[robbmorganf]

Does anyone understand why a third dose of the same vaccine improves immunity to Omicron?

I'm willing to believe the empirical evidence that boosters make a meaningful difference, but I can't figure out intuitively why the same mRNA a third time helps to address this new spike.

[thinkharderdev]

From what I understand it is about affinity maturation. Basically, when you get an initial vaccine (or infection) your immune system learns how to recognize the antigen (the virus spike protein) and produces a bunch of antibodies to recognize it. But your immune system also preserves the spike protein in antigen presenting cells so it can continue to produce antibodies to recognize more features of the spike protein. Over time, your immune system learns how to produce a broader range of antibodies that are (in aggregate) more likely to recognize partially mutated versions of the antigen. That's the affinity maturation part.

So when you get a booster (or a breakthrough infection) your immune system kicks into gear again but now it produces a broader range of antibodies. In addition the number of antibodies produced from the booster is quantitatively much larger than from the first vaccine. So with a booster you end up with more antibodies but also a larger variety of antibodies that can recognize different features of the spike protein (including features that are consistent between variants).

That's my understand at least but I am not an immunologist.

[corin_]

> So when you get a booster (or a breakthrough infection) your immune system kicks into gear again but now it produces a broader range of antibodies.

Would/could it not also be the case for exposure to the virus that doesn't result in a breakthrough infection i.e. the body detects it and fights it off successfully? (I daresay you didn't mean to imply that, just checking.)

[thinkharderdev]

I would assume so but it probably depends on the "level" of exposure and such.

[eagsalazar2]

Maybe it is less about it being the 2nd or 3rd shot and more about how recently you received your last shot? I got my 2nd shot 7 months ago and we've already heard that protection fades over time, so maybe the booster just works because it boosts, not because it is really any different than my 2nd shot.

[SideburnsOfDoom]

> Maybe is ... about how recently you received your last shot .. not because it is really any different than my 2nd shot.

No. That appears not be the situation. Immunity shortly after the thirds shot is substantially higher than shortly after the second

https://twitter.com/PaulMainwood/status/1460191035531878405

https://twitter.com/PaulMainwood/status/1458026852249919490

[eightysixfour]

I have seen speculation that the second dose was given too quickly.

[SideburnsOfDoom]

Firstly, YMMV, different people got different separations of different vaccines. The US doing Pfizer 3 weeks apart was the fastest. The UK gave out AZ and Pfizer. First at a 12 week interval, then shortened to 8 weeks

The question is: too quickly for what? My understanding is that

a) If the goal was optimal immunity in the longer term then yes, it might be overly quick.

b) But if the goal was fighting the raging pandemic that needed urgent actions right now as "the house is on fire", and you have a lot of vaccine doses, then no, maybe not too fast.

Finally, a lot of vaccine courses require more than 2 doses, separated by more than a couple of months. UK standard childhood vaccination schedule for instance. "Polio" is in there 5 times. Polio is a memory, but only because because to this day they don't mess around with vaccinating against it

[eightysixfour]

Agreed, I was only referencing a.

[wlesieutre]

I wonder if that's a factor in the Pfizer/BioNTech vs Moderna performance. Moderna had a higher dosage, but it was also 4 weeks between doses instead of 3.

[SideburnsOfDoom]

> but it was also 4 weeks between doses instead of 3.

YMMV. The UK gave out AZ and Pfizer. First at a 12 week interval, then shortened to 8 weeks.

[Symmetry]

If you assume an unlimited supply of vaccine then the shorter dose interval gets everybody to good level of sterilizing immunity as quickly as possible.

[SideburnsOfDoom]

Yep. if you need to fight against a raging pandemic, then quickly as possible (as quickly as is tested to be safe, quickly as makes a significant difference) is the over-riding concern.

[astrange]

That implies we thought about it in the US, but we didn't really, and our public health people seem to be completely inflexible about everything. The schedule we used for vaccines is just what was done for their trials.

[xchaotic]

Given how quickly the virus mutates, giving it less frequently makes even less sense.

[eightysixfour]

My response was with respect to maximizing immuno response following vaccination. There is some evidence that larger spacing between doses increases response.

[afterburner]

Because of the way your immune system works. Vaccines aren't medicine, they work by provoking an immune response. What happens after that immune response is triggered is way more complicated than just "molecule X get response Y", there are multiple stages of responses, and the deeper, longer span ones create a resilience against mutations as well.

It is extremely common for a proper vaccination regimen to require multiple doses, and it has entirely to do with how the immune system works.

[notabee]

From what I understand, the immune system has some capacity to anticipate mutations. The most basic function of antibodies is to stick to and neutralize the target, in this case the spike protein that the mRNA vaccine presents to the immune system via producing some copies in muscle cells. But the immune system doesn't just produce exact form-fitting duplicate antibodies, it also has something like a biological "fuzzer" that also produces antibodies to target anticipated mutations to its main target, the spike protein. Each time this system gets stimulated, it not only makes more antibodies and more memory cells to produce them, it also runs some more anticipatory mutations. So in aggregate, hopefully the increased quantity plus maturation of these various antibody tweaks produce enough antibodies that stick well enough to the virus to incapacitate or slow it down so that the other aspects of the immune system have time to react instead of getting overwhelmed. And it makes sense to have an antibody arms race like this since viruses mutate so fast. Obviously, this doesn't always work and viruses frequently out-mutate the immune memory, but the immune system is pretty smart.

