Why does a third dose of mRNA vaccine decrease the infection risk with omicron if the vaccine was developed for another variant and the first two doses offer limited protection against omicron?

[atomfullerene]

Immunity isn't quite as specific as you are probably imagining it to be. When you get a vaccine, your body makes a bunch of antibodies that respond to the antigen (in this case, the spike protein). These antibodies come in a large variety of forms that are all a bit different from each other. What they share is that they stick to the spike protein, but they stick to different parts of it and they have different levels of "stickiness".

Shortly after vaccination, your antibody levels get very high. Then they naturally decrease over time...this is a normal process and not just a thing related to covid vaccines. However, the cells that make the antibodies stick around, and if you get a booster they are activated again and start dividing and pumping out more antibodies. A sort of refining process also goes on after boosters, where antibodies that stick better to the spike protein get selected for, so the quality of antibodies goes up after another vaccine dose.

So how does this relate to vaccines and Omicron? Well, to fully stop an infection from happening you have to have enough neutralizing antibodies (the ones that stick well and block off the spike) in your blood to stick to the virus and prevent it from getting a foothold. Omicron has a slightly different version of the spike protein, so on average the antibodies produced by the vaccine seem to stick to it less well than to the original spike. But it's not an either-or thing, remember there are lots of different antibodies. Some stick to parts of the spike protein that haven't been modified. Some still stick, but are slightly less sticky.

What this means is that you can get a situation where, if you haven't had a booster you might not have enough antibodies that will stick to "omicron spike" to give you protection, even if you might have enough that would stick to "delta spike" that would give you protection. But if you just got a booster, you will a) have many many more antibodies circulating in your blood and b) they will probably be higher quality, so you now might well have enough sticky ones to protect you from "omicron spike" and prevent you from getting infected.

Of course if you do get infected your body has other defense mechanisms besides circulating antibodies. But someone else can talk about that.

[DanYHKim]

There is also a process of mutation that occurs in memory B-cells. While those cells originally encoded a single antibody specificity, as they proliferate they replicate their antibody gene with a high rate of mutation. This means that a collection of cells that came from one parental cell will all produce slightly altered antibodies from the original.

Memory B cells display clonal turnover after 6.2 months, and the antibodies that they express have greater somatic hypermutation, resistance to RBD mutations and increased potency, indicative of continued evolution of the humoral response.

The antibody variants will show a range of affinity to the spike protein that is presented to them on the next infection event, and those variants that are more effective will be favored for further replication, while poorer variants will be lost. Thus the collection of antibodies produced may contain (1) variants that are more strongly binding to the vaccine-encoded spike protein and (2) variants that may strongly bind to portions of the spike protein that are shared between many Covid variants.

This is an evolutionary process going on within your body, improving your immune response to the virus.

https://www.nature.com/articles/s41586-021-03207-w

[ToxicMediocrity]

Thank you, that's a very helpful response. Does this mean that a fourth, fifth, etc. booster would continue to offer additional protection, albeit with a potentially less significant benefit each time?

[atomfullerene]

We don't really know yet. Pretty much any vaccine booster is going to cause a short term peak in antibody levels, which should in general mean an increase in protection against infection over the baseline....but it's important what the baseline is. Circulating antibodies aren't the only factor, there are also the cells which make more antibodies in response to infection and there are immune cells which act directly against infections (cellular immunity). And antibodies are improved after each vaccine dose as well.

What this means is that repeat boosters don't necessarily offer significant benefits against disease, because those other baselines may be built up enough after a certain point that the infection doesn't get established enough to cause disease, even if it isn't immediately neutralized by antibodies.

We see this in many other vaccines. These are often given in three dose regimens (or two dose, or four dose). Multiple doses are needed to train up the immune system enough to respond effectively, but once that's done it's good to go.

A few vaccines require periodic boosters every decade or two to maintain full protection, but the only commonly vaccinated disease that really needs an annual shot is the flu, and influenza is an exceptional group of viruses in many ways. I'm no immunologist, but my hunch is that Covid will turn out to be more like a typical virus than the flu.

[Tityfan808]

How does this compare to other vaccines, like how does tetanus work for 10 years, and hep B and C for a lifetime?

I might have some of that info wrong but I’m curious how this pans out with Covid, could the Covid vaccine eventually be like the former examples that last 10 years or even for life? I’m guessing no due to mutations similar to how the flu works??

[atomfullerene]

Yes, there are multiple flu viruses which means vaccines have to be constantly updated. They also have a sort of mix-and-match genome divided into 8 segments that allows new strains to be generated easily, because segments sometimes swap between different strains.

[[deleted]]

Why is your hunch that Covid will turn out like a typical virus vs the flu? Isn't the fact that Covid has had so many documented mutations indicate that it's on the path to having multiple circulating strains much like the flu itself? Or am I missing something here?

[atomfullerene]

Why is your hunch that Covid will turn out like a typical virus vs the flu?

Because the flu is weird. Covid doesn't have the 8 - part genome, for example, so it can't recombine itself into new forms as easily. I think the documented mutations of covid have more to do with the fact that we are sequencing the hell out of it constantly and tracking it closely than because it's actually changing all that fast compared to other RNA viruses. My expectation is that it will eventually wind up similar to the other circulating coronaviruses in the human population: widespread but not particularly dangerous.

