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Comment by mikedilger | Hacker News Reader

Not that I have any knowledge on this subject, but why would a vaccine that stimulates the creation of a bit of spike protein create a "much broader and more durable immune response" than the actual virus which I presume creates a hell of a lot more of that exact same spike protein? Genuinely curious, because my simpleton assumption would be the opposite.

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The rough theory - as I understand it - is that the virus is composed of other things as well as the spike protein e.g. the proteins in the viral shell. The immune system can learn to attack _whatever_ foreign materials it encounters. So a person that clears the infection might have a strong immune response to the spike protein, but the response could also be focused on some other part of the virus (or a mixture of different viral features).

Problem is, the "some other part" can mutate more easily into a form that the immune system no longer recognizes than the spike protein can, because the spike protein has to keep its form in order to react with the ACE2 receptors and enter a human cell. So the concern isn't that a real infection doesn't leave you immune to the virus you got sick with, but that the immunity might not apply or be as robust against a variant where the "some other part" has mutated into a different form.

The mRNA vaccines only cause your cells to make the (difficult to significantly mutate) spike protein, so the expectation is that vaccinated people would have a robust immune response against any variants which have that spike protein, regardless of whatever else changed, and a variant with an unrecognizable mutation of the spike protein would be less infectious anyway, as it could no longer successfully enter human cells either.

The results of the paper seem to indicate that this is not a problem in practice (so far - new variants are still evolving), but it's nice that someone checked.

A 2-dose vaccination regime (separated by 8-12 weeks) also gives our immune system time to build up the spike protein. An actual infection doesn't last as long and hence our immune system doesn't process it in the same way.

> separated by 8-12 weeks

Who's doing that? Isn't the separation 3 weeks for Pfizer and 4 for Moderna?

Canada/the UK have been doing that.

Odds are it does make things more effective rather than less, based on our experience with other vaccines. But IMO it's not wise, because it wasn't studied.

Still, 2 huge peaks separated by 3-4 weeks provokes really big immune responses.

> Odds are it does make things more effective rather than less, based on our experience with other vaccines. But IMO it's not wise, because it wasn't studied.

It has since been studied[1] (preprint) and that was exactly what was found -- delaying the second dose provoked a stronger response, similar to many other vaccines.

[1] https://www.birmingham.ac.uk/news/latest/2021/05/covid-pfize...

Sure, so far preliminary data looks OK. I still don't think it was a wonderful roll of the dice-- it didn't lower susceptibility so much in the short term (because a single dose's efficacy is limited, especially in the old) and it could have made things much worse.

A key limitation of the study is that it's in the USA, where some of the most concerning variants are not as widespread.

For example, in Brazil there is evidence that the P.1 variant can lead to reinfections.

Many reasons, that I don't fully understand. A few are: adjuvant properties of the vaccine, and the fact that there's a booster dose given, and that there's a whole ton of spike protein made and not many other targets.

But the reasons don't really matter -- studies like https://www.nejm.org/doi/full/10.1056/NEJMc2032195 have shown those vaccinated have significantly higher neutralizing antibody titers in their plasma than convalescent plasma, and slow decay of this response.

Of course, this isn't perfect evidence, as it is just the neutralizing antibody responses and the adaptive immune system response is much more complicated than this single measure.

Also no knowledge on the subject, but I can image a case where it is more durable:

If the spike protein is absolutely critical to the virus, but can't change too much without affecting function, an immune response that is specifically targetted against it would be better than an immune response against any other protein that could change without affecting the function.

It's not entirely the same. The Pfizer, Moderna and J&J (and Novavax) vaccines adjusted the protein to present a more consistent target than the viral spikes:

https://cen.acs.org/pharmaceuticals/vaccines/tiny-tweak-behi...

I think the key is that you get 2 shots. The second one might result in antibodies that bind the antigen better. This might happen because the immune cells undergo another round of mutation and selection after a second round of antigen exposure.

It's typically because of the adjuvants added to vaccines, and some other mutations done for stability.

The major covid vaccines have fewer adjuvants (to allow for boosters) and 2 shots because that's just how the trial was run, and it turned out to work, but later testing shows they're pretty effective just with one and some countries have been delaying the second one until everyone gets their first.

My mental model of this (and I'm not a medical expert) is that (a) for a given amount of spike protein, the immune response is similar, whether the protein originates from the vaccine or the actual virus, but (b) since the vaccine is lacking the actual health threatening properties of the virus, you can expose people to massive doses of it without incurring much risk.

My place employment had almost 280 people get vaccinated (myself included). On the second dose well over 50 percent came down with flu like symptoms about 12 hours later. I was sick for 3 days and my wife was sick for 2.

  Would be curious on this forum on how many people got sick from Moderna.

30 percent+ have significant side effects on the second dose. This is more significant in people in their early 20's.

My wife and I are in our 40s. I had a really sore arm (like, the whole arm, not the injection site) and we were both tired for a day afterwards.

You got that backwards, my friend

The mRNA vaccines (among others) include adjuvants that enhances the immune response.

No, they don't. The lipid nanoparticles they use seem to have an adjuvant effect, but they are also directly functional, and there's not anything else in the mRNA vaccines.

It's such a complicated semantic distinction, though. The formulation chemistries chosen for mRNA drug development efforts have a much smaller adjuvant effect (to allow people to better tolerate repeated administration of the agents). But here, using an (older, simpler) formulation chemistry that pisses off the immune system is useful. So is it an adjuvant or not?

So, it's otherwise functional but also chosen to have an adjuvant effect.

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