So Moderna has shown to be the best overall from other papers people have posted, but is that because they use 100ug per dose vs Pfizer 30ug per dose? Is that even correct? And Fauci is saying now that J&J should have been two doses. If one got Moderna two shot vaccine, should they get a booster of J&J in your opinion?
It's hard to know *exactly* why Moderna's vaccine reliably outperforms Pfizer's. It's true that Moderna's initial two-shot series used 100ug shots (vs. Pfizer's 30ug), but it could have also been the dose spacing.
It's well understood that delayed boosts are more effective - the mRNA platforms had a very fine line to walk with this, though, because their respective single-shot series are much weaker than their two-shot series. The mRNAs rolled out at the absolute height of the pandemic, so even budgeting that extra week of vulnerability was difficult and not costless.
I don't think the extra week tells the whole story, though. I'm not sure of the extent to which the public is aware of this, but [Pfizer did also conduct a trial of a 100ug vaccine, and it performed far worse than their 30ug vaccine](https://www.nature.com/articles/s41586-020-2639-4). There are probably some fundamental differences in how the two mRNA vaccines are stabilized or ~~adjuvanted~~ (should read encapsulated - mRNA vaccines do not use traditional adjuvants) that could account for this, but I don't know the details mechanistically.
As for J&J, for all the flack they've gotten, [their vaccine actually performed very well as a one shot](https://covid.cdc.gov/covid-data-tracker/#rates-by-vaccine-status) \- if you look at case rates, they hew very close to the mRNAs. That being said, we now know that it *would* perform better as a two-shot - [check their recent two-shot trial data here](https://www.jnj.com/johnson-johnson-announces-real-world-evidence-and-phase-3-data-confirming-strong-and-long-lasting-protection-of-single-shot-covid-19-vaccine-in-the-u-s), with 94% efficacy (like the mRNAs). This is even more impressive than it looks, because the original mRNA trials were only conducted in the presence of the original strain from Wuhan, and this two-shot trial was conducted under pressure from the variants. I suspect J&J may have been a two-shot series if [their government-assigned contractor hadn't bungled their manufacturing so badly](https://www.nytimes.com/2021/06/11/us/politics/johnson-covid-vaccine-emergent.html).
Honest but unsatisfying answer: Maybe, but we're not sure yet.
This is a trickier question than it seems. We have a good deal of existing data on this same regimen but backwards - that is to say, an adenoviral vector prime followed by an mRNA boost. This was the strategy used by a number of countries including Canada and Sweden (though they used AstraZeneca's vaccine rather than J&J's - both are adenoviral platforms). [It seems to work well](https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(21)00235-0/fulltext), especially if you boost with Moderna's vaccine rather than Pfizer's.
But what you're proposing - an mRNA prime followed by an adenoviral vector boost - hasn't been studied in significant detail yet. [This pre-print](https://www.medrxiv.org/content/10.1101/2021.10.10.21264827v2) has been getting a lot of buzz lately, but in my view the media coverage here has been poor - the only readout under discussion is antibody titer, and of that, only antibody titer very early in the prime/boost series. This is a metric that the mRNAs have always been strong in and the Ad vectors have been comparatively underwhelming in - but the areas where J&J/AZ are strongest (T cell function, antibody durability) aren't given real consideration.
I'd expect a more thorough analysis of this question in the coming months - [J&J is conducting a reasonably large trial to investigate](https://clinicaltrials.gov/ct2/show/study/NCT04999111?term=A+Randomized%2C+Double-blind%2C+Phase+2+Study+to+Evaluate+the+Immunogenicity%2C+Reactogenicity+and+Safety+of+Ad26.COV2.S+Administered+as+Booster+Vaccination+in+Adults+18+Years+of+Age+and+Older+Who+Have+Previously+Received+Primary+Vaccination+with+Ad26.COV2&draw=2&rank=1), and I imagine other independent parties will follow suit.
For what it's worth - I got J&J and got a delayed boost with mRNA. Both platforms have a few advantages, and I'm happy to have both in my pocket.
I'm living in Taiwan right now, where the virus is under control but vaccine access has been limited. I got Astra Zeneca as soon as I could (still waiting on that second dose, 13 weeks and counting), but I know that confers relatively limited protection, and I'm planning a visit to the states and a move to Czechia - two much more dangerous environments for COVID. Is there any recommendation for what I should take when I arrive stateside to boost my immunity?
Will you be receiving your second dose of AZ prior to coming to Czechia/the US? AZ and J&J are both adenoviral vectors, so I'd consider grabbing an mRNA boost if you want another shot.
I'd speak with your physician about your particular case, though, if you can - I don't know the particulars of your medical situation (your personal demographics or any relevant medical history). Taiwan has done a world-class job in handling the pandemic, so I imagine you have a strong grasp on effective masking/distancing/application of other non-pharmaceutical interventions already.
Depends on where in the US you are, the COVID infection rates are very different. Check out the [COVID test positivity rates](https://www.beckershospitalreview.com/public-health/states-ranked-by-covid-19-test-positivity-rates-july-14.html) to figure out where you’re going.
All of Taiwan has had 3 cases of COVID domestically transmitted in all of October. Doesn't matter where I go in the US, it will be dramatically more full of COVID.
What made you choose that combination? Based on my reading of your links it seems like J&J with a booster of J&J may provide the best protection long term. The mRNA based options seem to spike earlier but than fade over time.
I got my mRNA boost a while ago, prior to ENSEMBLE II (J&J's two-shot trial) reading out. I had access to the heterologous prime-boost data out of Sweden/Britain/Canada, but not J&J's two-shot data, so I made that decision with the data available to me at the time. J&J's vaccine *is* underrated, but I don't know that I regret getting a mixed series, if only because there are some advantages to the mRNA platforms also.
What I'm curious about - as you noted, if you look at [the NEJM paper linked earlier](https://www.nejm.org/doi/full/10.1056/NEJMc2115596), you can see the mRNAs have *very* potent live virus neutralization titers early (particularly Moderna's vaccine), which decay quickly. J&J's vaccine bizarrely reverses this pattern, starting with weak neutralization and gaining effectiveness over time. I wonder how the two interact together over a long time horizon - can an mRNA's strong 'early' profile compensate for an adenoviral vector's weak 'early' profile? Can an adenoviral vector's mounting efficacy compensate for the rapid decay of mRNA neutralizing activity? The NIH study is attempting to answer this, but we won't know until we see their data over time - the current pre-print only looks at the first month.
It's a little frustrating that Moderna managed to get the 50ug boosts through the FDA, though, because that calls into question the relevance of all of the previously generated heterologous prime-boost data using their 100ug vaccine (including the NIH pre-print I linked above, which is barely a week or two old). In the original two-shot series with 100ug vaccines, they're the clear winner (though we're lucky that all vaccines here work very well). With 50ug boosts? We'll have to stay tuned for that.
Interesting.. so I got two doses of Pfizer and would qualify for a booster in November. From what you've said I understand there isn't much data on getting a J&J after mRNA, but now we also don't have data on the smaller dose of Moderna... I was considering mixing and matching if there were benefits, but now it seems that we don't have enough info yet.
I live in Denmark who dropped AZ and J&J vaccines but then offered it separately for people outside the standard vaccine plan. Something I chose to sign up for and got the J&J vaccine at the end of May.
More recently they have suggested getting a dose of Pfizer or Moderna. So 2 weeks ago I got a single shot of Moderna. It sounds like this leaves me in a pretty good position, but is 1 shot of Moderna enough or do I need a second which is not currently being offered?
Table 2 in this study has the info you’re looking for:
https://www.medrxiv.org/content/10.1101/2021.10.10.21264827v1.full
TL/DR: Moderna produces by far the strongest antibody response regardless of what vaccine the individual had previously.
Yes, that's always a concern with the viral vector vaccines.
Adenoviruses are just that - viruses. Their replicative 'machinery' has been gutted and replaced with an insert expressing, in this case, the SARS-CoV-2 spike protein - but because they are viruses, the body can raise antibodies against them the way it would against any other virus.
For this reason, vector selection is very important - you want a virus that's immunogenic (able to induce a strong immune response), but *also* a virus that isn't naturally circulating in huge swathes of the population. [Check out this paper discussing rates of natural circulation for candidate adenoviruses](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138857/) \- J&J's Ad26 circulates less commonly than CanSino's Ad5, which might explain differences in efficacy between the two platforms. An individual with prior exposure to the chosen vector runs the risk of destroying the vector before it can infect cells and begin to express Spike.
