Some experts believe that the pandemic appears to be on an evolutionary slide toward becoming endemic, a “new normal” in which humans and the virus co-exist, as we currently do with influenza. But coronaviruses are clever. While an endemic resolution may be in sight, SARS-CoV-2 could still shock the human species with a devastating evolutionary leap.
Here are four possible scenarios, each taken directly from the known evolutionary playbook of coronaviruses.
What I find most impressive about this virus is that it appears mutation, selection, and recombination continues to be able to find new effective immune-escape variants by altering the very same protein the virus also uses gain entry into cells by interacting with the hACE2 receptor.
Apparently it just keeps being the case that there are available mutants that change the spike protein so antibodies bind it less effectively, yet without compromising the receptor binding domain. Even after the emergence of the apparently milder omicron new variants quickly popped up, and BA2 relatively quickly outcompeted BA1. And yet it also doesn’t seem to be causing more severe disease. Which also shows there must be numerous other pathways by which the virus can further adapt to it’s human host population, that don’t necessarily relate to receptor binding ability.
And it is striking how quickly strains with small advantages in transmission and escape completely supplant prior strains in circulation. When competing in the same space, the fitter variant has actively displaced the former with remarkable dispatch. This is in direct contrast to Sanford and Carter’s thesis that virus’s go extinct as they accumulate mutations.
Yes, and that those changes were so extensive that at least one of the first omicron papers tested the hypothesis that it was now using a different receptor altogether (it doesn’t).
Viral evolution is expected to go in the direction of less severe disease, because killing the host tends to reduce transmission. Delta was an anomaly.
And it contradicts the assumption that we can somehow automatically assume virulence is equivalent to fitness. The fact that the disease caused by the virus has become milder, while the virus is simultaneously also more transmissible provides a perfectly good counterexample to show that even while there might be some correlation between the two, the relationship can wax and wane over time.
And it also shows the importance of environmental context in understanding how the fitness-effects of mutations can depend on host factors etc. etc.
I think Delta was a surprise, not an anomaly.
Not sure that will be the case with this virus, as it is most infectious in the pre-symptomatic stage, and generally kills by cytokine storm after the active virus has been dealt with by the immune system. IOW, it’s not the virus per se that’s fatal.
I’m well aware of that, thanks. All other things being equal, killing the host reduces fitness, regardless of whether the virus or its sequelae are responsible.
Ah, OK, I wasn’t aware of that. Can you explain how that works?
I’d be very interested in your hypothesis that it wouldn’t.
People who die from the inflammatory feed-forward cascade (which appears to me to be a catastrophic failure of the immune system to deal with the virus) would tend to transmit it less, both behaviorally and virologically.
It’s not my hypothesis, it’s something I read from a virologist.
The explanation was that the evidence suggests that SARS-CoV-2 is most infectious very early, i.e.in the pre-symptomatic phase and up to peak symptoms, then it drops off rapidly as the virus is destroyed. The immune cytokine storm that can incapacitate or kill generally follows in the post-viral stage, when the virus is no longer active, or significantly less active.
Since the host no longer infectious when the cytokine storm starts, there is no significant selective disadvantage for the virus in killing the host (other than incentivising the community to take serious precautions and having one less host to reinfect).
Many if not most who died in the 1918 H1N1 epidemic succumbed to bacterial pneumonia. The virulence of respiratory viral diseases seems to often involve secondary effects. Pre-symptomatic transmission, of course, makes for an insidious strategy for a virus if it can pull it off. My family just experienced such a case first hand.
Less, yes; gone, no. They’re not temporally separate. Nothing about this is as neat and tidy as what you are suggesting or what you have been told.
See Fig. 2, panels b and c here, showing that there’s plenty of virus around–more in more severe cases. Note that panel c is an assay for a viral RNA present only during active replication.
Less, yes; gone, not at all. See the paper linked above and Fig. 2 of this meta-analysis:
No, because “less infectious” is not the same as “no longer infectious.”
I’m a virologist too.
That’s a pretty big selective disadvantage–at least with the subpopulation of prospective hosts for whom the expression “avoid it like the plague” has some meaning.
OK, thanks for the clarification. It still seems to me that the bulk of transmission will have occurred prior to host death, which reduces the selective disadvantage of killing the host compared with a virus that kills by overwhelming the host; although as you suggest, the wider behavioural effects of lethality are likely to be significant.
By coincidence, last night I heard another virologist on TV saying that the high transmissibility of this virus early in infection, particularly pre-symptomatic, means we shouldn’t expect it to gradually become milder ¯_(ツ)_/¯
In the immediate, perhaps not. But all large scale epidemic viruses face the red queen problem, that it takes all the running they can do just to stay in the same place. The virus must alter itself to avoid recognition as the host population acquires immunity. But there are only so many ways to avoid detection while still retaining the capability to target and infect, so the virus eventually has to compromise. Even with early transmissibility, this general trend should play out with sars-cov-2. Eventually. Hopefully.
Personally, I don’t see a strong enough selective pressure to reduce the severity of infection. On the flip side, I don’t see a strong selective pressure pushing towards higher severity. The one overriding pressure is to evade innate immunity, and secondarily to evade adaptive immunity. I am hoping that mutations which reduce severity will link themselves to mutations that aid in immune evasion. There are currently other coronaviruses that have been circulating within the human population for decades now, and they aren’t associated with severe disease, so it’s not as if virulence is necessary for transmission.
The one prospect that does worry me is non-human reservoirs.
It seems that way because you are viewing transmission simplistically and linearly, when it’s nothing of the sort. It’s four or five exponential equations overlaid on a threshold for infection.
Put more simply, requiring care from others increases the likelihood of transmission, probably exponentially.
Ron’s larger-scale point is valid too. And people tend to be put on TV for being contrarians.
Thanks all for responding - it’s good to have a range of well-informed views
I have been working with SARS-CoV-2 sequences. Part of the process is running the data through Nextclade which gives you a clade designation and also maps mutations for you. I thought readers here might like a graphical representation of the the latest variants of concern.
Each vertical stripe is a mutation (compared to the initial 2019 Wuhan sequence). There are two sequences mapped, Delta on the top and Omicron on the bottom. The boxes along the bottom right are genes. In order from left to right: ORF1a, ORF1b, S, ORF3a, E, M, ORF6, ORF7a, ORF8, ORF9b, N. What I find so striking is the much higher concentration of mutations in the S gene for the Omicron variant. It’s a nice little visual that can quickly tell you where selection is probably occurring. It also shows how different Omicron and Delta are, and why Omicron kind of came out of left field.
For curious amateurs, Nextclade is actually kind of a fun tool to mess around with. You can find plenty of SARS-CoV-2 fasta files at GISAID or Genbank. If you want to compare multiple sequences at once, just merge single fasta files into a single file.
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