[mlyle]

> Selective responses against the vaccine are only selected for if those pressures persist during replication. It's not enough to have that pressure at the very beginning, it needs to persist all the way. This isn't really the case for a vaccine.

I disagree. You have the weak vaccine response the entire duration of infection applying selective pressure. What you say seems to disagree with the consensus of the literature, e.g.

https://www.medrxiv.org/content/10.1101/2020.11.17.20233726v...

> The UK variant isn't better at evading the immune system from what we know. It's simply more infectious in general.

The mutations have been broadly described as "immune escape mutations" and are thought to have emerged from pressure to escape low numbers of existing sterilizing antibodies within the host, e.g.

"The unusually high number of spike protein mutations, other genomic properties of the variant, and the high sequencing coverage in the UK suggest that the variant has not emerged through gradual accumulation of mutations in the UK. It is also unlikely that the variant could have arisen through selection pressure from ongoing vaccination programmes as the observed increase does not match the timing of such activities. One possible explanation for the emergence of the variant is prolonged SARS-CoV-2 infection in a single patient, potentially with reduced immunocompetence, similar to what has previously been described [17,18]. Such prolonged infection can lead to accumulation of immune escape mutations at an elevated rate"

https://www.ecdc.europa.eu/sites/default/files/documents/SAR...

[sudosysgen]

The article you linked first assumes only one or two antibodies.

As I said before, there is some pressure for antibodies, but the immune system is way more than that, and people can clear infections very effectively without any antibodies at all.

As for your other link, it's important to know that this a preliminary article that, on those subjects, gives ideas without data. Further research has shown that this variant does not seem to increase disease severity, and instead is just more infectious, as the spike protein evolved for higher binding affinity.

[mlyle]

> The article you linked first assumes only one or two antibodies.

Assumes only a couple of neutralizing antibodies, which is fair for the vaccine candidates-- immune assays of Moderna's vaccine show two typical antibody binding sites against the RBD that are strongly neutralizing. I haven't seen the ELISA data for Pfizer's vaccine.

Given that we've got several papers describing how immune escape variants of other viruses have emerged in the past... I'm curious why you don't think it's much of a risk here?

e.g. https://pubmed.ncbi.nlm.nih.gov/11410701/

> As I said before, there is some pressure for antibodies, but the immune system is way more than that, and people can clear infections very effectively without any antibodies at all.

Of course. I'm not speculating that there's going to be some nasty variant that completely eludes our immune response. I'm saying that it is likely-- and the consensus opinion-- that there is a real risk that the virus mutates to render the vaccine less effective.

> Further research has shown that this variant does not seem to increase disease severity, and instead is just more infectious, as the spike protein evolved for higher binding affinity.

Some of the mutations slightly increase binding affinity. Other deletions look like their primary fitness advantage is immune escape. A missing stop-codon also increases mutation rates for a portion of the RBD, which implies we can expect quicker emergence of subvariants.

It's like you're having an argument I never was having: I have never said that this is likely to cause more severe disease. I am just saying that the virus will be under selective pressure to evade the vaccine-induced immune responses-- which is something I think everyone agrees. This is less likely to happen if there's less infection around and people get vaccinated quicker.

Even in the worst case, where such a variant evolves quickly-- I don't think we're that bad off. As you mention, there's other immune responses. Strong T cell mediated immunity will almost certainly be cross-reactive and strongly reduce the risk of severe illness. We'll have more time to adjust vaccines without mortality accruing as quickly. It is still something we'd prefer to avoid at all costs.

[sudosysgen]

The point of the argument here, from my point of view, is this. In the one to three months between full vaccination of vulnerable individuals and drastically reduced R due to general vaccination, is a variant of the virus going to appear that will be able to effectively infect vaccinated people and spread enough for the pandemic to continue?

The answer to this is very probably no. There is a huge difference between the virus making the vaccine less effective eventually, the virus making the vaccine less effective within one to three months, and the virus making the vaccine sufficiently less effective that it can sustain an epidemic among vaccinated individuals. The second is not very likely at all, because for it to happen a variant of the virus would have to mutate, and outcompete the dominant variant, that has a spike protein sufficiently different that it can keep R>1 among vaccinated individuals.

For this, the virus would not only have to evade antibody response sufficiently for there to not be sterilizing immunity, but it would have to do evade the much swifter and effective non-serological immune response enough to stay infectious.

All of this would have to happen in a subset of the population that has a 20x lower chance of being infected and even when that happens, the infection would be much shorter with most of it with completely different evolutionary pressures.

In one to three months.

It would also have to compete effectively against other variants in the non-vaccinated population while it is doing so, because non-vaccinated people are by very far the dominant infection vector. So it would have to evolve this not only in vaccinated, but also non-vaccinated patients, unless you believe that these extensive mutations will happen in one, vaccinated, patient, which is pretty much impossible.