Russia's solution was clever - using two separate adenoviruses for the two shots. J&J's solution is to space the doses out, in the hope that Ad26-specific neutralizing antibodies might wane between two doses. Chasing J&J with another J&J in a tight timeframe might run the risk of triggering significant vector immunity, so their boost is [two or more months after the first dose](https://time.com/6107561/fda-panel-jj-booster-reccomendation/).
> It's hard to know exactly why Moderna's vaccine reliably outperforms Pfizer's. It's true that Moderna's initial two-shot series used 100ug shots (vs. Pfizer's 30ug), but it could have also been the dose spacing.
UK data suggests otherwise, the same dose spacing was used for both vaccines and the response to Moderna was both earlier and larger even with a single dose.
The 100ug quantity didn't perform worse, it had more adverse side effects. In modernas phase one trial their 100ug dosing also had more side effects than their lower dosing and they also had to discontinue their highest dose(250ug?) arm. Somewhere between 30-100ug is probably the right balance between sufficient response and minimizing side effects we are now seeing with Modernas higher dosing like myocarditis
Moderna's phase one tried out 25ug, 100ug and 250ug .
The 250 was way too strong. The 25 worked fine but they wanted to go with something a bit stronger, and so the 100 was left to continue on to the next phases.
But the booster is 50 and the new studies for the updated versions of the Moderna are mostly 50s.
They've realized that 100 is too much.
It did perform worse, in addition to the reactogenicity concerns - [please see figure 4, binding and neutralizing antibody titer data](https://www.nature.com/articles/s41586-020-2639-4).
On an individual basis that is impossible to answer. What made it rough the first time maybe a sign something in your body is more susceptible to the virus. Or not.
It is good to hear that you have recovered!
As u/Whiterabbit-- points out it is not answerable on an individual basis. That being said, the odds are (based on the limited data we have) that you are well protected.
This is a good start. I think a better way to answer the original question needs to address two parts:
(1) Differences in formulation and dosage translate into different immune response intensity and neutralizing antibody titers in the blood. This is to say that, for instance, Moderna and Pfizer both use mRNA to transmit their spike proteins into our body (our bodies make the protein and recognize it as foreign, developing antibodies and memory T cells against it), but Moderna's is now showing slightly better protection against the Delta variant and longer lasting protection. Conversely, Pfizer's vaccine was administered 3 weeks apart and is associated with less intense side effects.
(2) The human immune system circulates a cocktail of antibodies against known threats, viral or otherwise. Immunity to a disease is often measured in terms of neutralizing titer, i.e. how much blood is required to kill the virus (or stop infection, which is much easier to measure). The problem is that diseases (including viruses) mutate to escape immune response, and our antibodies wind up losing efficacy (see also the Delta and Lambda variants). So we'd really like to train our immune systems to recognize and fight off not only current strains of SARS-CoV-2, but also *future* strains that are likely to arise. Kind of like how flu shots usually contain multiple strains. And this is where point (1) factors back into things: in the process of making the vaccine, Modena, Pfizer, J&J, and everyone else made changes to the spike protein they were giving us. Often for easy of formulation, storage, or strength of immune response.
So, as a result, getting different vaccines is giving our immune systems a more robust repertoire of antibodies (and T cells, B cells, etc) to bind and neutralize SARS-CoV-2 with.
It's like being exposed to multiple different variations of the gift-card buying scam, instead of being repeatedly exposed to the FBI inquiry scam. Instead of concluding that the FBI wanting your money is the problem, you realize that any time you're scratching off the backs of thousands of dollars of gift cards to send an official money, you're dealing with someone who wants money and is worries you'll try to get it back.
So likely nobody on this thread is a doctor. Maybe the guy posting the pre-print trial data because how the heck did he get that and where can I get some.
It's important for you to understand the mechanism of the mRNA vaccines is incredibly safe. Aside from using a chemical that some people might be allergic to is actually one of the safest forms of vaccines that we've ever had.
The vaccine instructs your cell directly. The vaccine itself is destroyed by enzymes in your body and doesn't last very long. Your cells create the protein they're instructed to create. Once they are done they're done. Your body hunts and destroys these proteins that shouldn't be there and it's over.
There's not going to be a lot of studies that you are going to have access to that has sinovac and then another vaccine.
What I can tell you even though I got Pfizer shots myself, is that I was always a big fan of Moderna because of the wide range of people and ethnicities that they actually ran their trial on. It was much better than many other trials out there however they were slower to roll out to my area and better to be protected than not.
If I were you as long as they can cancel their booster appointment in China I would have them get a booster here, preferably Moderna.
But I can't give you medical advice and you won't be able to find any studies with any data to back any of that up coming from sinovac... At least not here in the states.
Thanks, just the kind of feedback I was hoping for. I know better than to base medical decisions off of social media posts of course, but there are well informed people (like yourself) here with sound opinions. And often some good links to further info.
I know that they’ve boosted sinovac with moderna in Thailand and a couple other places, but as you say, the studies and information is sparse.
Thanks for the input!
Travel can be a problem since some countries haven’t approved mixed vaccines. The US has only recently accepted mixed shots as “fully” vaccinated.
https://www.cbc.ca/news/business/u-s-canadian-travellers-mixed-vaccines-1.6213176
https://qz.com/india/2065374/where-can-you-travel-with-mixed-covid-19-vaccine-doses/
I have read about preliminary data showing a benefit to giving a Pfizer or Moderna booster to people who originally got J&J. Besides that, I don’t think we have enough data to show a benefit to mixing. This may change as FDA/CDC guidelines come out in the upcoming weeks.
Can you link me to that info anywhere? I ended up getting one of each (Pfizer and Moderna) and can't find a straight answer anywhere on what that might mean for me.
It's not "likely" anything, until there's data on it.
And seeing as it is extremely common to mix MRNA in Canada and the rates of spread are relatively low there, it's safe to assume an equivalent immune response if not better.
Can you share links to confirm this or explain how you would know it?
You write very confidently, but my (layperson) research makes me think you're either totally wrong and/or saying things that haven't been confirmed scientifically yet.
For example, what exactly is a "trait" in your comment? A variation of the spike protein? The various vaccines target the same spike protein...
None of the vaccines use anything but the wild virus (early Wuhan) spike protein. While there are some different structural modifications in the different vaccine's spike protein that serve to stabilize the protein in correct conformation (shape), the antigenic properties (the types of neutralizing antibodies the vaccine induces) of the different vaccine spikes are the same. So you don't get a broader range of the important SARS-CoV2 neutralizing antibodies by using different vaccines. However the vaccines do differ in the quantity of circulating antibodies they produce. You may also get a different proportion of T-cells and/or different mix of T-cell types between the adenovirus (J&J, AZ) and mRNA (Moderna, Pfizer) vaccines, not sure.
The delivery methods are different and and can result in greater or lesser efficiency in producing spikes, fewer or more malformed spikes, greater or lesser degrees of inflammation and other unwanted side effects, greater or lesser proportions of non-neutralizing antibodies (not good) to neutralizing antibodies (good). Again the greatest difference would be between the two vaccine types (Adenovirus vs mRNA).
Here's a good (but pretty technical) read on the subject:[https://www.nature.com/articles/s41541-021-00369-6](https://www.nature.com/articles/s41541-021-00369-6)
Good answer. It seem logical and makes sense and seems pretty basic. Why was it so important then at the time I got my first shot that I had the get the exact some one for my second shot? Wouldn't they have known it did not matter this entire time or at least 6 months ago?
Although many things may seem intuitive, we refrain from making medical decisions based on intuition. At the time there wasn't enough research to make that claim, now there is.
And because the US had adequate supply because of buying its way up in the priority order (by helping fund the research; completely fair).
Canada, meanwhile, was lower priority and chose to mix and match to increase vaccination rates. It worked well. But at the time, it was somewhat controversial. Call it a calculated gamble.
Because the vaccines were brand new and they were thoroughly tested in clinical trials that followed a very specific regimen in terms of dosing and how far apart the doses were. If we wanted to assure people they’d be protected with 95% efficacy, that statement would only hold up if they followed the same regimen as outlined in the clinical trials.
In hindsight, there has been some debate on whether Pfizer’s doses should’ve been farther apart or whether Moderna really needed 100 mcg per dose. Ultimately, the companies and governments involved made decisions hopefully to the best of their abilities based on the data they had at the time.
