If you look at the big picture, humanity seems to be losing its struggle with the betacoronaviruses (the subset of coronaviruses that infect humans). Over the last 20 years there have been three incursions of these viruses into the human population – SARS-CoV, MERS-CoV, and SARS-CoV-2. The latest spillover event resulted in a massive pandemic that dramatically affected the whole world. SARS-CoV-2, the virus that causes COVID-19, is still ongoing, evolving new variants to evade our immunity from prior infections and vaccines. As we will see below, however, we may have a new weapon in this war.
The latest variants, BA.4 and BA.5, are subvariants of Omicron, and appear to be spreading. It is now in fashion to observe that while we may be done with this pandemic, it’s not done with us. The vaccines have provided an effective weapon against COVID, but existing vaccines produce immunity that wanes after six months and are less effective against the newer variants. Many people have already received their second booster, and it will not be long before we need a third.
In addition to maintaining vigilance against spreading the virus, one approach to keep the pandemic at least manageable is to update the vaccines, targeting them against the newer variants. I think most people have already accepted the fact that SARS-CoV-2 is here to stay, like the flu, and we will all have to get our annual COVID vaccines. Hopefully they will be annual; so far it appears we need to get boosted every six months. We’re all just hoping there is a cumulative immunity, and tracking the newer variants will produce longer-lasting immunity.
There is another theoretical approach, however – developing a universal betacoronavirus vaccine. If we can do this, such a vaccine would not only protect against current and future variants of COVID, it would protect against the next potential spillover event (SARS-CoV-3, or perhaps MERS-CoV-2). But universal vaccines have proven technologically tricky to develop. We have been researching for years, for example, a universal flu vaccine, but have yet to approve one. The problem is that viruses are clever. They hide their conserved bits, the important structures that all variants have in common, and cover them with highly variable proteins that constantly mutate and create new variants. But they can not do this perfectly because often those conserved proteins are functional – they need, for example, to bind to receptors on human cells in order to invade and do their thing.
The coronavirus family derives its name from the crown of spike proteins that are the business end of the virus. These spike proteins are what allow the coronaviruses to invade cells, and existing vaccines target one or more spike proteins. But these spike proteins can also mutate, causing new variants that not only evade existing immunity (whether from prior infection or vaccines) but can alter how infectious and deadly the viruses are.
A newly published study presents a potential new technology that might result in a universal betacoronavirus vaccine – not just effective against all variants of SARS-CoV-2, but perhaps against all related viruses. Pamela Bjorkman from Caltech and her team created a nanoparticle they refer to as a cage protein. The cage is a platform on which other proteins can be attached, including spike proteins from coronaviruses. They created two versions of the nanoparticle. The first contains receptor binding domains (RBDs) from the spike proteins of SARS-CoV-2. This is the homotypic particle, because all the proteins are from the same virus.
They also made what they are calling mosaic-8, which contains 60 RBD particles from 8 different betacoronaviruses. They then injected mice with either a naked cage protein as a control, a vaccine made from the homotypic nanoparticle, or another from the mosaic-8. The mosaic-8 specifically did not contain any RBDs from SARS-CoV. After first determining that the vaccines produced antibodies, they then challenged the mice with infection from SARS-CoV and SARS-CoV-2. The mice injected with the naked cage protein all died. Those injected with the homotypic vaccine were protected against SARS-CoV-2 but not against SARS-CoV, and those injected with the mosaic-8 vaccine were protected against both viruses.
It is important to emphasize that the mosaic-8 vaccine protected against SARS-CoV even though it did not contain any RBDs specific to that species of virus. Armed with that preliminary data, they then tested the vaccines in non-human primates, with the same results. They are now planning for a phase-I study in humans.
What the researchers hope this means is that the mosaic-8 approach, by targeting enough RBDs from a variety of betacoronaviruses, will target enough important sections of the spike proteins that they will have affinity for any betacoronavirus that can infect humans, regardless of species or variant. Again, viruses can mutate and change their proteins, but they cannot change them too much or they will lose the ability to infect human cells and propagate. It’s likely that different strains may shuffle around different variants of the spike proteins, but there are some key RBDs that any infectious strain must have. By targeting enough of the RBDs the viruses simply have no where to hide.
Translation to humans from animal studies does not always work, so we have to wait until we see the results of human trials to know how well this approach will work. It seems theoretically sound, and the early data is encouraging. Perhaps we will need to develop future versions that target more than 8 RBDs. We may need a mosaic-10 or mosaic-12. Or perhaps eight is enough (sorry, couldn’t resist).
This platform may have applications beyond coronaviruses. If this all works well it may spawn a new vaccine technology, just like the mRNA vaccines did, that give us a powerful tool against current and future pandemics. Vaccines that target multiple proteins, creating antibodies with cross reactivity, produce a much more effective immune response, and may get us to the ultimate goal of universal coverage. This approach might get us to that universal flu vaccine we have been seeking, or at least a giant step closer. HIV is another virus that likes to hide by spawning variants.
It is also clear that we are now living in a world where epidemics and pandemics, especially from zoonotic viruses that spill over from animal reservoirs, are becoming increasingly common. The COVID-19 pandemic is not an anomaly or a once-in-a-century event. It is a wake up call. Fortunately we have the infrastructure of scientific research to combat these pandemics. We may, however, lack the political and social infrastructure to adequately deal with them, despite having the technology.