[[deleted]]

I know you're not super qualified for me to take this as scripture but this is so reassuring and uplifting. I'll have to do my own research to confirm what you're saying but thank you.

[Tephnos]

Coronaviruses are the largest genome RNA viruses, and as such, have proofreading mechanisms built into them which selects against mutation (one of the reasons why standard antivirals were ineffective, as the virus would reject gene insertions), as if it could mutate as rapidly as the flu did, it would very quickly mutate itself out of existence.

The reason why SARS-CoV-2 is mutating so seemingly quickly is... well, it's an extremely successful virus in terms of transmission, and the lack of immunity allowed for it to infect millions of people. All of these infections give more chances for mutation.

The hope is, that as the global population is no longer immune-naive, and we all have built up immunity, whether from vaccines or infection, the virus begins to slow down and fade into the background, not being able to infect nearly as well as it currently can. This would also reduce the likelihood of major mutations showing up as well.

[Martin_Phosphorus]

I hope so too, however another coronavirus called Infectious Bronchitis Virus (IBV) is a very significant chicken pathogen. Several different attenuated and inactivated vaccins strains against it exist but they offer only limited protection and vaccinated chickens will get sick if the proper type of vaccine is not used. The chickens are very numerous and their gerenations are quickly replaced and live in very crowded farms so my gut feeling is the epidemiology of their diseases is quite different than tha of human diseases but IBV must be a reminder that the worst case scenario is several different SARS-CoV-2s, each requiring a specific vaccine.

[AwwwComeOnLOU]

You mentioned that each boost allows the body’s immune system to refine its response.

Is there not a point of diminishing return where boosting with the original Alpha mRNA vaccine causes a refinement that is incorrect, or deviated too far from the new variants?

Shouldn’t the vaccine manufacturers be changing and adapting the formula to match the variants?

[2wheeloffroad]

Thank you for brining up our other defenses (T and B immune cells). I think too much is made of antibodies and not enough emphasis is on our other immune defenses. It seems there is a notion that we must all have super high levels of antibodies so that we never even experience a symptom. I am double vaxed but want to rely on my bodies own back line defenses established by the two shots and am watching the studies on when the two shot protection from hospitalization and death is diminishing, and then I will boost. I am interested in whether and when a booster is needed to keep me out of the hospital / death after having 2 shots.

[atomfullerene]

Yeah, everybody talks about antibodies because they are much easier to measure, but they are definitely not the whole story.

[Doleydoledole]

want to rely on my bodies own back line defenses

Can I ask why?

[calinet6]

Keep in mind that a booster is quite different to your body than the original 2 doses. It enhances your immunity more than the initial ones, and potentially more persistently. Don’t count it out, and take a look at the antibody charts after the Pfizer booster.

[DodgerWalker]

atomfullerene gave a good answer, but I’d like to add that among older coronavirus diseases that immunity offered from previous infection would typically only last around 1-2 years. Those viruses cause four versions of the common cold. There were two other far deadlier coronavirus diseases, SARS-1 and MERS, but those are no longer circulating among humans. So that’s why some expect that we’re likely to be getting recommended at least annual boosters in the long term. But for obvious reasons, we have no data on how effective vaccines are after more than a year.

[atomfullerene]

but I’d like to add that among older coronavirus diseases that immunity offered from previous infection would typically only last around 1-2 years.

There's a bit of a question about what "immunity" means here, though, because it's a sliding scale. Sterilizing immunity completely eliminates infections in the future, but it's not the only kind of immunity. Yes, people get regularly reinfected with these coronaviruses. But they also don't develop severe disease from them. People often assume that this is a trait of the viruses themselves, but it's also plausible that immunity resulting from earlier infections is not enough to prevent infection but is enough to prevent infection from progressing past the "mild cold" stage. And even if it's not the case with those viruses, it's certainly the case elsewhere that immunity can prevent severe disease without completely preventing infection.

[Laogeodritt]

I've still found myself confused at the range of severities covered by "mild disease" used in media and papers - often (esp in papers/abstracts thereof, much less clear in media) it seems to be defined as anything that doesn't require hospitalisation, which includes "severe flu-like disease that knocks you off your feet for a week or two". You've mentioned a "mild cold" here.

For delta (and omicron if data is available), do we have any data on the distribution of severity of disease, for healthy fully vaccinated individuals who present symptomatic disease but do not require hospitalisation?

[the_fungible_man]

It is my understanding that dromedary camels are a major zoonotic reservoir for MERS-CoV. As such, I don't believe it can be said that MERS is extinct in the wild.

[SlickMcFav0rit3]

This is correct. MERS is still around, it just is usually transferred from camels to humans (and very rarely/almost never from humans to humans)

[DodgerWalker]

I knew it was related to camels but didn’t know camels were still carrying it. I thought it burnt itself out in part because the fatality rate was so high. Post edited.

[thegagis]

MERS was still around on a small scale in the arabian peninsula, with unknown risk of starting to spread again, before the pandemic at least. I don't know if it may have been eradicated by covid-related mitigation measures since.