By the way, if there are any actual scientists here that spot some atrocious mistake I've made describing this, please let me know. I find it really interesting to learn about but I'm certainly no expert.

[lborsato]

Unfortunately as a result of original antigenic sin, the fact that the immune system has been trained for by a vaccine for a certain strain means that the body will respond to that strain, likely unable to mount a new defence for the different strain.

https://pubmed.ncbi.nlm.nih.gov/33692194/

[freemint]

Virologist are aware of this but I seen no indication that it applies to the CoVi variants we are currently dealing with.

[Retric]

Mutations in spike proteins don’t completely change it’s shape so they render a percentage of antibodies infective vs that specific strain. A boosted immune response can therefore be less efficient but still useful.

To simplify, Vaccines provide long term protection because the immune system builds infrastructure to rapidly create antibodies after infection cutting days off of the immune response. That’s huge because the virus has less time to replicate in your body. Vaccines use multiple injections to increase how much infrastructure is built and the number of types of antibodies being produced. Also this infrastructure decays over time if you never see the strain again.

However, in the short term your body reacts like it’s infected actually flooding the body with the appropriate antibodies. This isn’t sustainable but can crush most infections before they go anywhere. Kind of a bonus turbo mode which can be really helpful if your say going to treat people infected with the disease.

[SideburnsOfDoom]

> Does anyone understand why a third dose of the same vaccine improves immunity to Omicron?

From what I've read, 2 doses in 8-12 weeks is a small separation, as these things go.

A third dose 6 months after the second is not just a third revision of the lesson (metaphorically), but a more appropriate spacing to re-enforce it.

[pa7x1]

The CEO of BioNTech said they don't know for sure but speculated that memory B cells may keep hypermutating after a third shot which could result in the improved effectiveness against Omicron. Or that's what I understood with my very rudimentary knowledge of biology.

[Symmetry]

After exposure to a pathogen the levels your body starts evolving antibodies against it. It also quickly ramps up antibody production, but ramps that down over time without additional exposure.

Having had a more recent jab will mean a higher quantities of antibodies. But more vaccinations also means your body has done more cycles of evolving better targeted antibodies against the threat. I assume that there's a certain level of diminishing return to the second factor, as well as questions about how much the extra work translates against a new variant. But the second effect exists alongside the first.

[SubiculumCode]

I am not an immunologist, but I imagine repeated infection is a signal to the body to build and expand immunity to the virus.

[ufo]

One of the theories is that the booster raises the levels of neutralizing antibodies. While the antibodies against the original strain don't work as well against Omicron, having more of them does help.

[kgwxd]

Is it not just timing? I thought the effectiveness of the vaccines only lasted around 6 months. In the US 18+ were able to get it 7 or 8 months ago.

[Retric]

Vaccines can last your entire lifetime, but their effectiveness decays over time it largely depends on the disease and your risk of infection. Booster shots for various vaccines have been common for example, it’s recommended people take a Tdap booster every 10 years, Tetanus every 4-6 etc.

The flu vaccine is a special case as it’s changed every year.

[chasil]

In the original use of the vaccina virus against variola (smallpox) infection, symptomatic smallpox could present after vaccina exposoure of at least five years past.

https://en.wikipedia.org/wiki/Smallpox#Prevention

"Smallpox vaccination provides a high level of immunity for three to five years and decreasing immunity thereafter. If a person is vaccinated again later, the immunity lasts even longer. Studies of smallpox cases in Europe in the 1950s and 1960s demonstrated that the fatality rate among persons vaccinated less than 10 years before exposure was 1.3 percent; it was 7 percent among those vaccinated 11 to 20 years prior, and 11 percent among those vaccinated 20 or more years before infection. By contrast, 52 percent of unvaccinated persons died."

[dsmnd]

The 'T' in Tdap stands for tetanus

[Retric]

Yes, though to be clear your supposed to get a both.

“It is recommended that adults get a Tdap shot for one of their tetanus boosters.” https://www.verywellhealth.com/booster-shots-1298291

It simply reduces the number of injections when you get multiple vaccines at the same time.

[SideburnsOfDoom]

> Is it not just timing? I thought the effectiveness of the vaccines only lasted around 6 months

No, it is not (just) timing.

"Three doses gives better protection than two doses ever did" (1)

Immune response is very complex (2) and we're not experts; but we should not measure it in just 1 number: that gives the impression that the response is a range from "high alert for this recent threat" through to "threat forgotten" - effectiveness did not last that long.

There are there are other states as well when the threat is "on file" in the immune memory. Another exposure months later influences this process. My guess is that the evolved heuristic is that "a threat that recurs more is worth remembering better".

1) https://twitter.com/PaulMainwood/status/1460191035531878405

2) https://www.theatlantic.com/health/archive/2020/08/covid-19-...

3) https://www.theatlantic.com/science/archive/2021/09/waning-i...

[awillen]

My understanding is that they've studied people with 2 vs. 3 shots, both groups having received their most recent shot in a similar timeframe to account for that.

[hackerfromthefu]

And no one is talking about whether we will be expected to take a fourth and subsequent

[SideburnsOfDoom]

No-one really knows that yet. Novel virus is new.

If I had to guess, I would expect another anti-COVID jab in 2022. I expect 1 injection in 2022, maybe in autumn, of a mRNA vaccine, against a strain such as Omicron, that is not original COVID-19-alpha. Not a firm prediction, just a guess at what's IMHO most likely.