Are we ready for the next pandemic?

“The World is not ready for the next pandemic. If a new virus emerges, it would take at least a year for the first vaccines to be developed. 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. Just a couple of months later, in the same city which hosted the event, the professor’s prediction would be realised in the global havoc we all experienced. 

“If you have an enemy attacking you, then you’d better have your weapons ahead of the attack. 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.”

It’s true: the European Union has spent billions of euros fighting the Covid crisis, but only a few million trying to prevent it, failing to do so precisely due to a funding shortage for research. According to researchers, far more lives and economic losses could have been spared had decision-makers in Brussels pursued the drug development investment strategy implemented in the wake of the first SARS outbreak in 2003. If such a shortsighted, emergency-based approach persists, European citizens will be left unprotected against future epidemic threats. 

The EU still prefers to finance reaction to – rather than preparation for – pandemics. This is a mistake, especially when it comes to the development of broad-spectrum antivirals which could be manufactured beforehand and used right when any outbreak occurs. 

The numbers seem to confirm this conclusion. The European Commission (EC) has pledged 600 million euro from the Horizon Program for 2023-24 to tackle both Covid and future health crises through cross-border collaboration on pathogen surveillance, medical research and improvement of health systems. 

While the sum appears generous, no more than 50 million euro will be allocated to drug development, which is less than 2 percent of the sum paid by the EC to Big Pharma to partly cover Covid vaccine development costs – amounting to 2.9 billion euro (including 350 million for the research stage). Moreover, there are genuine concerns that funding cuts beyond the next two years, given how such cuts occurred in the past, could undermine Europe’s preparedness for future pandemics.

“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 seeing what happens, or trying to be prepared,” says Neyts. The EU paid for its lack of preparedness against SARS-2 with almost 439,000 deaths and a GDP decline of 6.5 percent in 2020, the first year of the Covid surge, and 2.018 trillion euro mobilised through the Recovery Plan to rebuild the economy ravaged by the lockdown. One could assume that 30 billion euro, the amount that the 27 member states eventually had to spend on vaccine doses, could have been a fair premium to pay in advance 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 disappeared after a few months,” Neyts says. “I think the rich countries are to be blamed. They did not create the necessary incentives for companies to develop drugs that can be stockpiled.”

The problem is that the most boring pandemic is the one we will have prevented from happening because nobody will know about it; those in power will not get any credit for countering it, and governments don’t like to invest so much public funds in prevention without 100% assurance of success. Politicians tend to look 3-5 years ahead because that is normally the time for which they have been appointed or elected, while a long-term drug development plan takes 10 to 20 years. We cannot achieve tangible results with projects that the EU usually funds for up to 5 years. But scientific anticipation, which takes time, is less visible to taxpayers than reaction.

According to the prominent researchers we interviewed, the 18 years that have elapsed between SARS-1 and SARS-2 were enough time to develop many good inhibitor prototypes and, with antiviral medication Paxlovid, Pfizer showed it is possible even in just two years with adequate investment. Many other scientists agree that we might have had a chance to contain SARS-2 in Wuhan through distribution and use of such drugs, and that, although there is no guarantee that the virus would not have spread across the globe, at least it would have bought more time for vaccine development.

Neyts, together with Eric J. Snijder , head of molecular virology research at Leiden University Medical Center, Rolf Hilgenfeld , Head of the Coronavirus Team at the Institute of Molecular Medicine at the University of Lubeck, and Bruno Canard , Director at the French National Center For Scientific Research and specialist in virus structure and drug-design at Marseille University, was one of the key pioneers of the trans-European network of scientists who have collaborated on coronaviruses since the discovery of the first SARS. They were all part of three promising projects, co-funded by the EU with a total 30 million euro with the 6th and 7th Framework Programs, that could have paved the way for an effective response to Covid. Each project was the logical continuation of the previous one; they were named SARS-DTV (2004-2007), Vizier (2004-2009) and Silver (2010-2015).

What can be anticipated

"The overarching principle underlying the three projects is that in time of peace we cannot predict which pathogen will emerge next, but we can anticipate that it will belong to one of the families of viruses we have already identified as having epidemic or pandemic potential, such as the coronaviruses (also responsible for human flu), for which we had two warnings with SARS-Cov-1 in 2003 and MERS in 2012," one of the researchers said. "So, the objective was to develop for each of these families a broad set of potent antivirals, after studying their biological structure and finding their weak points."

First, with Vizier, researchers characterised the virus target molecules, then with Silver they intended to create inhibitors that could precisely hit such targets.

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 tailored to the exact virus - as in the case of Omicron.

The probability that an antiviral which works on SARS-CoV-1 would have worked on SARS-CoV-2 was very high, according to scientists. Had they had at least the possibility to test the safety of our molecules for SARS-Cov-1 through phase one of clinical trials, as soon as SARS-Cov-2 emerged, they could have moved directly to phase two instead of starting from scratch, and they could have had inhibitors in six months after coding the virus sequence.

The common dream of Neyts, Snijder, Hilgenfeld and Canard did not live long. There were other crises, such as Ebola in 2014 and Zika in 2015 and the EU turned money away from coronavirus research to respond to these other viruses. The EC’s website proudly claims that, from 2007 to 2019, over 4 billion euro were invested, including more than 650 million into vaccine research and innovation. And yet, all this money was incapable of preventing 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,” one of the researchers said. “But when the Silver funding period was over, the EC told us it was not worth going further, there's a lot of lobbying both at national and EU level and apparently it's wasn't the structural biology in antivirals that won the race.”