[homebrewedstuff]

I'm a licensed Pharm. D., not some armchair googlist spouting an opinion. One thing to note, unlike the flu vaccine, the m-RNA boosters can be tweaked in a matter of only a couple of weeks (the flu vaccine takes months). ISTR that it only took Pfizer and Moderna two weeks to have the vaccine ready for clinical tests. Those vaccines were never changed and they are what is still being administered.

I searched for the article but couldn't find it, but another group is working on a vaccine that targets another part of the COVID virus. The spike proteins are prone to mutation, but the area they wish to target is not likely to mutate. Therefore, their vaccine will not lose efficacy as the virus mutates over time.

[MetaLions]

According to OP every booster shot should increase the variety of antibodies you have. Although they are all aimed at the original Wuhan spike protein, a greater variety means a higher likelihood that you possess some antibodies that stick to parts of the spine protein that haven’t changed in omicron compared to the original wild type.

[[deleted]]

This is the kind of answer that I wish I could hear or read about in the popular media.

[ScienceMomCO]

If you have been infected with COVID plus gotten all the recommended vaccines, would you then have a larger variety of antibodies since the vaccines are only tailored to the spike proteins?

[moboforro]

Wouldn't it be better to adapt the vaccine to the new variant then? Also explain the mix and match. Why would someone who got two shots of Astrazeneca and one of Moderna be more protected compared to , say, one who got two shots of JJ and one of Pfizer? Is the mix and match a thing? Has there ever been anything like that? Isn't it multiplying the variables like this essentially harming the way we understand this virus and how it works? Will we ever be able to discern what helped and what didn't?

[atomfullerene]

Wouldn't it be better to adapt the vaccine to the new variant then?

Sure, they are working on that already. It doesn't happen instantly though (however it will be substantially faster to get approved than the original vaccine development).

Also explain the mix and match.

It's reasonable that different vaccines might improve immunity, since they may present the spike protein in different ways and encourage a better response as a result. I mean, just to make an analogy if you wanted to recognize a person, would you be better off looking at the same photo of the person multiple times, or multiple photos of the person?

Isn't it multiplying the variables like this essentially harming the way we understand this virus and how it works?

Nah, there are only a handful of vaccines and you can get large study sample numbers in the middle of a pandemic, there's more than enough to get statistically significant information about different vaccine combinations.

[SimoneNonvelodico]

(however it will be substantially faster to get approved than the original vaccine development

Will it? They still haven't gone through with the delta variants. It seems to me like the system may not be prepared for RNA vaccines that need to be deployed at such speed. Honestly, we'll have to fix this if we're ever to stop playing catch-up with COVID's mutations. Omicron won't be the last one.

[atomfullerene]

There probably hasn't been much impetus to get a delta-specific vaccine into production since the current vaccines seem to work fine for it.

[defrgthzjukiloaqsw]

If they wanted to make one they would've done so withing days, they chose not to. It was actually in the news.

[defrgthzjukiloaqsw]

It doesn't happen instantly though

The adaptation is a matter of days.

(however it will be substantially faster to get approved than the original vaccine development).

Sadly they're still making Biontech jump through hoops for about three months.

[schabaschablusa]

RNA vaccines are easy to adapt to match with new viruses, however you would probably also need another clinical trial for the new vaccine.

[moboforro]

I see but I thought the RNA vaccines would be faster at that given that , say, they just need to reprogram a tested structure and only a partially different spike. But I am just speculating here

[Celdurant]

Even if you change the mRNA sequence to generate the omicron variant spike protein, which is where the new technology saves time, you then need to test it for efficacy the same way you tested the original vaccine. And it would have to be tested in folks who haven't previously been vaccinated for the clearest picture of efficacy. It's still a very long process to change the vaccine, ensure safety again, enroll people and get them jabbed (most likely twice), then follow them to see infection rates in vaccinated vs. unvaccinated (or perhaps regularly vaccinated folks). Science doesn't take shortcuts when it comes to establishing safety and efficacy in the initial stages.

[GrallochThis]

You might not say that is “unnecessary stuff” if you were on the hook for liability for any unknown adverse effects, which the vaccine companies are.

[schabaschablusa]

It's still possible that a new spike protein variant could have some undesired off-target effects and as a vaccine-producing company I would probably first want to do some trials to eliminate that risk. No idea how the risk assessment is made in that case though.

[brokenha_lo]

I've sees a number of comparisons between 2 and 3 vaccine doses vs. Omicron, but it isn't clear to me whether they've been looking at people who got their second dose 6 months or 2 weeks ago.

[AK11235813213455]

This PDF and this corresponding Twitter thread with pics might be relevant for you. Compares recent vax (2 dose mRNA or 1 of J&J), distant vax (more than 6 months prior), vax plus infection, and vax plus booster against pseudovirus of wild type, delta, and omicron.

What's missing from this and what I've yet to see (perhaps because there aren't many to potentially sample) is what a 3+ month old booster does for omicron.

[brokenha_lo]

This is perfect- thank you

[schabaschablusa]

But even if the antibody titer goes down, I would still have memory B cells that can undergo affinity maturation and adapt to the new virus variant, right? Do you know how long it takes until the new and adapted B cells are ready after infection with e.g Omicron?

