I expect it to return as an endemic seasonal virus, especially in areas of low vaccination uptake, with continued antigenic drift allowing occasional mild infection of those with immune memory after enough time has passed. It’s the first infection of a naive set of lungs that matters though.
I’m thinking of the vaccines as a time machine. Imagine if you will that a time traveler could go back in 15 years and release the virus into the population, with no interventions or treatments. Lots more people would get sick and die, and we’d get enough herd immunity to turn it into a mild seasonal illness, mostly for children.
The vaccines get us to that point without the use of a TARDIS.
FWIW I expect the equilibrium severity in the absence of continued immunization and presence of continued drift whenever it manages to slip through preexisting memory to be rather worse than the other human coronaviruses, at least for a while. This bugger has a clutch of fancy accessory proteins that help hide from and screw up immune reactions, and for other reasons is very good at forming syncytia and infects such a wide range of cell types. But NOTHING like what happens when people get it never having seen anything like it. Think closer to flu on the cold and flu spectrum. But we deal with that, and the antigenic drift after this explosive adaptation-to-humanity phase should be slower than we are dealing with now. All the evolution we have seen lately is about becoming better able to infect human cells, with mild immune evasion from previous memory a side effect. It is even possible that once the primary selective pressure is for immune evasion, the infectivity declines again due to the different set of trade-offs encountered—the best analysis I have seen of the D614G mutations that took over the world in the first half of 2020 suggests that it increased the avidity of the protein to human cells at the expense of making the S1 domain more open to neutralization and immune deactivation by immune memory, but this did not matter because all the infections were directed towards those with no memory.
Decent possibility that over the coming decades the fancy accessory proteins (which are very necessary for infection in bats, less so for humans) start falling to bits due to Muller’s Ratchet, as mutations that degrade them hitchhike along for the ride with spike and nucleocapsid mutations that actually allow infection of those with immune memory. This already sort of happened once in the Alpha lineage, where accessory protein ORF8 that hides T-cell epitopes from the immune system broke but got dragged along for the ride linked with a spike that was better at attacking human cells.
I expect it to return as an endemic seasonal virus, especially in areas of low vaccination uptake, with continued antigenic drift allowing occasional mild infection of those with immune memory after enough time has passed. It’s the first infection of a naive set of lungs that matters though.
I’m thinking of the vaccines as a time machine. Imagine if you will that a time traveler could go back in 15 years and release the virus into the population, with no interventions or treatments. Lots more people would get sick and die, and we’d get enough herd immunity to turn it into a mild seasonal illness, mostly for children.
The vaccines get us to that point without the use of a TARDIS.
FWIW I expect the equilibrium severity in the absence of continued immunization and presence of continued drift whenever it manages to slip through preexisting memory to be rather worse than the other human coronaviruses, at least for a while. This bugger has a clutch of fancy accessory proteins that help hide from and screw up immune reactions, and for other reasons is very good at forming syncytia and infects such a wide range of cell types. But NOTHING like what happens when people get it never having seen anything like it. Think closer to flu on the cold and flu spectrum. But we deal with that, and the antigenic drift after this explosive adaptation-to-humanity phase should be slower than we are dealing with now. All the evolution we have seen lately is about becoming better able to infect human cells, with mild immune evasion from previous memory a side effect. It is even possible that once the primary selective pressure is for immune evasion, the infectivity declines again due to the different set of trade-offs encountered—the best analysis I have seen of the D614G mutations that took over the world in the first half of 2020 suggests that it increased the avidity of the protein to human cells at the expense of making the S1 domain more open to neutralization and immune deactivation by immune memory, but this did not matter because all the infections were directed towards those with no memory.
Decent possibility that over the coming decades the fancy accessory proteins (which are very necessary for infection in bats, less so for humans) start falling to bits due to Muller’s Ratchet, as mutations that degrade them hitchhike along for the ride with spike and nucleocapsid mutations that actually allow infection of those with immune memory. This already sort of happened once in the Alpha lineage, where accessory protein ORF8 that hides T-cell epitopes from the immune system broke but got dragged along for the ride linked with a spike that was better at attacking human cells.