Other interests

“We informally recommended Silver 2 to the European Commission, but they did not agree,” one of the researchers said. “I think that we would have been much better prepared for Covid, if they had given us money to continue our project.”

“There were no more tenders 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 funding for the previous one,” an anonymous researcher 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.”

Amid the crisis escalation in 2020, the EC provided emergency funding of 45.5 million euro to several Covid response projects . Around 10 of these focus on drugs. “All of these projects run for two or three years and will then have to find a way to continue, and that's going to be hard,” said one of the researchers who coordinate one of these EU-funded efforts called Score , which builds upon the experience the researcher acquired with his colleagues through previous research before SARS-2 emerged. 

Along with Neyts, Snjider, Canard and Hilgenfeld, he also participates in Care , a larger consortium aiming to discover Covid 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 which were part of Score. “Indeed, we kept collaborating on certain topics, although without external funding it is more difficult to keep going,” one of the researchers said. “I would like to avoid this from happening again by finding new resources to work on the goals we have set for Score, and actually making them broader than just for Coronaviruses, by going back to the Silver concept.”

The inhibitors developed within Score are based on those identified over the past two decades, particularly in studies on SARS-1 and MERS coronavirus. This shows how investing in basic research eventually pays off, but it’s easily forgotten when EU programmes are all too often focused on short-term products instead of long-term research investments. Science-politics has turned to focus on the former.

When SARS-2 began, everyone said “Oh, we didn't learn the lessons of SARS-1”. Now the question is: are we really learning the lessons from SARS-2 and building a prevention strategy for SARS- 3, and for other groups of viruses? With the panic gone, we can respond by relaxing and saying “Ok, this is over, and we’re just going to wait and see if the next crisis comes around the corner”; or we can assume it will likely reoccur and use all available capacities, with a clearly defined roadmap and dedicated funding, to produce, including the required trials, drugs we can immediately deploy when needed. Expanding this beyond coronaviruses should be the next step.

New call for proposals

This is precisely the right direction that the EU has recently taken. The final report of the workshop organised by the EC Directorate-General for Research and Development, and the EU Health Emergency Preparedness and Response Authority (HERA) acknowledges that “developing broad-spectrum antiviral drugs for the major virus families of concern is no longer beyond 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 from the industry in the absence of a guaranteed market, clarifications on the regulatory pathway, and the rapid approval of multinational clinical trial protocols, similar to the joint action of the EC and the European Medicine Agency (EMA) on Covid-19 therapeutics launched in January 2022.

Research consortia are now competing for the first call for proposals opened last January. Neyts and his companions are rushing to meet the April deadline, longing for the opportunity to resume their work. 

In line with the goals that inspired Vizier and Silver, the EC will prioritise projects focusing on broad-spectrum antiviral compounds, including the repurposing of previously approved or in-pipeline drugs, which target viruses with high epidemic potential. 

In the spotlight are the diseases listed by the World Health Organization (WHO) and HERA. Last December, the two organisations signed a new partnership with a 15 million euro allocation under the EU4Health programme 2021-27 to boost capacities at national, regional, and global levels for better preparedness for and response to health emergencies.

However, researchers are concerned that history could repeat itself. The role of antivirals, which could be a real first line of defence, seems still underestimated. Indeed, strings attached to the current EU grant scheme could compromise the long-term sustainability of the awarded projects.

The 50 million euro offered for drug development under the Horizon Program is of course nothing compared to such offers in the United States, but the EU is still performing well for the moment. 

The current EU tender only supports preclinical work, proof-of-concept studies and early safety and efficacy trials. This means there is no funding for phase IIb/III phase trials which are crucial to determining the potential for success of an antiviral therapeutic. Such stages, which are the most expensive part of medicine development and approval, are rarely covered by EU calls for proposals because the general line nowadays is that they should be done by the industry, although at least Phase-2 could be easily done within an EU grant, since it has a relatively lower cost of around one million euro.

Another limiting factor is that the EU rarely provides funding for GMP (good manufacturing practice) production which is needed to make material available for clinical trials and is much more expensive than the trial study itself. For example, in Care (which includes only phase-2A clinical trials), GMP production was excluded and, as a result, several promising products have already been terminated or moved outside the consortium. 

“Score ended in September 2022, so even if our new Score 2 proposal is successful, we will have a gap of at least one year in the funding, unless we find other interested parties,” one of the researchers said.“ In any case, after securing additional funding, we will have to bring our compounds to a pharma company which, if interested, will invest in further development and trials, since there is no university that can afford to do these things. However, we can still try to move some of our Score activities into Care, which lasts for five years and is coordinated by the pharma industry, which, hopefully, may have an interest in extending further the short funding period offered by the EU.”

Within Care, phase 1 and 2 clinical trials are co-funded by private companies. “I think in cases where we come out with a compound which looks great at the end of phase 2, the European Commission would top up the money to finance phase 3 studies,” one of the researchers said. “However, another complication may get in the way. According to the terms of IMI-backed projects, it is apparently not permitted to grant an exclusive licence, since any partner must be able to access the compounds themselves as well as the research. Given such conditions, no pharma company would be willing to invest large sums of money. This kind of bureaucracy, which is common in EU-funded projects, slows down development tremendously.”