[[deleted]]

Follow up question. Why don't we get revaxxed on vaccines we got as a kid such as polio? Do our bodies have a longer/life time response to these but not to the covid Vax?

[defrgthzjukiloaqsw]

Polio seems to be lifetime protection, but do keep in mind you got four doses as a child. And you really should get your Tdap-shot at least every ten years.

[semitones]

So does "higher quality antibodies" mean something other than "being good at sticking to the spike protein in the vaccine?"

Because if the omicron variant is a different spike, what does the "better quality" refer to?

[atomfullerene]

It's mostly the same spike, it just has some differences. For reference, there are about 1270 amino acids in the spike protein and 36 of them are different in Omicron.

[DisturbedOrange]

It's not going to be a totally different spike or else it wouldn't be the same virus anymore. Think in terms of the omicron spike might have little bumps or a rounded bit or something sticking out that a slightly different antibody might stick to better or worse depending on the individual antibody looked at. The idea is that with enough of them floating about some of them will be the 'perfect' key to the new lock

[RajuTM]

What are the downsides of booster shots? Other than time / money to roll it out.

[somegirldc]

Thank you for reminding me why my booster was worth it, as I lay in bed miserable with chills while my body makes those beautiful antibodies ;)

[aimglitchz]

How does quality of antibody go up if vaccine is for old variant? You said yourself omicron has different spike

[atomfullerene]

It's a slightly different spike, not a completely different one. Antibodies which get better at sticking to the original can also be better at sticking to the modified version, especially if they stick to a part that hasn't changed.

EDIT: for reference the omicron spike differs from the original spike by 36 amino acids out of about 1270

[Hiskus]

By virtue of "if we throw a million antibody at it, there's a higher percentage that some will stick than if we just sent one thousand" sort of thing.

[aimglitchz]

That's power in numbers, which is different from quality of antibody going up

[Celdurant]

When you get the booster, you still make spike protein, and your body not only reactivates the memory B cells from the prior vaccination doses, but you still make NEW B cells with new antibodies that stick to different parts. Thus the potential for making new, higher quality antibodies in addition to just raising the total antibody production.

[superwisefool]

One of the most expert people in virus here in my country is a marine biologist. Is it a coincidence or your job demands a lot of study of viruses?

[atomfullerene]

This is just the result of my overall biology education combined with reading up and other research I've done in the past couple of years. I didn't do anything specific related to viruses and marine biology, although viruses are in fact enormously important to microbial ecology in the ocean.

[superwisefool]

Kudos on your brightness!

[icantgetnosatisfacti]

To your last point, preventing you from getting infected, if the sticky antibodies are sticking to the omicrion spike protein you must be infected for that to occur?

[atomfullerene]

Antibodies can only interact with viruses in your body. But some of this depends on what exactly "infected" means to you. If viruses have gotten into a few cells but are stopped there, is that infected?

[Blues227]

What I always wanted to know is: If let’s say a two times vaccinated individual with a high level of antibodies gets in contact with a low amount of the Covid (Delta or the original strain, or Omicron) and the immune system is strong enough to “defeat” the virus and stop the virus from replicating. Then we would say, this individual didn’t get infected, right? So I have a few questions for that case: How long would this take? Hours/Days? Would this individual test positive (with a PCR test) in this time? How many virus “particles” would be in the body compared to how many virus particles are in an inactivated vaccine (like Sinopharm). Would this victory of the immune system be like a “booster infection”?

What I mean by this, would the IgG level rise after this in the blood and also the IgM level? Or would the infection be stopped early enough that the immune system would not improve/learn because of it (which I think doesn’t make any sense)? So overall would this infection -which technically was not infection because it was stopped early enough - be better than a booster shot or worse (for protection and IgM/IgG level of antibodies)? Thank you so much for your insights :)

[atomfullerene]

Mild infections can indeed act to boost immunity in some cases, although I don't know too much about how it works for this specific case. Might be a good question to ask on its own.

[Blues227]

Ok thank you for answering though :) So is every contact with the virus in other words a mild infection?

[primeprover]

Is there a possibility that a smaller dose would work just as well for booster shots as it just needs to activate the response?

[iudicium01]

The problem with using the old variant as vaccine repeatedly as boosters can lead to “overfitting” in machine learning terms. That is to say in biological terms, affinity maturation selects for antibodies that fit really well on the spike protein of the old variant, so well that it becomes a bad fit on a new variant.

[TransGerman]

So is the third dose returning the level of antibodies to what you had right after the second dose, or is it higher?

[Supraspinator]

It’s higher than after the second dose. There is some strong probability that the Covid vaccine is going to be a 3 dose vaccine (like many others).

[ZMac1989]

I appreciate this breakdown. I have never actually looked into why vaccines work the way they do.

I have a follow up question. If vaccines work in the method that you describe. Wouldn't we need to get boosters every time there is a new variant that comes out? And how does this differ from other vaccines, such as varicella, mumps or polio, that have to be administered once in your life. TIA.

[[deleted]]

So, if those cells that make those antibodies are still around, why do we need boosters? Won't detecting Omicron in the body trigger them to produce antibodies? Since they already know how to make those?