[mlyle]

> The point of the argument here, from my point of view, is this. In the one to three months between full vaccination of vulnerable individuals and drastically reduced R due to general vaccination,

Not a given. It's very likely, but we don't know how effective the vaccines will be in preventing transmission. Certainly there is past precedent for the opposite.

Also, there's likely to be pockets of population with poor vaccine penetration, so even if it confers sterilizing protection, we're likely to see endemic spread in these subpopulations continually challenging the vaccinated population.

> is a variant of the virus going to appear that will be able to effectively infect vaccinated people and spread enough for the pandemic to continue?

We see a hepatitis B vaccine escape variant every year or two, despite a much lower community disease burden. I don't think anyone can know how likely this is.

> All of this would have to happen in a subset of the population that has a 20x lower chance of being infected and even when that happens,

It's not very likely that the population has a 20x lower chance of being infected; the vaccine almost certainly does more to prevent symptomatic illness than any infection. They've shown a 20x lower chance of symptomatic illness. You're also leaving out the critical window before the first dose where protection (against symptomatic illness) slowly climbs over weeks to 70-80%.

> It would also have to compete effectively against other variants in the non-vaccinated population while it is doing so

Already the currently circulating variants are not equally neutralized by the vaccine. There's going to be immediate pressure making the variants that are least impeded more prevalent.

> unless you believe that these extensive mutations will happen in one, vaccinated, patient, which is pretty much impossible.

Again, the most likely scenario for the emergence for the UK variant is prolonged infection in one person with a low immune response. People like this are well represented in the groups we're immunizing first, too.

These things aren't mutually exclusive, though: you start off by favoring the current variants that the vaccine is least effective against. Then, you have ongoing evolution in vaccinated individuals with lower responses. Then the favored variants become endemic, circulating mostly in subpopulations with lower vaccine coverage and occasionally finding vaccinated people who are more susceptible.

How quickly it all happens depends upon total disease burden. I agree we will probably not get a worst-case escape variant in the first few months of the vaccination campaign, but I think we'll probably see some adaptation towards escape and lowered efficacy. Indeed, you don't even need mutation for that: just preferential selection for existing variants with lower vaccine efficacy.

No one's done the assays on the UK variant yet, but I will not be surprised if the current vaccines are somewhat less effective against it.

If the disease remains endemic with relatively high levels of circulation, variants that escape the current vaccines will be all but certain in the long term.

[sudosysgen]

>We see a hepatitis B vaccine escape variant every year or two, despite a much lower community disease burden. I don't think anyone can know how likely this is.

Hepatitis B is a disease that lasts much, much longer than COVID-19, which exponentially increases the likelihood of such an event. Moreso, Hepatitis B immunity from vaccines is often very weak due to a lot of people not getting booster shots in adulthood.

>It's not very likely that the population has a 20x lower chance of being infected; the vaccine almost certainly does more to prevent symptomatic illness than any infection. They've shown a 20x lower chance of symptomatic illness. You're also leaving out the critical window before the first dose where protection (against symptomatic illness) slowly climbs over weeks to 70-80%.

Vaccines have been trialled using not symptomatic illness, but actually PCR tests for immunity, and found over 90% immunity with symptoms||viralRNA as a standard. So no, it's actually around 10-20x less likely to have infection, too. For things like severe ilness, it's more like 99-100%.

>It's not very likely that the population has a 20x lower chance of being infected; the vaccine almost certainly does more to prevent symptomatic illness than any infection. They've shown a 20x lower chance of symptomatic illness. You're also leaving out the critical window before the first dose where protection (against symptomatic illness) slowly climbs over weeks to 70-80%.

During this window if the individual is vaccinated before antibodies show up there is very little pressure to evolve resistance against them.

>Again, the most likely scenario for the emergence for the UK variant is prolonged infection in one person with a low immune response. People like this are well represented in the groups we're immunizing first, too.

Given the fact that we have seen zero severe illness in even very old people with many vaccines, this is even less likely than for a non-vaccinated but immunocompromised person, for which this scale of mutation didn't even happen yet, 1 year in. And by the way, the hypothesis - which is as of yet unconfirmed and whose certainty became lower after similar mutations were found in South Africa - is that this process happened in an unvaccinated immunocompromised individual during a month+ infection period. If the same individual was vaccinated, this would have been impossible, and we haven't seen this kind of illness in any vaccinated individuals.

>These things aren't mutually exclusive, though: you start off by favoring the current variants that the vaccine is least effective against. Then, you have ongoing evolution in vaccinated individuals with lower responses. Then the favored variants become endemic, circulating mostly in subpopulations with lower vaccine coverage and occasionally finding vaccinated people who are more susceptible.

Even for those, the vaccine is still incredibly efficacious. The differences IIRC are barely statistically significant. If you have a source for more significant variations I'd love to see it.

