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Let’s get back to a topic that has featured here many times in 2020 and 2021, but not so much recently: coronavirus vaccines. There’s a good amount of work going into another generation of these that could have broader activity against more coronaviruses (and coronavirus variants), but this is going to be taking us up to the edge of what we think is possible in the field. How might these work out?
This article in Nature Reviews Drug Discovery will give you a good overview of the field. One of the things it rightly emphasizes is that “pan-coronavirus” can mean different things in different press releases. To get a handle on that, I think it would be worthwhile to go over the coronavirus landscape itself – there are a lot of the little beasts, and there are various levels of coverage that one could imagine.
So, the coronavirus family that we know and love is technically a subfamily of orthocoronaviruses – there’s one other subfamily in there under the coronavirus-proper banner, but it only has one member, so I’m going to ignore it and just act as if there are only the “regular” coronaviruses. But even then there are plenty to deal with – for starters, there are four different genuses within that subfamily. The alphacoronaviruses infect all sorts of mammals, including us (cold-type symptoms), but they probably stem from ancestors in bat species. The betacoronaviruses include the nasty ones (MERS, SARS, and SARS-Cov2), along with plenty of others, including some that just cause human common-cold symptoms as well. These also percolate around in various bat species and mostly seem to stem from them as well, although they do show up in other small mammals. The gammacoronaviruses and deltacoronaviruses, meanwhile, derive from ancestors in pigs and bird species, although there’s one of them that shows up infecting beluga whales, of all things.
Just zooming in on the betacoronovirus genus, since that’s been grabbing all the headlines, we find several sublineages. Embecoviruses (lineage A), have some of those common-cold viruses already mentioned. Sarbecoviruses (lineage B) are the SARS and SARS-CoV-2 strains and variations thereof. Merbecoviruses (lineage C) include the one that caused the MERS outbreak in humans, and then there are the Nobecoviruses (Lineage D) and a single variety (so far) of Hibecovirus (Lineage E). Those last two are, I believe, found exclusively in in bats, who are certainly well stocked with these things. This means that when you talk about broader vaccine coverage, you could be referring to several different things. For the purposes of this blog post, I’ll classify them as follows:
Type I Vaccines: generate immunity to all four genuses of coronavirus
Type II Vaccines: generate immunity to the betacoronaviruses
Type III Vaccines: generate immunity to the sarbecovirus (lineage B) betacoronaviruses
Type IV Vaccines: generate immunity to current and future variants of just the particular sarbecovirus we’re dealing with, SARS-CoV-2.
Right now, I think everyone would be very happy with a Type IV, should one suddenly appear. It’s quite possible that one of those would have some broader effects, though – these aren’t thick-walled silos, since we are, in the end, talking about immunology here. There are actually several vaccines along this spectrum that are in the clinic, and I would roughly assign them this way:
Type I: None at the moment (that’s a tall order)
Type II: DIOSynvax, from a Cambridge startup working with CEPI.
Type III: Walter Reed’s SpFN ferritin-nanoparticle vaccine. GBP511 is coming along towards the clinic here, too.
Type IV: Gritstone Bio’s (GRTS) GRT-R910, ImmunityBio’s hAd5 S+N.
The NRDD article linked above will tell you about several more candidates that are a bit further back. All of these are (naturally) taking somewhat different approaches than the current vaccines. A popular one is to present a whole range of different Spike proteins (or their receptor-binding domains) at the same time, often by conjugating them to some sort of multifaceted nanoparticle or carrier. Another approach is to present not only S (Spike) proteins (or parts of them) but also some of the conserved regions of the N (Nucleocapsid) protein as well. Vaccines using only that N protein did not fare so well against original SARS, so we’ll have to see how the combination works out. There were signs of antibody-dependent enhancement with one of these, which we have not seen with the current Spike-directed vaccines – but it’s also worth remembering that a natural infection with SARS-CoV-2 generates a whole range of antibodies to both the S and the N proteins and several others, so it’s not like N-directed antibodies are automatic trouble, either. You have to go to the clinic and find out, and the same goes for other possible adverse reactions, for real-world range of protection and its duration, and so on. We have no truly reliable ways to predict these up front.
As for platforms, they’re all over the place. The DIOSynVax candidate is an mRNA vaccine, with new optimized antigens. The SpFN is a ferritin nanoparticle decorated with multiple copies of the Spike protein), and GBP511 is another variety of nanoparticle carrying 60 copies of Spike RBDs from several different coronaviruses at once. GRT-R910 is another mRNA, but this one is self-amplifying, an approach that BioNTech (BNTX) and Pfizer (PFE) considered but chose not to pursue for their own vaccine. And ImmunityBio’s is an adenovirus vector, using an altered form of Ad5 that should evade immune surveillance itself while carrying a mixture of genetic instructions for both Spike and Nucleocapsid proteins. The other vaccine candidates in development are similarly varied, and I’d say that’s a good thing, because we’re going to need as many different shots at this as we can manage.
There’s no reason why broader coronavirus vaccines should be impossible to develop. It’s been hard to do against influenza, but those viruses have a constant mix-and-match changeover mechanism in their surface proteins that coronaviruses don’t share, fortunately, so the cases aren’t directly comparable. At the same time, there’s no reason for it to be easy, or for our most plausible ideas to be the ones that work. We have to do the work and go out and try them. Onward!
Disclosure: None
Editor’s Note: The summary bullets for this article were chosen by Seeking Alpha editors.
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