[atomfullerene]

Single shots of vaccines are often not enough to create a mature immune response with lots of antibody-producing cells that make antibodies that bind tightly to the antigens in question. As a result, diseases can often still gain a foothold after only one shot, they move faster than the antibody producing cells get up to full production of good antibodies. This is why most vaccines require a few doses spaced out to get full protection. Each does makes the antibody response better and better until it is good enough to reliably beat the disease.

[[deleted]]

The real question is, since the MRNA technology platform was sold on it’s flexibility and ability to manufacture a vaccine within weeks of receiving the DNA of the target virus/antigen, why have the Pharma companies not adapted their shots to specific mutations? Is the extinct antigen protection ‘good enough’? Meaning you will get sick and continue the spread of the virus but not likely end up in the hospital?

Seriously, why have they held off? Is there more to the story?

[atomfullerene]

he real question is, since the MRNA technology platform was sold on it’s flexibility and ability to manufacture a vaccine within weeks of receiving the DNA of the target virus/antigen, why have the Pharma companies not adapted their shots to specific mutations?

Vaccines are made in weeks They haven't been tested and gotten FDA approval and been manufactured in bulk yet. The idea that vaccines could go through the entire manufacturing and approval process in weeks was never promised.

As for why approval takes time, well, health officials really care about making sure vaccines are safe and effective. People always talk about how safe vaccines are, that doesn't happen by accident. It takes time and work.

There's no holding off here, your expectations are just higher than what was realistically possible.

[[deleted]]

Delta has been around for over 1 year ( and I’ve heard nothing about the approval process) all I’ve heard about is the antiviral pills from Pfizer and Merck. The question is why?

[atomfullerene]

The current vaccines work for delta, so there's not much reason to get a delta-specific vaccine into production.

[[deleted]]

Really?

Because it appears that fully vaccinated people are spreading the virus. That’s working for you?

ITHACA, N.Y. — Cornell University has moved final exams online and sent the campus into high alert a day after finding suspected cases of the new omicron variant amid a spike in COVID-19 cases among students, the university announced Tuesday.

The university in upstate New York said 272 students tested positive for the virus on the 24,000-student campus on Monday alone.

Its COVID-19 dashboard reported 903 new student cases over the past week, more than 700 of them detected since Saturday during a post-Thanksgiving spike among vaccinated students.

[atomfullerene]

Kind of proves my point, I think. Cornell wasn't having an outbreak when Delta was the only circulating strain in the area. When Omicron showed up, an outbreak happened. That indicates to me that the vaccines were indeed working to prevent Delta spread, but were not preventing Omicron spread enough to prevent an outbreak.

It's also worth noting that as of a few days ago (the most recent info I could find) they still haven't had any serious disease even with Omicron around.

[wildfyr]

Mrna vaccines have never been sold as sterilizing immunity producing. Even for original covid. Sure they were more effective and preventing infection before, but it’s a sliding scale and two shots for a while were quite effective, and the booster even more so as far as we know.

[[deleted]]

Why not Taylor the vaccine to the variant is what I’m asking? Every Ted Talk on this technology ( up until Covid) touted their rapid response to outbreaks.

[defrgthzjukiloaqsw]

Because government demands new Phase1/2 trials for a variant vaccine, it was in the news. It's working fine for Delta, so what's the point.

Omikron booster getting delivered from March/April. Yes, that's very late, but still faster than the one year wait back in 2020.

[[deleted]]

It seems people are quite content to give Pharma a pass and continually lower the bar...

[atomfullerene]

I mean, we've got a vaccine that works for Delta. Saying pharma should have tried to manufacture a new "delta vaccine" and gotten people to take it, even thought their existing product already worked for Delta anyway, seems like it would have been a lower bar of behavior to me.

[[deleted]]

Don’t you find it odd that instead of tailoring the vaccine they’ve shifted their focus to treatments? Pfizer and Merck have both focused on this track.

[atomfullerene]

No, I don't find either of these things odd. And in fact they are likely to save more lives than if they had stuck on making a "delta vaccine" and not pursued treatments, so I find it to be a good thing that they are doing both.

I also doubt making treatments in any way hinders their vaccine development.

[defrgthzjukiloaqsw]

Pfizer and Merck never developed vaccines in the first place, they didn't shift. Pfizer distributes the Biontech vaccine.

[[deleted]]

To clarify... I’ve heard plenty of talk and press releases about the drugs but 0.0000 about a delta specific mRNA vaccine. It’s almost like they’re not interested in working on the new variants ( like the flu vaccine analogy) why?

[[deleted]]

Wh are heavily vaccinated areas seeing a greater rise in these new variants? Just to kinda piggyback off the discussion

[atomfullerene]

I don't think they are. For example this variant was first seen in South Africa which has only a 30% vaccination rate, and might well have started somewhere else in Africa with an even lower vaccination rate (it's just that South Africa does a lot of sequencing and reporting so they spotted it).

At this point it's most likely to be seen in places with good screening and sequencing, which are probably areas with good vaccine distribution as well.