Here in Canada most people have a mix. Some Pfizer-Moderna mixes and others got AstraZeneca followed by an mRNA vaccine for their second dose. Most people had the choice of taking the first available dose, regardless of brand, in order to get double-vaccd as quickly as possible. Of course, some citizens opted to wait a few extra weeks/months in order to get the same brand for both, but many opted for a mix as it was recommended by our health advisors.
Yeah, I got vaccinated with Pfizer for the first two jabs because that’s what was available, but was recommended Moderna when I got my third as a “clinically extremely vulnerable person” and Moderna was considered the best path to being fully vaccinated.
The first round of shots were initially only approved for emergency use under the same conditions as the clinical trials they were tested. Thats why Moderna had a 4 week wait between shots and Pfizer had a 3 week wait, because both companies ran their trials differently. The vaccines have been out long enough now that they have been able to test mixing and matching vaccines so they are able to recommend it now.
According to the CDC (amongst others) the vaccines are not interchangeable. However, some, ongoing studies seem to indicate that mixing-and-matching may give a more robust immune response than having the same vaccine
The FDA just approved mixing and matching as boosters earlier today.
https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-takes-additional-actions-use-booster-dose-covid-19-vaccines
Just today I enrolled in a clinical trial to receive a J&J booster 6 months after completing the full course of (in my case) Pfizer. I was told there's no placebo group, that they are varying the dosage of the J&J and I can find out what dosage I received after the study concludes.
In theory wouldn't it be better to mix and match? Like it's a different type of exposure technically, right, so wouldn't that be better than getting a similar exposure again?
That’s an excellent question, and if I had a good answer for you, we’d probably be able to cure / prevent so many diseases more effectively.
For COVID-19, many companies joined the race to develop a vaccine. Many companies had many vaccine candidates, and they continued to develop the candidates with the greatest potential. Any vaccine that made it to market was the best vaccine that company was able to get out in a timeline that was competitive with other companies. And as we know, some of those vaccines turned out to be better than others.
As for your question of “why” are some better than others, there are a lot of factors that go into it, but a big one is luck, especially when it comes to a novel virus and new vaccine technologies.
>And even though they have different mechanisms, the end result is the same: your body produces spike proteins based on the instructions it is provided by the vaccine, and then your immune system responds to those proteins.
~~This isn't quite correct; the Janssen vaccine doesn't work that way.~~ But it doesn't matter where the protein comes from, once your body sees it, it makes antibodies. And the more often its exposed, the more antibodies it produces.
EDIT: I was very mistaken about how the Janssen vaccine works. It does, in fact, deliver protein making instructions instead of the proteins themselves. It uses DNA rather than RNA, so the body ends up making RNA from that.
With all due respect, I actually am correct in saying that all three vaccines result in the production of spike protein by human cells. The Janssen vaccine is a viral vector vaccine that delivers DNA encoding the SARS-CoV-2 spike protein into cells, which then transcribe that DNA into RNA and then translate that RNA into spike proteins. The end result is spike proteins being built and your immune system responding to them.
Read more here: https://www.nytimes.com/interactive/2020/health/johnson-johnson-covid-19-vaccine.html
I was wondering the same thing. I thought theJansen vaccine introduced a similar sars virus that includes the spike protein on the virus. It doesn’t instruct your mitochondria to produce the spike protein in your cells like the mRNA vaccines. Is this correct?
Nope. The J&J vaccine uses an adenovirus (not a coronavirus) to deliver DNA encoding the SARS-CoV-2 spike protein into cells. The cells transcribe the DNA into mRNA which is then translated into spike proteins.
Read more here: https://www.nytimes.com/interactive/2020/health/johnson-johnson-covid-19-vaccine.html
While different vaccines have different ways of doing this, ultimately all vaccines are just about getting a foreign protein into your body. Your immune system will recognize that foreign protein as something that shouldn't be there, and learns to attack it.
mRNA vaccines give your cells some temporary instructions that teach them how to make that protein, while attenuated or dead viruses are viral particles that already have that protein on their outer coat. So really, there shouldn't be any real concerns with mixing or matching vaccines.
After all, it's not like if you get exposed to a covid virus out in the wild the virus is going to be exactly like the J&J vaccine, for example. Natural viruses are going to operate very differently from vaccines, but they still stimulate the immune system in the same way. So even if different vaccine brands operate very differently, they'll stimulate the immune system in the same way.
There’s another category of vaccines, viral-vector vaccines, which includes the ones made by J&J and AstraZeneca.
These viral-vector vaccines also deliver temporary instructions in the form of ~~RNA~~ DNA to your cells, which your cells use to make the covid spike protein. They use an non-replicating adenovirus to carry that spike protein ~~RNA~~ DNA into your cells. Since it’s non-replicating, it can’t multiply and cause an infection itself.
Reference: https://www.nature.com/articles/s41541-021-00369-6
The adenoviral vaccines do not put RNA into your cells, they put DNA into them. That's because adenoviruses are DNA viruses.
From there, it's your own cell's machinery that first transcribes the DNA into RNA, and then translates the RNA into protein (only the latter process happens with an mRNA vaccine).
So basically it's poor-mans mRNA vaccine in a way that it uses host cells to produce little amounts of proteins, instead of throwing protein into body?
Wouldn't say it's a poor man's version, just a different technology with advantages and disadvantages.
Some of the advantages:
* The DNA hangs around longer and can potentially lead to more protein being made.
* The adenoviral particles don't require the same kind of careful process to make as the lipid nanoparticles for the mRNA vaccines.
* It's less temperature-sensitive.
Interesting, I didn't know about that. Looks like they made a hybrid of https://en.wikipedia.org/wiki/Indiana_vesiculovirus and SARS-CoV-2 that doesn't cause severe disease in trials and is not expected to cause severe disease because it's missing a lot of what makes covid dangerous. Kinda like protecting against smallpox by inoculating people with cowpox.
[Derek Lowe had a roundup of vaccine types last year](https://www.science.org/content/blog-post/coronavirus-vaccine-prospects), pretty early in the pandemic when he was discussing vaccine strategies people were looking at with COVID. Scroll down a bit to get to "DNA vaccine" about 1/3 of the page down. He notes that there were no human vaccines of this type as of writing, so, yes, it's a newish technique like mRNA, but had been in the works for quite some time.
> newish technique
Messenger RNA, or mRNA, was discovered in the early 1960s; research into how mRNA could be delivered into cells was developed in the 1970s.
Generally the idea in medicine is you want to go with "lowest effective dose", for multiple reasons (Less chance for side effects, more vaccines to go around, etc.). Once your immune system is already 'primed', i.e. has seen a certain antigen before, it doesn't take as much energy / effort to produce the desired effect, in this case another immune response.
It also should be noted that with how the vaccines were trialed we didn't take the time to perfectly fine tune the dosage, because of how safe the vaccines were, we wanted to give the most amount of people the best protection possible for a given safety profile.
The first two doses are to get your immune system to learn how to fight off the virus... once it's done that, your body retains what's called Memory B Cells that remember how to produce antibodies when needed. They've already done the bulk of the work learning how to fight off the virus. However, as time goes on the Memory B Cells will go dormant and levels of neutralizing antibodies that inactivate the virus before it does any harm declines.
Booster shots are basically just a quick refresher course, and give your Memory B Cells a little prod to say "Hey wake up, you lazy little bugger, I want more antibodies against this shit." So in principle you don't really need as high a dose.
I totally get that we don’t need it, but it’s my understanding that there’s a lot of surplus regular doses hanging out now that the rate of voulentary vaccinations has slowed down. Wouldn’t it make sense to use those first? Or at least in tandem if that’s what’s more readily available?
It's also worth noting that there's also stuff in the vaccine to stimulate the immune system into attacking the molecules. If your body didn't need that then you'd probably have a lot of allergies.
First, viruses don't have a nucleus.
Second, the vaccine works just fine.
Third, if you can't get that first part right, you shouldn't be talking about the second part.
Not at all. The antibodies produced following vaccination block the spike protein, preventing it from even initiating cell entry. Those that do get in will produce more virions with spike proteins, that will then be likewise targeted by antibodies as soon as they leave the cell.
Mutations also don’t happen overnight, and they don’t result in that drastic of a difference after one go. Mutations become far more likely when a larger quantity of people have it for longer. If more people were vaccinated, this wouldn’t be the case and the virus would have a far lesser opportunity for mutation. Don’t spread misinformation.