Crucially though, in the scenario you are suggesting where the virus is spreading in non-vaccinated populations, that the actual strain to acquire enough changes to become effective against vaccinated individuals absolutely needs to outcompete other strains, which isn't likely. This is because even if the virus were to infect one of the few vaccinated but less protected individuals, which would in this case probably be under 1% of infections, those mutations need not be a hindrance in the 99% of infections which won't be of less protected individuals that have more than benign infections in populations with low vaccination rates.

It's possible that this happens, eventually - think years. Not in the 1-3 months period we're talking about. The result is that it doesn't make sense to vaccinate 20-40 year olds in priority or to sell the vaccine on the free market, at all.

[mlyle]

> Vaccines have been trialled using not symptomatic illness, but actually PCR tests for immunity, and found over 90% immunity with symptoms||viralRNA as a standard. So no, it's actually around 10-20x less likely to have infection, too. For things like severe ilness, it's more like 99-100%.

The only vaccine I'm aware of that had weekly PCR surveillance was the Oxford/AstraZeneca vaccine, which showed an efficacy of 57% against a positive swab (95% CI -- 41% to 66%; 95% CI efficacy against asymptomatic illness -17.2% to 54.9%). If you know another one that showed 90%+, please cite! Both the Moderna and Pfizer trials relied upon symptomatic illness (symptoms + PCR confirmation) as an outcome measure.

> During this window if the individual is vaccinated before antibodies show up there is very little pressure to evolve resistance against them.

No, but you can get a infection that shows up as antibody response is ramping. Neither infection and vaccine response are nice clean instantaneous, atomic events.

> Given the fact that we have seen zero severe illness in even very old people with many vaccines

You have to consider the statistical power of the study. In the very old people (75+), you're talking about 0 vs. 5 cases (symptomatic) in the Moderna study, for instance, with unknown impact on any symptomatic infections. You seem to be concluding an awful lot based on 0 vs 5 symptomatic cases in a short study period for what the outcome will be across a population of 18 million people in the US.

> If the same individual was vaccinated, this would have been impossible

Why? We've seen it happen in the wild with COVID (long illness times and failed immune clearance), and we've seen it with existing vaccines in other illnesses. "Impossible" is a very stronk word.

> Even for those, the vaccine is still incredibly efficacious. The differences IIRC are barely statistically significant. If you have a source for more significant variations I'd love to see it.

We don't know the efficacy for subvariants. We have nowhere near enough n. We do know that even during the phase 2 trial, there are serum neutralization titers for variants that the error bars do not overlap for, and the MLEs are an order of magnitude apart.

> It's possible that this happens, eventually - think years. Not in the 1-3 months period we're talking about.

First, it's more like a 6 month period, and longer when we consider the entire world.

> The result is that it doesn't make sense to vaccinate 20-40 year olds in priority or to sell the vaccine on the free market, at all.

Which, I understand, are things the original article advocated for, but I never did-- indeed I mocked it in other comments e.g. here https://news.ycombinator.com/item?id=25609607 https://news.ycombinator.com/item?id=25609600 and in a comment on the original article. So really, come on. Argue with what I'm saying, not the make-believe argument you'd like to have.

The epidemiological and immunological communities consider it a risk, and I've shared papers. Here's what widely-followed Derek Lowe has to say:

"The good news continues to be that none of the mutations studied so far in the general population seem to be able to evade the antibodies raised by the current vaccines. That doesn’t mean that it can’t happen – and as we start putting selection pressure on the virus by vaccinating people we’ll have to keep a close eye out for anything like that developing. But then we have to consider transmission. If an antibody-evading form of the virus also becomes harder to catch, well, it’s going to be less of a worry. But if we were to start doing a better job at not spreading the virus in general, that would be sort of nice, because that would reduce the chance that any nasty mutated forms get any kind of traction in general. If some sort of supervirus mutation occurs in a single patient who doesn’t then get close enough to other people for it to spread, then it’s a tree falling in a forest that doesn’t make much of a sound."

"It’s all a race between several different factors. But here in the US we have so many people infected (and so much transmission going on) that frankly we’re making ourselves vulnerable to any more dangerous mutations that might crop up. In fact, if something like that were to emerge, the odds are better that it would do so here, from what I can see. We’re giving the virus every opportunity to reproduce and for the subsequent viral variations to then go out and try their luck infecting lots of other people. Vaccinating enough people quickly enough would interrupt these processes, and so would doing the sorts of public health measures that we’ve all been hearing about for months. But the first is going to depend on vaccine supplies, logistics, and public acceptance, and the second, well, look around you, si monumentum requiris."

https://blogs.sciencemag.org/pipeline/archives/2020/12/10/th...

Which is broadly in agreement with what I'm saying.