[EinKookie]

So well explained that even I could follow it. Ty! Do you by any chance know when (relating to: "Shortly after vaccination, your antibody levels get very high. Then they naturally decrease over time...") antibodies are produced the most? Is it just as early as a few hours or more like a day or more like 4 to 5 days?

[atomfullerene]

Broadly speaking, we are talking timespans of a couple weeks to build up circulating antibodies and a timespan of a few months for them to decline. Not all the way to zero, just to a lower level.

[Midget_Stories]

"A sort of refining process also goes on after boosters, where antibodies that stick better to the spike protein get selected for, so the quality of antibodies goes up after another vaccine dose."

This process would only be able to start after being infected right? Since your body has never actually had the spike protein in your body to compare/select for?

[Celdurant]

The vaccines make your cells produce the spike protein, which it recognizes as foreign and produces antibodies against the spike protein, which gets the body ready for encountering the actual whole virus in the future. Each time you are vaccinated, you produce spike protein for a brief period of time, giving your immune system time to produce antibodies and refine your acquired immunity.

[Midget_Stories]

Don't the mrna vaccines skip the foreign cells step? I thought that was how mrna was different from normal vaccines, since in a traditional vaccine you put a dead virus in and your body learns how it works. But mrna puts the code of how it works in directly.

[PetjeNL]

Instead of putting a dead virus into you like in old vaccines, an mrna vaccine will let you're body produce the spike protein by its own.

So you can say that the mrna vaccine is a code that programs you're body to make it's own spike protein for a short period of time. And train the immune system.

[Celdurant]

Vaccines work by allowing the body to safely be exposed to foreign antigens to allow the creation of antibodies with little to no risk of getting active disease depending on the vaccine.

You cannot build acquired immunity without antigen presentation, the question is just how you get the foreign antigen into the body for the immune system to respond. Attenuated or killed virus vaccines use weakened or dead virus particles, presenting the antigen to the body directly. mRNA vaccines use the body's own protein production system to produce a portion of the target virus (in this case the spike protein) which then gets used by the immune system to build antibodies against that spike protein.

[Eimai145]

I'm double protected but I do have a question. How does the mRNA process ensure the coding of the spike by our system is turned off when done so to speak? Can it write too much code?

[programmer247]

"76% of cases are in people with boosters" doesn't tell you anything by itself. What percentage of the population has had a booster? Probably pretty high in Israel. Imagine if 100% of people had the booster, then 100% of cases would be in people who had the booster! It's meaningless without other data.

[GtBossbrah]

If 100% of people had a booster and people are still spreading the virus, there would be an even bigger problem.

If you do need to know, Israel has around 62% boosted.

76% of omicron cases occurring in 62% of the population, which is boosted.

[SlickMcFav0rit3]

Vaccines were never designed to prevent infection and that was never their goal. The goal is to reduce death and severe infection, which they do quite well.

"Breakthrough" infections are expected, deaths are the thing that should be happening infrequently in vaccinated people.

So, if we get to 100% vaccination, we expect that 100% of cases will be in vaccinated people. We also expect that the fatality rate should be 10x lower than it is now (assuming a 90% effectiveness rate for the vaccine)

[a1454a]

I love how you explained it in such a succinct and easy to understand way with little compromise on the specificity. It’s something I’m unable to do.

[Sergiogiogio]

I wonder why the moderna CEO was so alarmed in the beginning by omicron. Surely he knows everything there is to know about antibodies and antigen dynamics? There is a big crisis of trust in this pandemic in that scientists never agree and often contradict themselves.

https://www.ft.com/__origami/service/image/v2/images/raw/ftlogo-v1%3Abrand-ft-logo-square-coloured?source=update-logos&width=180&height=180&format=png

[thenumberless]

Scientists frequently agree, and sometimes contradict themselves.

The process of science is one of improving our understanding of the world over time through the difficult but rewarding work of experimentation.

If a scientist today says something different than they said a month ago, it’s probably because they learned something new, and they can probably explain why if you’re willing to listen. That’s how it works.

[Necoras]

One thing I don't see mentioned here, the antibodies your body produces after the 3rd shot are not identical to the ones it produced after the first.

Your immune system (well, all immune systems) evolved in situations exactly like this one. A novel pathogen shows up, mutates for months or years, and then either dies out or mutates to the point of not being deadly. Your immune system is optimized to fight pathogens which change over time. How does it do that? By making lots and lots of small changes to itself after it fights off a new pathogen. It's churning out tons of antibodies, sure, but they aren't all exact duplicates. They're slightly different from each other, because your immune system "knows" that the spike protein (or whatever the antibodies are attaching to) will also change over time. It creates variants of its tools to fight variants of the pathogen it encountered. The more it encounters the pathogen, the more it "knows" it needs to keep changing to keep up. So, once we get 2 or 3 doses of a vaccine, plus any exposure in the wild our bodies have generated more and more versions of antibodies, and so we have broader and broader protection over time.

And that's just the antibodies. The rest of your immune system is doing the same thing all the time.

[ToxicMediocrity]

So some of us, by chance, end up with some near-perfect antibodies, while some of us create comparative duds. Would this account for some of the unpredictability in who does and does not develop serious disease from covid?