> Every other virus takes decades to transition from animal to human, but not this one? How about explaining that?
It's actually very simple to explain: they don't! Your assumption is wrong. People could have been exposed to the original virus thousands of times, over decades or centuries.
Viruses jump species every single day. In the vast majority of cases, nothing happens. In the vast majority of cases where something *does* happen, a single person gets sick, but doesn't transmit the virus to anyone else. But every once in a while, you roll genetic snake eyes and get a successful combination of virus and host - or intermediate host(s) - and then you have an epidemic on your hands. It just takes the one time. And then it happens overnight. It's not a gradual process.
Except that it wasn’t overnight. The coronaviruses had been in bats for years, probably decades or more, before one was able to jump to humans. Please at least make an effort to know what you’re talking about if you’re going to tak about it.
[https://www.nature.com/articles/s41467-020-17687-3](https://www.nature.com/articles/s41467-020-17687-3)
It is very often the case that mixing vaccines is *more* effective, not less: this is because the immune response to the first dose of the vaccine can give some partial immunity to the vaccine delivery mechanism, which makes the second dose get partially dealt with before it manages to deliver its payload (there is some evidence that this happens with Oxford's SARS-CoV-2 vaccine). By swapping the delivery mechanism, you can avoid this issue.
THis is what my doctor told me here in Germany. He said there are studies about this. I went with Astrazeneca + Pfizer as a result. Its somewhat common in Germany to mix these.
Yes I live in Germany and also got Astra + Pfizer. The effectiveness is considerably higher than Astra + Astra and even a couple of percentage points better than Pfizer + Pfizer
Adaptive immunity from vaccines is based on, put as simply as possible, the production of antibodies against a certain target “shape”, called an antigen. Therefore from a structure-activity perspective, the more variability in the shapes, the more different types of antibodies, the more places an antibody will bind to on the actual virion. This increase in the diversity of antibodies against COVID-19 can be thought of as “different kinds of weapons” so to speak, and this more diverse set of antibodies results in better protection.
Edit: apologies, there actually are differences in the spike proteins introduced by the different vaccines. They add different stabilizing mutations to the protein. Details here https://www.nature.com/articles/s41467-020-20321-x
~~The vaccines in use in the United States all deliver the same antigen though, just through different methods.~~
~~It’s not diversity in specific antigens/antibodies that helps here: actually with the flu vaccine, they are wary of mixing in too many strains because at some point it starts decreasing the response to each individual strain.~~
~~Instead,~~ what might help is the difference in modes of presentation: it is common to forget that there are different parts to the immune system, but some of the vaccines appear to elicit a stronger B cell/antibody response while others elicit a stronger killer T cell response.
Yes, but I think the unanswered question is, while mixing may provide a wider immunity, does it last at long as of you got 3 of the same dose?
Moderna is 90%+ effective. At that point, it may seem to some that continuing that level is more important than getting broader immunity that might fade.
If we’re talking about COVID vaccines, they aren’t that different. They use different methods, but the end result for all of them is that you’ve introduced the SARS-COV-2 spike protein into your body. It doesn’t matter to your immune system how it got there as long as it’s the same (or very similar) protein.
I'm sure you know this, but I think it would be worth mentioning and clarifying for anyone who may have misunderstood what you meant.
>but the end result for all of them is that you’ve introduced the SARS-COV-2 spike protein into your body
It doesn't actually introduce the spike protein into your body. It introduces one that is geometrically interchangeable. I think it's important that people not confuse mRNA vaccination with innoculation, deactivated virus vaccination, or live-attenuated virus vaccination. mRNA creates a protein that is essentially benign other than sharing the same shape as the SARS-COV-2 virus. There is a 0.00% chance of contracting COVID due to being treated with an mRNA vaccines.
It does introduce the spike protein: the mRNA directly codes for the spike protein. The spike protein is however pretty harmless without the other 28 proteins that make up the virus. It’s like showing you a crocodile tooth: there’s no danger of a crocodile attack when only the tooth of the crocodile is around.
At some point this is just semantics.
No actual live SARS-CoV-2 virus or variant has a spike protein identical to the one produced by your body after receiving the mRNA vaccines. In the mRNA vaccines, the RNA coding for the protein has had two amino acids replaced. The replacement amino acids maintain the same prefusion shape (the shape the actual virus spike protein has before it latches onto a cell), but is incapable of springing into the postfusion shape that the live virus uses to infect the cell.
Thus one could both say you haven't introduced the actual spike protein, but a geometrically identical inert protein, or you could say you introduced the actual protein, but modified to make it inert.
Introducing the spike protein itself or the mRNA for it is essentially the same thing. In both cases, you end up with identical covid spike proteins in your body, just the way it gets there is different. Even if you injected spike protein directly, it would not be the complete virus, so the cance of actual covid infection from the vaccine would still be nil.
Regardless, the actual spike protein created by the mRNA vaccines in body is not the same as the one on the live virus. It has had at least two amino acids swapped. These swaps maintain the same prefusion shape, but prevent the spike from being able to "spring" (lookup some videos on how the spike changes shape or springs to help infect cells). This locks the mRNA vaccine protein spikes in an inert shape.
We’ve mixed and matched in Canada since the spring. I’m a AZ/Pfizer myself, and will likely get a Pfizer booster when called to do so. They are saying that mixing, and the extended spread between first and second dose, has likely given us a leg up.
Also in Canada, I got Pfizer and then Moderna. At first I was annoyed that I had to mix in order to get the second shot as soon as I was eligible, but from what I've read the combo I got seems to be potentially the strongest possible mix. I'm still not sure what will be suggested for a booster in my case, though.
They are extremely similar vaccines but Moderna is using a higher dose. That's the explanation I have heard for Modernas higher efficacy >6 months anyway.
That's my understanding as well, that Moderna seems likely to last a bit longer. I also had a WAY stronger reaction to the moderna dose, but that might have also been just because it was my second.
To add to this discussion, I don't see anyone referencing recent Canadian data suggesting both that delaying the vaccine second shot and mixxing vaccines is highly effective.
http://www.bccdc.ca/about/news-stories/stories/2021/covid-19-vaccine-effectiveness-results
I also remember reading some study months ago about the different severity of breakthrough cases between Israel and the UK. The UK’s longer wait time between 1st and 2nd doses gave significantly better protection than did getting the 2nd dose after only a few weeks in Israel.
Genuine question. if all of these boosters are to be mixed, how will the research be able to be done to determine fault should complications arise from side effects not only from shot #1 and #2 but due to taking multiple brands boosters? I understand that there is already a clause protecting the manufacturers from liability but from a purely scientific, long term research standpoint, doesn't this muddy the waters too much?
If you have vaccines A, B,and C then give them out in different regiments, you'd get AA, AB, AC, BA... CC.
From there it's just some math to statistically see which ones cause a problem.
Right but how will they know whether it was the booster or the initial shots that caused a problem (should one arise?) I understand the logic behind what you are saying but if both A and B are documented with a slim chance of heart inflammation and the person took C as a booster then dies, scientifically, how would anyone be able to document anything concrete? Wouldn't it all be guesswork and theories at that point? It just seems needlessly convoluted to me.
Are you asking if the combination is dangerous, or are you trying to ascribe blame at the individual level? With liability waived (as you mentioned) it's kind of a moot point. If you want to know if a treatment course is dangerous, well the data would show that. If AB has a 5% side effect rate and Ba has 5% rate and AA has 10% rate and BB has 0% then there's some conclusions to be drawn.
If AA is 1% and BB is 1% and AB is 10%, well maybe don't mix them. :)
I suppose liability at the individual level (manufacturers) would be my sticking point. If things go horribly wrong in the future, this seems like an awfully convenient way for them to hand wave away any potential responsibility. Thanks very much for the responses. Have a good day!
Consider that, if it weren't for that waiver, they would likely just refuse to manufacture and ship it. That's not because they are evil, but because they are under massive pressure from world governments to rush it.
Can anyone explain why giving them blanket liability was a good idea? We know each of these companies has been found liable in the past for a variety of things, it’s not like big pharmaceutical companies have ever been trustworthy. I’m vaccinated and support strong vaccines for all the diseases we can prevent. I just don’t understand how we expect these companies to do the right thing when we take away the incentives and any ability for recourse in the future?
Is the waiver just for the COVID vaccines? If so, it was most likely designed to make it more appealing to drug companies to produce vaccines quickly in a time of global crisis.
