibitors available at that time. He noticed a similarity to an inhibitor against the common cold that Pfizer was developing. Structural elements of this compound were used almost twenty years later in Pfizer’s Paxlovid, which is now recommended for the treatment of mild and moderately severe cases of COVID-19. Hilgenfeld has developed his compounds further and also recently managed to licence his broad-spectrum coronavirus inhibitor Frank Grosveld, researcher at the Department of Cell Biology of the MC Erasus centre in the Netherlands, took part in the Zoonotic Anticipation and Preparedness Initiative (ZAPI), supported by the EU-funded Innovative Medicines Initiative (IMI). The project, started in 2015 and ended in 2021, aimed to set up platforms that would be ready to put into production vaccines and monoclonal antibodies to counter coronaviruses causing three zoonotic diseases which occurred in the past: MERS-CoV, Schmallenberg virus and RiftValley Fever. Grosveld’s team and his collaborator (Bosch’s team, University of Utrecht) developed a series of antibodies that would bind to all three viruses because they share the same Spike protein. In 2018 he put his cross-reactive antibodies to the freezer to conserve them. After the SARS-CoV-2 outbreak in China, in January 2020, the antibody 47d11 was first tested on animals and then on human cells and research findings proved it to be able to block COVID-19. Back in 2018 Grosveld and Bosch talked to pharmaceutical companies to take ZAPI antibodies for further development. But none was interested and Grosveld could not start production of antibodies 47d11 ahead of the pandemic. More recently they developed a more powerful anti-SARS-CoV-2 antibody 87G7 as part of a new European project called Monoclonal antibodies against COVID-19 (MANCO), which ended in May, which builds on technology generated during ZAPI. This antibody blocks most viral strains. |
This investigation was supported by the European Excellence Exchange in Journalism (E³J) and Free Press Unlimited
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