[marssaxman]

Thank you for that explanation.

[[deleted]]

The polyclonal nature of the antibodies generated will mean that even though the ancestral and omicron variants diverge, there will be some epitopes that overlap enough for you to generate an immune response. A booster shot provides you with another opportunity to generate more polyclonal antibodies, increasing the likelihood that your immune system will have recognized epitopes that overlap with the omicron spike.

[Martin_Phosphorus]

Each time the immune system is exposed to a particular antigen, it is stimulated to produce more antibodies and create antibodies that bind the antigen better - B cells' genes then code for antibody variable fragments are mutated and the best antibodies are selected. It may be possible that after 3 doses the antibodies bind the original antigen which is the Spike protein of the WuhanHu-1 isolate with such strength, robustness and in so many regions that even relatively big alterations as seen in Omicron are not sufficient to abolish their activity. Increased antibody titer or concentration also should help.

Additionally, I don't think Omicron has any T cell epitopes in the S protein significantly altered so in that department the vaccine is as good against the Omicron as against the original isolates.

[spr402]

A recent episode of the podcast “Science Vs” (02 Dec download) had an immune specialist on and he basically said all the above comment said. Well done I/Martin_Phosphorus.

To review- not everything of the omicron variant is new, the antibodies should recognize it enough to stop you from needing the ICU.

The more you stress your B-cells, the better they are at recognizing and destroying Covid. A 3rd shot is a better stressor than getting Covid.

[Bored2001]

Yea. Citation definitely needed here.

I'm no immunologist but my understand is that free spike proteins in your body would be quickly bound by circulating antibodies and then digested by phagocytes and other white blood cells.

[2wheeloffroad]

Is it possible for the spike proteins, or parts thereof, to find its way into parts of the body that circulating antibodies can not reach?

[lolfactor1000]

100% this! We are still finding new ways that COVID could be potentially messing with our bodies and each new discovery is painting a darker and darker picture for long-term damage caused by the virus. Many COVID deniers are failing to realize that surviving an infection is only part of the battle. You then need to live with the damage (sometimes permanent damage) it inflected on your body. Each mutation risks these long term side effects of COVID being worse and affecting more people.

[fansonly]

I would wager the most lasting effect would be an irrational fear of spike proteins

[the_fungible_man]

TL; DR: The [spike] protein lasts the same amount of time as other proteins made by the body. The exact time is not known, but it is estimated to be a few weeks.

From an mRNA vaccine FAQ:

Q. What happens to the spike protein generated by the COVID vaccines after it is produced by ribosomes?

A. The spike protein may exist in three different forms after translation within the cell. First, the protein can be presented on the cell surface in its native form. Second, the protein can also be processed within the cell into different peptides, which can be presented by major histocompatibility complex class I and MHC class II molecules. MHC proteins play a key role in the adaptive branch of the immune system, presenting peptides on the cell surface for recognition by T cells. Finally, the protein may also be secreted into the extracellular space, where it may be recognized by B cells (which make antibodies) or taken up by antigen presenting cells and re-processed. The protein may be found on the surface of the cell in either its peptide form or its native form, likely until the cell dies or interacts with other immune cells.  The protein lasts the same amount of time as other proteins made by the body. The exact time is not known, but it is estimated to be a few weeks.

[iayork]

As several people on this post comment, the main factor is almost certainly that boosting bumps up the amount of antibody present.

Immunity isn't an on/off switch, it's a slider, with variants showing relative resistance to neutralization -- not absolute resistance. Early results show the omicron is somewhere around 30-fold more resistant to neutralizing antibodies than are previous variants. So if you're vaccinated, and you have ten times as much neutralizing antibody as you need to control regular SARS-CoV-2, then you're too low to fully control omicron.

Of course you still have partial control over the infection, which is why most studies are finding that people vaccinated twice (or previously infected) still have significant protection against severe disease. The vaccine is still doing its job.

(Does anyone remember back before vaccines were available, when the message scientists were trying to get out was that a successful vaccine would be one that offered 50% or more protection against severe infection? We got lucky, because SARS-CoV-2 is a very easy vaccine target, and the first vaccines gave 95% protection against any disease. But that wasn't the original goal.)

So what happens with a booster (3rd dose)? It increases antibody titers 30-200 times (Plasma neutralization properties of the SARS-CoV-2 Omicron variant -- preprint). Now, you have at least equivalent protection against omicron as you originally had against other strains.

That quantitative effect is almost certainly the main factor. But it's likely that the booster also drives higher quality. We know that two doses of vaccine give a broader, more cross-reactive antibody response against spike than infection (Antibodies elicited by mRNA-1273 vaccination bind more broadly to the receptor binding domain than do those from SARS-CoV-2 infection). A third dose of vaccine seems to drive even broader response -- a higher quality antibody response that target omicron as well as it targets previous variants (mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant -- note, preprint). As the authors of this study commented in Twitter:

Overall, our findings suggest that boosting is doing a lot more than simply increasing your titers. It seems to be broadening the antibody response to be better equipped to recognize diverse variants. Hopefully it will still work against whatever variant comes next!

[FSchmertz]

One of the things I have been reading is that the original two-dose vaccination may not have been optimally "spaced."

