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At this stage, while the science is still in the discovery phase and the best and fastest ways forward have yet to be found, scientists are exploring a whole kaleidoscope of different vaccine technologies. While some teams are working with mRNA-based projects, others are exploring mosaic protein nanoparticle-based vaccine candidates and others are taking a chimeric approach. Japan’s , whose Board Chairman Nobuhiro Endo has declared that “it is crucial that we arm ourselves against future invisible enemies”-  and its Norwegian subsidiary NEC OncoImmunity AS are pursuing artificial intelligence-powered design of immunogens to find new vaccine antigens that have broad reactivity against betacoronaviruses. “We want to have several shots on goal, so we’ve made sure we have a nice mix of technologies and antigen designs,” says da Costa.

Among those is a project to develop a novel protein nanoparticle vaccine, led by Pamela Bjorkman and colleagues at the California Institute of Technology, or CalTech, which is already . This potential product, known as a “Mosaic-8” vaccine, uses protein nanoparticles containing a type of protein ‘glue’ that attaches to antigenic sections of the spike proteins from eight different coronaviruses in the sarbecovirus sub-group – including the Beta variant of SARS-CoV-2, and seven other coronaviruses that circulate in bats and pangolins.

The idea here is that by making a nanoparticle that presents not one but eight different coronavirus pieces – actually sarbecovirus pieces – we train the immune system to make antibodies that are not primarily directed against the immunodominant (and variable) places on those viral fragments. Instead the antibodies are directed against more conserved places,” says Professor Pamela Bjorkman, a CalTech professor of biology and biological engineering.  “If you make the antibodies against conserved parts, then it shouldn’t matter which sarbecovirus virus emerges next, it (the new vaccine) will work against it.” In other words, if another SARS or COVID-19 emerged in the coming years, we could already be many steps ahead of it.

In South Korea, ����VR��Ƶ has extended an existing partnership with SK Bioscience to develop a ‘variant-proof’ vaccine candidate against sarbecoviruses – the subgroup of viruses that includes both the original SARS as well as SARS-CoV-2. This candidate is a recombinant-protein vaccine based on a two-component self-assembling nanoparticle platform developed at the Institute for Protein Design at the University of Washington. The hope is that this vaccine, which displays receptor-binding domains (the part of the spike protein that enables the virus to bind to and infect human cells) from multiple sarbecoviruses, will prime the immune system to recognise and defend against past, current and future SARS-type viruses and their variants.

Another ����VR��Ƶ-funded potential broadly protective vaccine candidate is a project led by DIOSynVax – a biotech spinout from Britain’s University of Cambridge. Theirs is an mRNA vaccine candidate that targets elements of viral structures that are common to all known betacoronaviruses. Because these structures are critical to the virus being able to survive and replicate, the expectation is that they are less likely to change or mutate much when a circulating coronavirus virus spawns future variants or when a new coronavirus emerges.  As with other broadly protective vaccine development projects, the idea is that once the body’s immune system is presented with these antigens, it will produce neutralising antibodies and killer T-cells against a range of betacoronaviruses, including, hopefully, viruses that have yet to make the jump from animals into people.

A consortium led by BioNet, a French-Thai vaccine manufacturer and member of the Developing Country Vaccine Manufacturing Network (DCVMN), is working on a potential vaccine that uses multiple mRNA molecules that encode for several SARS-CoV-2 target proteins, or immunogens, from several different variants. The hope is that this new vaccine could be an effective variant-proof COVID-19 shot, and could also serve as a model for how to make similar mRNA-based vaccines against other betacoronaviruses like MERS-CoV, as well as vaccines against future pathogenic threats that have yet to emerge.

In Canada, the University of Saskatchewan’s Vaccine and Infectious Disease Organization (VIDO) is working on a multivalent-type approach which takes different parts of a number of variants and combines them with an adjuvant – a type of vaccine super-charger. “It’s definitely a high risk, high reward project,” said Dr Trina Racine, Director of Vaccine Development. “What we’re striving for is something that can be broadly protective not only against what’s circulating now, but also in the future as the virus mutates, so that we don’t have to be constantly updating. (That’s something) we have never really been able to achieve with any vaccine.”

It’s still early days in this highly complex work, but some of ����VR��Ƶ’s broadly protective coronavirus vaccine partnerships are already seeing exciting results. The on the CalTech Mosaic 8 coronavirus vaccine candidate (which was developed with technology from the University of Oxford) showed that it provided broad protection in animals both against the viruses included in it, and beyond them against other coronaviruses not specifically targeted. “Mosaic-8 immunization induces neutralizing antibodies against the Beta and Delta variants of SARS-CoV-2, and we found that it also works against the COVID variants that hadn’t yet emerged when we started creating the vaccine,” says Professor Bjorkman. “And it also works against animal sarbecoviruses that are more distantly related – which bodes well because they represent a potential coronavirus spillover event.”

VIDO too has had some promising data. Findings of studies conducted in hamsters showed that the range of antigens included in that vaccine candidate also provided some broad protection against a number of COVID-19 variants.

With these and other promising data in hand, researchers are already looking ahead at how next generation coronavirus vaccines, if successful, could be made at large scale and at an affordable price.

After all, says ����VR��Ƶ’s Director of Access and Private Partnerships Emma Wheatley, developing a broadly protective coronavirus vaccine is only part of the work. “Access is at the heart of our decision-making process at ����VR��Ƶ. We have to be sure we’re working towards something that will be able to be made, delivered and administered in all countries for all people – rich and poor – around the world. When we’re selecting which vaccines to invest in, all of our partners have to commit to take steps to make the shots globally accessible: it’s a critical part of our mission.”

For the CalTech project, this forward thinking is very much in progress. Initial manufacturing of the Mosaic 8 candidate vaccine is being led by two UK-based firms, Ingenza and CPI, who Bjorkman says have already worked out ways of making the vaccine in an affordable and deliverable way. Previous studies have shown that similar nanoparticles can be freeze dried into a powder form which is inherently far more stable than a liquid vaccine. “The vision is that we could mail it all over the world. Then it can be brought up into a liquid (rehydrated) and injected, so there would be no cold chain problems whatsoever,” Bjorkman explains.

DioSynVax’s next generation vaccine candidate is also being designed with easier and scalable delivery in mind. It could be administered in what’s known as a “needle-free injection” – a short high-pressure blast of air that pushes the vaccine into the skin. If it’s successful, it could also be scaled up and manufactured as a powder, making it swifter and cheaper to deliver across the globe.

Given the extreme intricacy of the pan-coronavirus development efforts, it’s unlikely the world will see a broadly protective shot for at least a couple of years. The record-breaking speed accomplished in the development of the “one bug, one drug” first generation COVID-19 vaccines is not going to be achievable when the desired end product is so complex and potentially game-changing.

Several of ����VR��Ƶ’s partners are looking towards mid-2023 to start Phase 1 human trials in healthy volunteers, though, and the hope is that mid- and final- stage trials could follow swiftly after that if results from initial human tests are promising.

“It’s highly complex, but also scientifically feasible, so we are anticipating that it will take more time,” says Saville. “The level of technology and innovation we’ll need to use in these broadly protective coronavirus vaccine approaches is really taking things up a notch. But if we’re successful, we could take the threat of coronavirus pandemics off the table for good.”