Future-proofing against COVID-19

Could a new generation of combination vaccines help us stay protected for longer?
07 September 2021

Interview with 

Pablo Penaloza-Macmaster, Northwestern University


Covid vaccine vials


The vaccines we have against COVID-19 continue to work spectacularly well to protect people against severe diseases. But, as we’ve been hearing, they are less good at preventing infection and their effectiveness does drop with time. So can we improve on them to combat some of these weaknesses? That’s the goal that Pablo Penaloza-Macmaster from Northwestern University in Illinois has set for himself with what he dubs “Covid vaccine 2.0”, the next generation of Covid vaccinations, as he explained to Chris Smith...

Pablo - Most SARS-CoV-2 vaccines are based only on the spike antigen, which is the surface protein of SARS-CoV-2. And these vaccines are tremendously effective. But as you were saying, there's evidence of breakthrough infections. So we wanted to go one step further and we asked a very simple question. What if we teach the immune system, not only how the outside of the virus looks, but also how the inside of the virus looks? And for this, we gave mice this vaccine that not only expresses the outside protein of the virus, but also the inside or the guts of the virus. And what we saw is that these mice were better protected against breakthrough infections.

Pablo - And there's two reasons why we chose the nucleocapsid or the inside protein. Number one, because it is highly expressed in the coronavirus life cycle. So it's a perfect target for early detection by the immune system. But number two also because it is very stable, through many different variants and even other strains of coronaviruses, it doesn't mutate as much as the spike protein. That's the first part.

Pablo - The second part, the other piece of data, is that we have shown that SARS-CoV-1 vaccines made in 2003-2004 for the original SARS-CoV-1 also seemed to protect against SARS-CoV-2. And we have also shown in mice that some common cold coronavirus infections seem to protect mice against other coronaviruses. So what this suggests is that the vaccine does not have to be a hundred percent matched with the virus. You could have vaccines that are only 75% match, and that will still confer protection. And the follow up rationale is that it is possible to maybe make an arsenal or stockpile of vaccines based on the available known sequence of coronaviruses. And then in the future, in the case of a pandemic, we could deploy the ones that are more antigenically matched to the pandemic.

Chris - So in essence, using other parts of the virus to educate the immune system rather than just the outer coat, these spike proteins, might give the immune system more to get hold of when it's dealing with the virus. Why didn't we do that in the first place then? Why did the first generation of vaccines we're all using focus exclusively on that spike protein?

Pablo - The reason why is because data from the original SARS-1 and also MERS have pinpointed to the spike or the surface protein of the virus as being the Achilles heel. So we didn't want to take any risks. We went to the best target. And we're not saying that spike-based vaccines are worse than the nucleocapsid based vaccines. We're saying that if you combine them, it's a lot better, but if you compare them side-by-side - spike-only versus nucleocapsid-only - then the spike-only does a lot better. So people were just trying to make a vaccine very fast with the educated guess, which is based on the other coronaviruses. So that's why people focused on the spike protein.

Chris - And now you've taken it a step further. How much better is it in head-to-head trials when you do this? Admittedly, this is in mice. This is not in humans with COVID-19, but you know, we can learn a certain amount this way, can't we. How much better is it when you have the extra bit of the guts of the coronavirus, as you put it, in there alongside the spike, compared with just using a vaccine that uses the spike?

Pablo - If you compare in distal sites, for example, if you compare in the brain, it seems to be more than 10-fold better at protecting the mice from the breakthrough infection. And now we're actually trying to make it better by incorporating other vaccines. So basically, we're just trying to increase the coverage of the vaccine.

Chris - In essence then, what you might have your hand on is the ability to deal with the problem we've highlighted quite a few times in this programme, which is that at the moment we have a tool which is really good at stopping people ending up in hospital. But what it's not doing is stopping the virus circulating through society, which at the end of the day is what we really want to achieve. And with the better immunity conferred by these enhanced vaccines that you're potentially developing, we might have a way of doing that.

Pablo - Precisely. We think so.

Chris - I'm intrigued by your idea that it might also be possible to come up with a sort of pan-coronavirus vaccine, something that can counter all coronaviruses and all variants, both the knowns and the unknowns as yet. What evidence have you got that that might be achievable?

Pablo - We vaccinated mice with a SARS-CoV-1 vaccine from 2003. That is the original SARS-1. And we observed that these mice were protected against a SARS-2 challenge. That's one of the experiments. The other one is that we have infected mice with common cold coronaviruses, and then they're protected against related but different coronaviruses. So what this means is that the vaccine does not have to be 100% matched. You could have some genetic similarity, but it doesn't have to be a 100% match. So what that means is that you could potentially make a stockpile of vaccines based on the known sequences of coronaviruses, because we know a lot of different sequences. We have sequenced so many different coronaviruses. So, as long as in a future pandemic, if we pick up the right one, the right arsenal, and we take them out of the freezer - they're already made - and we take the one that is closest, genetically speaking, to the future pandemic, then we may be able to have a quick immediate response to a future pandemic.

Chris - Would you see this being realisable for this pandemic or is it too far away right now? And can we do this this time or is this going to take a lot more development?

Pablo - I honestly don't know. I think the most important thing right now is for the whole world to get vaccinated with the vaccines that we currently have available because although they don't prevent infection, they do prevent severe disease and death. So to me, that's the most important thing. So I would focus mostly on getting the whole world vaccinated.


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