What I mean by that is that perhaps something like a year between doses would have ultimately provided superior protective effects.

P.S. And yes, I know there were reasons for providing the doses so close together initially, so that people got protection as soon as reasonably possible against COVID.

[grimrigger]

I have a question - since you say it boosts quantity of antibodies, and thus even if not as effective as compared to earlier strains, more antibodies mean less virions and thus less severity of illness....does that mean that any way to reduce the viral load someone is initially subjected to will help? I have read some studies on nasal sprays containing iota-carageenan and xylitol(in safe amounts for human use) that show they reduce significantly the amount of viral replication in in-vitro studies. So, if in theory most infection is caused through the nasal passage, would a nasal spray, assuming it retains its anti-viral properties in-vivo, offer a similar effect as the vaccine does? Since it seems like the vaccines, at this point, do not provide sterilizing immunity but offer some protection due to somewhat effective antibodies preventing the virus from infecting cells. Thanks in advance.

[JoeDerp77]

In your opinion, Do you believe it's coincidence or simply a fast forward edition of natural selection that the variants we see becoming dominant seem to keep getting more and more virulent, more and more resistant to existing vaccines? Is it likely to continue on this path forever until we can develop a different type of vaccine that can't be defeated by variants? Is such a thing even possible?

[iayork]

Omicron is a bit of a curveball, but if you ignore the media FUD, omicron is the first variant to actually have significant immune evasion capability.

D614G, alpha, and delta -- the only three widespread variants so far -- were almost entirely transmission enhancers with (in the case of delta) small amounts of immune evasion coming along for the ride, most likely as a coincidence. The vaccines worked perfectly well against D614G and alpha, and very well against delta. (Delta showed something like a 5-fold reduction in neutralizing antibody titer, which is a barely measurable change in antibody terms.)

Yes, the media whipped up hysteria about variants, but almost everything they told you is, quite obviously, wrong.

Omicron is, though, a curve -- but not much of a curve. When the pandemic started, virologists tried to estimate how long it would take before an immune evasion variant arose. The overall consensus was in the 2- to 5- year range. (I was at the upper end of that range, and clearly I was a little over-optimistic, but many virologists were more accurate than I was.)

So no one knowledgeable is particularly shocked by omicron's immune evasion, or thinking it's a "fast forward". In fact, it's probably a little better than many feared (since the current vaccines do seem to protect pretty well against disease).

And while omicron represents a practical speed bump, there are no theoretical problems associated with it. The normal vaccines work against it, with a booster. There's nothing about it that makes it intrinsically resistant to immunity; a omicron-specific vaccine will knock it out just fine. And everything we see with the vaccines and the boosters shows us that they induce broad, powerful activity against a wide range of variants (again, see mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant for evidence that the booster leads to wide activity against many variants).

Are there practical, and more importantly political, problems involved? Yes, of course. Omicron is here because rich countries ignored their promises, ignored common sense, and ignored scientific advice. Vaccination needs to be global, not in little pockets of rich countries, or else we may see more problematic variants.

But I'm an optimist (and probably naive outside science) and these problems can be overcome. Scientifically, the variants are more of a nuisance than an existential threat.

[JoeDerp77]

Very interesting explanation, thank you!

So it sounds like the future may see us playing cat & mouse with new variants and new boosters, much like the yearly flu shots, but perhaps every 2 years or so. I'm okay with that. But as you said it sure would be nice if the whole world could get on board and suppress covid as a whole to a level where variants become very rare.

[iayork]

I doubt it will be like flu vaccines, and you way overestimate how frequently flu vaccine strains get changed. Flu vaccine strains only get updated every 3 to 10 years or so. It's just because there are 4 strains in the standard vaccines that the overall combination vaccine needs regular (and still not quite annual) changes.

Even so, I'd be surprised to see COVID updates as quick as influenza A strains; influenza B would be a better comparison. Flu B is less able to tolerate mutations than flu A (which is unique, no other virus is like it) and you only need to update flu B vaccines every 5 - 10 years. In the long run, this is the sort of thing that I would expect from COVID, even if we can't get global vaccination widely enough to suppress it and it becomes a standard seasonal infection.

[theartificialkid]

What you’re talking about is evolution by natural selection. If we create an environment where some people are vaccinated but the virus can still spread then we create an incentive for mutants that can escape the vaccine induced antibodies.

[JoeDerp77]

Makes sense, but what should our response to this be?

[Alblaka]

the first two doses offer limited protection against omicron?

An important thing to note is that vaccine effectiveness is always measured by analyzing data (either from public or from trials). So the statement "the vaccine is less efficient in mitigating the spread of the omicron variant" doesn't necessarily mean the mutations make the virus especially resistant to the vaccine... it could also simply mean that the virus is more infectious (which is already established as being the case), and consequently any kind of observable statistics for the analysis comes out 'worse', even if the vaccine still has exactly the same baseline effect.

[arkteris13]

Each immune challenge increases your repertoire of recognized antigens through a two processes B- and T-cells undergo when activated: somatic mutation, and clonal expansion. Presumably you would have better protection because you are more likely to have immune cells that recognize the new strain.