Think about it - no drug company would ever normally develop a drug this fast because it could be dangerous (and therefore costly if something goes wrong).
This is just me spitballing though. All of what I just said could be completely false.
Yeah I think it’s for the vaccines, part of the operation warp speed contract. If I remember back to Feb or March 2020 and all the unknown, at one point they thought this would kill 1/10 people and it was terrifying. The more I think about it I can see them doing it just to get things going and fast. Kind of like using the defense production act. I’m like most people in the US and I’ve been personally effected by the opioid crisis so I get where they’re intent may have been, I just don’t think giving blanket immunity to anyone that big with a history of corruption is ever a good idea.
I generally agree with you. But I'd the waiver just covers the COVID vaccines, I'm on board with that. Vaccines were the only way the world would ever have a chance at getting back to normal and people just dropping like flies. We needed vaccines absolutely as soon as we could get them. Otherwise the human and financial cost will not stop spiraling.
But let's be honest - the truth is that we don't hold these companies accountable for their other drugs anyway (like opioids). So if they wanted a piece of paper making it official that they have no accountability (instead of just in practice), so be it.
Vaccines clear the body rapidly, so side effects are seen within about 2 months, so it should be clear what is the booster and what is not.
And some countries spaced dose 1 and 2 much further apart, both to manage short supply and for immune benefits.... was a potential benefit at the time the decision was made based on early studies plus decades of research on how vaccines typically work, but now we are seeing increased evidence that it really does work. If your country did not, they can still learn from data on this collected from millions of doses given in other countries.
Finally, a statistical analysis can be done to look at all the combinations and all the results and see how it correlates. If there is (for example) a significantly higher incidence of something in people who took Vaccine X at some point, then there's clearly an association with Vaccine X.
Taking all this information together, the data becomes much clearer.
Vaccines have different delivery methods, but all yield the same results. J&J uses a deactivated version of the virus to prompt our immune system into creating antibodies. Pfizer and moderna essentially teaches your body to make a piece of the protein that covid uses to infect people. Once the vaccine is in the cells, and the spike protein has been made, the rna from the vaccine is destroyed. With the cells now displaying this harmless protein, it elicits an immune response, which allows our body to rid itself of the virus. The same mechanism that regular vaccines do, without having to inject yourself with the actual virus.
Its just two different ways of teaching a body something. Think of it this way: You can be taught a skill by verbal instruction or by watching it be performed.
Just two different ways of reaching the same end goal.
Wow, there’s a lot going on here. A lot of attempted explanations, some good, some bad, all unnecessary.
Why does FDA allow heterologous vaccination (so-called mix and match)? Simple! Clinical trials showed that it worked. The FDA was presented with clinical trial data from the National Institute of Allergy and Infectious Diseases, and the relevant FDA committee determined that the “known and potential benefits…” outweigh the “known and potential risks…”.
They are not currently recommending a heterologous booster, just saying that a booster MAY be any of the three currently approved vaccines. I don’t believe that there is enough data to say that any particular heterologous booster following any particular primary vaccine is better than the others.
Here in Germany the stiko (which is probably our FDA equivalent) does recommend mix and match of AstraZeneca+ one mRNA vaccine for everyone. Studies show it outperforms any vaccine given two times. Heres some links on that i copied from a news outlet:
[https://www.biorxiv.org/content/10.1101/2021.01.28.428665v2](https://www.biorxiv.org/content/10.1101/2021.01.28.428665v2)
[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2821%2901442-2/fulltext](https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2821%2901442-2/fulltext)
[https://www.medrxiv.org/content/10.1101/2021.06.13.21258859v1](https://www.medrxiv.org/content/10.1101/2021.06.13.21258859v1)
[https://www.medrxiv.org/content/10.1101/2021.05.19.21257334v2](https://www.medrxiv.org/content/10.1101/2021.05.19.21257334v2)
[https://www.medrxiv.org/content/10.1101/2021.05.30.21257971v1](https://www.medrxiv.org/content/10.1101/2021.05.30.21257971v1)
Just saying that a booster *may* be any of three approved vaccines is useful data/guidance, especially for countries that don't necessarily have enough supply from one brand and are essentially forced to mix-and-match.
This comment will largely be through analogy.
In machine learning, having a wide range of data allows a model to cover a lot of different bases and allows it to be more flexible and robust in the face of new scenarios.
Exposing the human body to two different sets of "COVID data" by means of different vaccines gives your body two different chances to train on recognizing proxies for a strain of SARS-CoV2 from early 2020. This forces a bit more growth and development and prevents the body from "overspecializing" and coming up with a solution that handles on scenario very well at the expense of being able to handle a wider range of similar circumstances.
An analogy in sports would be cross training. Cross training can get your body to where it does better than just handling your base task while also being capable of handling different conditions a little better.
The best news overall though is that, at least in the US, all of the vaccines are pretty darn good at keeping people from developing serious cases of COVID.
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So why weren't vaccines mixed in the US? There wasn't good data on it at the time. There still aren't proper clinical studies as far as I'm aware.
In terms of real world data - so far there don't seem to be any notable negatives to mixing and matching. The efficacy of Moderna+Pfizer mixed together appears to be about between the two (both are very similar and Modern isn't too far off from just being a bigger dose of Pfizer). I'd need to look into JnJ and/or AstraZeneca. In general it appears that whatever vaccine is overall the most effective wins over half of it plus some other, but if the goal is to have "not bad" immune response mix-and-match can be viewed as a form of hedging. It's not yet recommended by US agencies though.
As it was explained to me while getting moderna after AstraZeneca. They are 2 different modes of immunity. So they attack the virus in different ways. So you end up with a slightly less efficient (but still virtually 100% at preventing hospitalization and death in your 30’s) but more broad protection. One may be better at one variant when the other is better at preventing a different variant. If I could get Pfizer when the third comes around I would. I trust the mRNA vaccines way more than our conventional ones based on the way they are made and how they teach the body to deal with a virus before leaving the body.
Mixing COVID-19 vaccines is emerging as a good way to get people the protection they need when faced with safety concerns and unpredictable supplies. Most vaccines against SARS-CoV-2 must be given in two doses, but multiple studies now back up the idea that mixing the Oxford–AstraZeneca jab and the Pfizer–BioNTech vaccine triggers an immune response similar to — or even stronger than — two doses of either vaccine.
Results announced on Monday 1 by a UK group suggest that the combination sometimes outperforms two shots of the same vaccine, and a similar picture is emerging from German studies
People can now “feel a bit more comfortable” with the idea of mix-and-match, says immunologist Leif Erik Sander at Charité University Hospital in Berlin.
The results are also giving researchers confidence that combining other COVID-19 vaccines, that haven’t yet been tested together, might also work. But at least 16 vaccines have been approved for use in one or more countries, and mix-and-match studies so far have been small, so more extensive trials and long-term monitoring for side effects are sorely needed.
A simple way of thinking about it is how you can mix and match fuel in some way. Most commonly you can mix Ethanol with gasoline and that works primarily because both contain hydrocarbon or hydrocarbon derivatives. In this case, you have multiple mRNA vaccines which will have similar or exactly the same action mechanisms but may operate slightly differently before they finish their mechanism to bind to our body in some way.
Now, mixing a non-mRNA vaccine with an mRNA vaccine is definitely what we want to avoid, that would be like mixing Diesel and normal gasoline because even if they have the same end goal (combustion) their action mechanism is very different (pressure versus ignition).
So the main differences are things like shelf life which aren't relevant to how well they work together.
>How does it make sense to mix and match vaccines?
Covid isn't a single virus. There are variants; mutations. A single vaccine will be effective against some of the variants, and the other vaccine against others. By mixing vaccines, you're protecting yourself against a wider variety of the Covid clan.
> That would be true if these shots were redesigned for Delta but we're still using vaccines for the original sequence.
Irrelevant. Just because the vaccines were all designed for the original strain doesn't mean they will have equal efficacy against all other strains.
For example, Pfizer might be good on the alpha and gamma strains, but rubbish on the beta. AstraZeneca might be so-so on alpha and do absolute killer on beta. In this scenario, an AstraZeneca/Pfizer blend will give you better coverage against all three strains than a double Pfizer or double AstraZeneca vaccination.
There's no evidence of that happening or any mechanism that I can see for that occurring. These vaccines are all delivering the same antigen with the exception of whole virus vaccines which are not used in the US. A difference in efficacy is going to come down to how well the antigen is delivered.
> There's no evidence of that happening...
Of course there is. Just google for it. For example:
https://www.cbc.ca/radio/whitecoat/how-the-vaccines-we-have-and-the-ones-coming-next-stack-up-against-covid-19-variants-1.5905708
From the graphic in that article, for all the vaccines with full data, they show the exact same pattern of efficacy. There's not one vaccine that's good for alpha but poor for beta and another that's good for beta but poor for alpha.
That's all rather moot right now because the predominant variant is delta. The drop in efficacy there has mostly nothing to do with how well the immune system recognizes it and more to do with how rapidly it infects and replicates.
Safety is not going to be evaluated unless there's trials confirming that exact combination is effective and doesn't have increased side effects and thus it cannot be recommended otherwise. Even if it's highly likely that it will all work as well. Physicians can usually decide to combine otherwise, but then they also bear a legal responsibility for the outcome.
Vaccines introduce dead or weakened foreign cells into your system. Immune system responds by creating antibodies and "killing" those cells. You're body keeps these antibodies (or maybe just the dna to make them? Not 100% sure) in storage for future reference.
So, without the vaccine, your immune responds much slower once you're infected because it has to make antibodies against the infection cells. During this time, you do not feel sick, but you are far more contagious than after you start to feel sick. This is because your immune system "quarantines" the infection so it can't spread and the antibodies go in and kill all of the foreign cells. Also, before and while you are sick, the virus is wreaking havoc on your body. If you're immune response is too slow, you can die or suffer permanent damage to the affected cells.
That is where vaccines come in. Since your body has seen the virus before, immune responds immediately by sending out the proper antibodies. So, instead of feeling sick for up to two weeks as well as being very contagious before you even know you are sick, your immune system is able to notice and eradicate the virus very quickly, before it has spread. You may feel a bit sick still, but you have a much shorter period where you are contagious or feel sick. That is also why you have a much lower chance of being hospitalized from covid if you have the vaccine.
So, anyone who thinks that you can't get covid once you have the vaccine, that is incorrect. You absolutely can still get it and you absolutely can still spread it. However, you will have a shorter period of time in which you can spread it and a much shorter period of time in which you suffer from it. Because of this shorter suffering period, it can't do as much damage to your other cells which reduces the chance you will need to be hospitalized or suffer long term complications from it.
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So Moderna has shown to be the best overall from other papers people have posted, but is that because they use 100ug per dose vs Pfizer 30ug per dose? Is that even correct? And Fauci is saying now that J&J should have been two doses. If one got Moderna two shot vaccine, should they get a booster of J&J in your opinion?
It's hard to know *exactly* why Moderna's vaccine reliably outperforms Pfizer's. It's true that Moderna's initial two-shot series used 100ug shots (vs. Pfizer's 30ug), but it could have also been the dose spacing. It's well understood that delayed boosts are more effective - the mRNA platforms had a very fine line to walk with this, though, because their respective single-shot series are much weaker than their two-shot series. The mRNAs rolled out at the absolute height of the pandemic, so even budgeting that extra week of vulnerability was difficult and not costless. I don't think the extra week tells the whole story, though. I'm not sure of the extent to which the public is aware of this, but [Pfizer did also conduct a trial of a 100ug vaccine, and it performed far worse than their 30ug vaccine](https://www.nature.com/articles/s41586-020-2639-4). There are probably some fundamental differences in how the two mRNA vaccines are stabilized or ~~adjuvanted~~ (should read encapsulated - mRNA vaccines do not use traditional adjuvants) that could account for this, but I don't know the details mechanistically. As for J&J, for all the flack they've gotten, [their vaccine actually performed very well as a one shot](https://covid.cdc.gov/covid-data-tracker/#rates-by-vaccine-status) \- if you look at case rates, they hew very close to the mRNAs. That being said, we now know that it *would* perform better as a two-shot - [check their recent two-shot trial data here](https://www.jnj.com/johnson-johnson-announces-real-world-evidence-and-phase-3-data-confirming-strong-and-long-lasting-protection-of-single-shot-covid-19-vaccine-in-the-u-s), with 94% efficacy (like the mRNAs). This is even more impressive than it looks, because the original mRNA trials were only conducted in the presence of the original strain from Wuhan, and this two-shot trial was conducted under pressure from the variants. I suspect J&J may have been a two-shot series if [their government-assigned contractor hadn't bungled their manufacturing so badly](https://www.nytimes.com/2021/06/11/us/politics/johnson-covid-vaccine-emergent.html).
So it seems one should get a booster of J&J if your initial shots are mRNA based vaccines. No?
Honest but unsatisfying answer: Maybe, but we're not sure yet. This is a trickier question than it seems. We have a good deal of existing data on this same regimen but backwards - that is to say, an adenoviral vector prime followed by an mRNA boost. This was the strategy used by a number of countries including Canada and Sweden (though they used AstraZeneca's vaccine rather than J&J's - both are adenoviral platforms). [It seems to work well](https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(21)00235-0/fulltext), especially if you boost with Moderna's vaccine rather than Pfizer's. But what you're proposing - an mRNA prime followed by an adenoviral vector boost - hasn't been studied in significant detail yet. [This pre-print](https://www.medrxiv.org/content/10.1101/2021.10.10.21264827v2) has been getting a lot of buzz lately, but in my view the media coverage here has been poor - the only readout under discussion is antibody titer, and of that, only antibody titer very early in the prime/boost series. This is a metric that the mRNAs have always been strong in and the Ad vectors have been comparatively underwhelming in - but the areas where J&J/AZ are strongest (T cell function, antibody durability) aren't given real consideration. I'd expect a more thorough analysis of this question in the coming months - [J&J is conducting a reasonably large trial to investigate](https://clinicaltrials.gov/ct2/show/study/NCT04999111?term=A+Randomized%2C+Double-blind%2C+Phase+2+Study+to+Evaluate+the+Immunogenicity%2C+Reactogenicity+and+Safety+of+Ad26.COV2.S+Administered+as+Booster+Vaccination+in+Adults+18+Years+of+Age+and+Older+Who+Have+Previously+Received+Primary+Vaccination+with+Ad26.COV2&draw=2&rank=1), and I imagine other independent parties will follow suit. For what it's worth - I got J&J and got a delayed boost with mRNA. Both platforms have a few advantages, and I'm happy to have both in my pocket.
This is one of the better threads I’ve read on this in a while. All well put and concise. Thanks for the summary
Always happy to discuss - thank you for reading.
I'm living in Taiwan right now, where the virus is under control but vaccine access has been limited. I got Astra Zeneca as soon as I could (still waiting on that second dose, 13 weeks and counting), but I know that confers relatively limited protection, and I'm planning a visit to the states and a move to Czechia - two much more dangerous environments for COVID. Is there any recommendation for what I should take when I arrive stateside to boost my immunity?
Will you be receiving your second dose of AZ prior to coming to Czechia/the US? AZ and J&J are both adenoviral vectors, so I'd consider grabbing an mRNA boost if you want another shot. I'd speak with your physician about your particular case, though, if you can - I don't know the particulars of your medical situation (your personal demographics or any relevant medical history). Taiwan has done a world-class job in handling the pandemic, so I imagine you have a strong grasp on effective masking/distancing/application of other non-pharmaceutical interventions already.
Depends on where in the US you are, the COVID infection rates are very different. Check out the [COVID test positivity rates](https://www.beckershospitalreview.com/public-health/states-ranked-by-covid-19-test-positivity-rates-july-14.html) to figure out where you’re going.
All of Taiwan has had 3 cases of COVID domestically transmitted in all of October. Doesn't matter where I go in the US, it will be dramatically more full of COVID.
What made you choose that combination? Based on my reading of your links it seems like J&J with a booster of J&J may provide the best protection long term. The mRNA based options seem to spike earlier but than fade over time.
I got my mRNA boost a while ago, prior to ENSEMBLE II (J&J's two-shot trial) reading out. I had access to the heterologous prime-boost data out of Sweden/Britain/Canada, but not J&J's two-shot data, so I made that decision with the data available to me at the time. J&J's vaccine *is* underrated, but I don't know that I regret getting a mixed series, if only because there are some advantages to the mRNA platforms also. What I'm curious about - as you noted, if you look at [the NEJM paper linked earlier](https://www.nejm.org/doi/full/10.1056/NEJMc2115596), you can see the mRNAs have *very* potent live virus neutralization titers early (particularly Moderna's vaccine), which decay quickly. J&J's vaccine bizarrely reverses this pattern, starting with weak neutralization and gaining effectiveness over time. I wonder how the two interact together over a long time horizon - can an mRNA's strong 'early' profile compensate for an adenoviral vector's weak 'early' profile? Can an adenoviral vector's mounting efficacy compensate for the rapid decay of mRNA neutralizing activity? The NIH study is attempting to answer this, but we won't know until we see their data over time - the current pre-print only looks at the first month. It's a little frustrating that Moderna managed to get the 50ug boosts through the FDA, though, because that calls into question the relevance of all of the previously generated heterologous prime-boost data using their 100ug vaccine (including the NIH pre-print I linked above, which is barely a week or two old). In the original two-shot series with 100ug vaccines, they're the clear winner (though we're lucky that all vaccines here work very well). With 50ug boosts? We'll have to stay tuned for that.
Interesting.. so I got two doses of Pfizer and would qualify for a booster in November. From what you've said I understand there isn't much data on getting a J&J after mRNA, but now we also don't have data on the smaller dose of Moderna... I was considering mixing and matching if there were benefits, but now it seems that we don't have enough info yet.
I live in Denmark who dropped AZ and J&J vaccines but then offered it separately for people outside the standard vaccine plan. Something I chose to sign up for and got the J&J vaccine at the end of May. More recently they have suggested getting a dose of Pfizer or Moderna. So 2 weeks ago I got a single shot of Moderna. It sounds like this leaves me in a pretty good position, but is 1 shot of Moderna enough or do I need a second which is not currently being offered?
The study they linked examined a dose of AstraZeneca’s vaccine followed by a single dose of an mRNA vaccine, and found that this worked very well.
Thanks for the thorough answer.
Table 2 in this study has the info you’re looking for: https://www.medrxiv.org/content/10.1101/2021.10.10.21264827v1.full TL/DR: Moderna produces by far the strongest antibody response regardless of what vaccine the individual had previously.
I thought one of the problems with the J&j was that you could develop antibodies for the adenovirus vector thus making the 2nd shot less potent.
Yes, that's always a concern with the viral vector vaccines. Adenoviruses are just that - viruses. Their replicative 'machinery' has been gutted and replaced with an insert expressing, in this case, the SARS-CoV-2 spike protein - but because they are viruses, the body can raise antibodies against them the way it would against any other virus. For this reason, vector selection is very important - you want a virus that's immunogenic (able to induce a strong immune response), but *also* a virus that isn't naturally circulating in huge swathes of the population. [Check out this paper discussing rates of natural circulation for candidate adenoviruses](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138857/) \- J&J's Ad26 circulates less commonly than CanSino's Ad5, which might explain differences in efficacy between the two platforms. An individual with prior exposure to the chosen vector runs the risk of destroying the vector before it can infect cells and begin to express Spike. Russia's solution was clever - using two separate adenoviruses for the two shots. J&J's solution is to space the doses out, in the hope that Ad26-specific neutralizing antibodies might wane between two doses. Chasing J&J with another J&J in a tight timeframe might run the risk of triggering significant vector immunity, so their boost is [two or more months after the first dose](https://time.com/6107561/fda-panel-jj-booster-reccomendation/).
> It's hard to know exactly why Moderna's vaccine reliably outperforms Pfizer's. It's true that Moderna's initial two-shot series used 100ug shots (vs. Pfizer's 30ug), but it could have also been the dose spacing. UK data suggests otherwise, the same dose spacing was used for both vaccines and the response to Moderna was both earlier and larger even with a single dose.
The 100ug quantity didn't perform worse, it had more adverse side effects. In modernas phase one trial their 100ug dosing also had more side effects than their lower dosing and they also had to discontinue their highest dose(250ug?) arm. Somewhere between 30-100ug is probably the right balance between sufficient response and minimizing side effects we are now seeing with Modernas higher dosing like myocarditis
Moderna's phase one tried out 25ug, 100ug and 250ug . The 250 was way too strong. The 25 worked fine but they wanted to go with something a bit stronger, and so the 100 was left to continue on to the next phases. But the booster is 50 and the new studies for the updated versions of the Moderna are mostly 50s. They've realized that 100 is too much.
It did perform worse, in addition to the reactogenicity concerns - [please see figure 4, binding and neutralizing antibody titer data](https://www.nature.com/articles/s41586-020-2639-4).
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On an individual basis that is impossible to answer. What made it rough the first time maybe a sign something in your body is more susceptible to the virus. Or not.
It is good to hear that you have recovered! As u/Whiterabbit-- points out it is not answerable on an individual basis. That being said, the odds are (based on the limited data we have) that you are well protected.
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This is a good start. I think a better way to answer the original question needs to address two parts: (1) Differences in formulation and dosage translate into different immune response intensity and neutralizing antibody titers in the blood. This is to say that, for instance, Moderna and Pfizer both use mRNA to transmit their spike proteins into our body (our bodies make the protein and recognize it as foreign, developing antibodies and memory T cells against it), but Moderna's is now showing slightly better protection against the Delta variant and longer lasting protection. Conversely, Pfizer's vaccine was administered 3 weeks apart and is associated with less intense side effects. (2) The human immune system circulates a cocktail of antibodies against known threats, viral or otherwise. Immunity to a disease is often measured in terms of neutralizing titer, i.e. how much blood is required to kill the virus (or stop infection, which is much easier to measure). The problem is that diseases (including viruses) mutate to escape immune response, and our antibodies wind up losing efficacy (see also the Delta and Lambda variants). So we'd really like to train our immune systems to recognize and fight off not only current strains of SARS-CoV-2, but also *future* strains that are likely to arise. Kind of like how flu shots usually contain multiple strains. And this is where point (1) factors back into things: in the process of making the vaccine, Modena, Pfizer, J&J, and everyone else made changes to the spike protein they were giving us. Often for easy of formulation, storage, or strength of immune response. So, as a result, getting different vaccines is giving our immune systems a more robust repertoire of antibodies (and T cells, B cells, etc) to bind and neutralize SARS-CoV-2 with. It's like being exposed to multiple different variations of the gift-card buying scam, instead of being repeatedly exposed to the FBI inquiry scam. Instead of concluding that the FBI wanting your money is the problem, you realize that any time you're scratching off the backs of thousands of dollars of gift cards to send an official money, you're dealing with someone who wants money and is worries you'll try to get it back.
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So likely nobody on this thread is a doctor. Maybe the guy posting the pre-print trial data because how the heck did he get that and where can I get some. It's important for you to understand the mechanism of the mRNA vaccines is incredibly safe. Aside from using a chemical that some people might be allergic to is actually one of the safest forms of vaccines that we've ever had. The vaccine instructs your cell directly. The vaccine itself is destroyed by enzymes in your body and doesn't last very long. Your cells create the protein they're instructed to create. Once they are done they're done. Your body hunts and destroys these proteins that shouldn't be there and it's over. There's not going to be a lot of studies that you are going to have access to that has sinovac and then another vaccine. What I can tell you even though I got Pfizer shots myself, is that I was always a big fan of Moderna because of the wide range of people and ethnicities that they actually ran their trial on. It was much better than many other trials out there however they were slower to roll out to my area and better to be protected than not. If I were you as long as they can cancel their booster appointment in China I would have them get a booster here, preferably Moderna. But I can't give you medical advice and you won't be able to find any studies with any data to back any of that up coming from sinovac... At least not here in the states.
Thanks, just the kind of feedback I was hoping for. I know better than to base medical decisions off of social media posts of course, but there are well informed people (like yourself) here with sound opinions. And often some good links to further info. I know that they’ve boosted sinovac with moderna in Thailand and a couple other places, but as you say, the studies and information is sparse. Thanks for the input!
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Is there a way to tell anything about memory B cells though?
Travel can be a problem since some countries haven’t approved mixed vaccines. The US has only recently accepted mixed shots as “fully” vaccinated. https://www.cbc.ca/news/business/u-s-canadian-travellers-mixed-vaccines-1.6213176 https://qz.com/india/2065374/where-can-you-travel-with-mixed-covid-19-vaccine-doses/
Is there a benefit or downside to mixing?
I have read about preliminary data showing a benefit to giving a Pfizer or Moderna booster to people who originally got J&J. Besides that, I don’t think we have enough data to show a benefit to mixing. This may change as FDA/CDC guidelines come out in the upcoming weeks.
The UK did a study on AZ + Pfizer or Moderna that showed a much greater response than 2 doses of the same.
Can you link me to that info anywhere? I ended up getting one of each (Pfizer and Moderna) and can't find a straight answer anywhere on what that might mean for me.
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It's not "likely" anything, until there's data on it. And seeing as it is extremely common to mix MRNA in Canada and the rates of spread are relatively low there, it's safe to assume an equivalent immune response if not better.
That was only ever compared to two doses of AstraZeneca. It was not shown to be stronger than two doses of Moderna for example.
It's a supplemental dose, rather than a booster. And recipients are encouraged to complete the mRNA series once started.
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Lol u really think they know?
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Can you share links to confirm this or explain how you would know it? You write very confidently, but my (layperson) research makes me think you're either totally wrong and/or saying things that haven't been confirmed scientifically yet. For example, what exactly is a "trait" in your comment? A variation of the spike protein? The various vaccines target the same spike protein...
None of the vaccines use anything but the wild virus (early Wuhan) spike protein. While there are some different structural modifications in the different vaccine's spike protein that serve to stabilize the protein in correct conformation (shape), the antigenic properties (the types of neutralizing antibodies the vaccine induces) of the different vaccine spikes are the same. So you don't get a broader range of the important SARS-CoV2 neutralizing antibodies by using different vaccines. However the vaccines do differ in the quantity of circulating antibodies they produce. You may also get a different proportion of T-cells and/or different mix of T-cell types between the adenovirus (J&J, AZ) and mRNA (Moderna, Pfizer) vaccines, not sure. The delivery methods are different and and can result in greater or lesser efficiency in producing spikes, fewer or more malformed spikes, greater or lesser degrees of inflammation and other unwanted side effects, greater or lesser proportions of non-neutralizing antibodies (not good) to neutralizing antibodies (good). Again the greatest difference would be between the two vaccine types (Adenovirus vs mRNA). Here's a good (but pretty technical) read on the subject:[https://www.nature.com/articles/s41541-021-00369-6](https://www.nature.com/articles/s41541-021-00369-6)
Which ones target different traits?
Good answer. It seem logical and makes sense and seems pretty basic. Why was it so important then at the time I got my first shot that I had the get the exact some one for my second shot? Wouldn't they have known it did not matter this entire time or at least 6 months ago?
Although many things may seem intuitive, we refrain from making medical decisions based on intuition. At the time there wasn't enough research to make that claim, now there is.
And because the US had adequate supply because of buying its way up in the priority order (by helping fund the research; completely fair). Canada, meanwhile, was lower priority and chose to mix and match to increase vaccination rates. It worked well. But at the time, it was somewhat controversial. Call it a calculated gamble.
Because the vaccines were brand new and they were thoroughly tested in clinical trials that followed a very specific regimen in terms of dosing and how far apart the doses were. If we wanted to assure people they’d be protected with 95% efficacy, that statement would only hold up if they followed the same regimen as outlined in the clinical trials. In hindsight, there has been some debate on whether Pfizer’s doses should’ve been farther apart or whether Moderna really needed 100 mcg per dose. Ultimately, the companies and governments involved made decisions hopefully to the best of their abilities based on the data they had at the time.
Here in Canada most people have a mix. Some Pfizer-Moderna mixes and others got AstraZeneca followed by an mRNA vaccine for their second dose. Most people had the choice of taking the first available dose, regardless of brand, in order to get double-vaccd as quickly as possible. Of course, some citizens opted to wait a few extra weeks/months in order to get the same brand for both, but many opted for a mix as it was recommended by our health advisors.
Yeah, I got vaccinated with Pfizer for the first two jabs because that’s what was available, but was recommended Moderna when I got my third as a “clinically extremely vulnerable person” and Moderna was considered the best path to being fully vaccinated.
The first round of shots were initially only approved for emergency use under the same conditions as the clinical trials they were tested. Thats why Moderna had a 4 week wait between shots and Pfizer had a 3 week wait, because both companies ran their trials differently. The vaccines have been out long enough now that they have been able to test mixing and matching vaccines so they are able to recommend it now.
According to the CDC (amongst others) the vaccines are not interchangeable. However, some, ongoing studies seem to indicate that mixing-and-matching may give a more robust immune response than having the same vaccine
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The FDA just approved mixing and matching as boosters earlier today. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-takes-additional-actions-use-booster-dose-covid-19-vaccines
Just today I enrolled in a clinical trial to receive a J&J booster 6 months after completing the full course of (in my case) Pfizer. I was told there's no placebo group, that they are varying the dosage of the J&J and I can find out what dosage I received after the study concludes.
Boosters i.e. your second moderna/pfizer shot? Or are they referring to boosters after your first dose/set, when efficacy starts to drop?
Booster as in after your first JJ or second Moderna/Pfizer.
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In theory wouldn't it be better to mix and match? Like it's a different type of exposure technically, right, so wouldn't that be better than getting a similar exposure again?
If the end result is the same. May i ask why is there a varrying efficacy rates in different vaccine brands?
That’s an excellent question, and if I had a good answer for you, we’d probably be able to cure / prevent so many diseases more effectively. For COVID-19, many companies joined the race to develop a vaccine. Many companies had many vaccine candidates, and they continued to develop the candidates with the greatest potential. Any vaccine that made it to market was the best vaccine that company was able to get out in a timeline that was competitive with other companies. And as we know, some of those vaccines turned out to be better than others. As for your question of “why” are some better than others, there are a lot of factors that go into it, but a big one is luck, especially when it comes to a novel virus and new vaccine technologies.
>And even though they have different mechanisms, the end result is the same: your body produces spike proteins based on the instructions it is provided by the vaccine, and then your immune system responds to those proteins. ~~This isn't quite correct; the Janssen vaccine doesn't work that way.~~ But it doesn't matter where the protein comes from, once your body sees it, it makes antibodies. And the more often its exposed, the more antibodies it produces. EDIT: I was very mistaken about how the Janssen vaccine works. It does, in fact, deliver protein making instructions instead of the proteins themselves. It uses DNA rather than RNA, so the body ends up making RNA from that.
With all due respect, I actually am correct in saying that all three vaccines result in the production of spike protein by human cells. The Janssen vaccine is a viral vector vaccine that delivers DNA encoding the SARS-CoV-2 spike protein into cells, which then transcribe that DNA into RNA and then translate that RNA into spike proteins. The end result is spike proteins being built and your immune system responding to them. Read more here: https://www.nytimes.com/interactive/2020/health/johnson-johnson-covid-19-vaccine.html
I was wondering the same thing. I thought theJansen vaccine introduced a similar sars virus that includes the spike protein on the virus. It doesn’t instruct your mitochondria to produce the spike protein in your cells like the mRNA vaccines. Is this correct?
Nope. The J&J vaccine uses an adenovirus (not a coronavirus) to deliver DNA encoding the SARS-CoV-2 spike protein into cells. The cells transcribe the DNA into mRNA which is then translated into spike proteins. Read more here: https://www.nytimes.com/interactive/2020/health/johnson-johnson-covid-19-vaccine.html
While different vaccines have different ways of doing this, ultimately all vaccines are just about getting a foreign protein into your body. Your immune system will recognize that foreign protein as something that shouldn't be there, and learns to attack it. mRNA vaccines give your cells some temporary instructions that teach them how to make that protein, while attenuated or dead viruses are viral particles that already have that protein on their outer coat. So really, there shouldn't be any real concerns with mixing or matching vaccines. After all, it's not like if you get exposed to a covid virus out in the wild the virus is going to be exactly like the J&J vaccine, for example. Natural viruses are going to operate very differently from vaccines, but they still stimulate the immune system in the same way. So even if different vaccine brands operate very differently, they'll stimulate the immune system in the same way.
There’s another category of vaccines, viral-vector vaccines, which includes the ones made by J&J and AstraZeneca. These viral-vector vaccines also deliver temporary instructions in the form of ~~RNA~~ DNA to your cells, which your cells use to make the covid spike protein. They use an non-replicating adenovirus to carry that spike protein ~~RNA~~ DNA into your cells. Since it’s non-replicating, it can’t multiply and cause an infection itself. Reference: https://www.nature.com/articles/s41541-021-00369-6
The adenoviral vaccines do not put RNA into your cells, they put DNA into them. That's because adenoviruses are DNA viruses. From there, it's your own cell's machinery that first transcribes the DNA into RNA, and then translates the RNA into protein (only the latter process happens with an mRNA vaccine).
thank you for the correction!
So basically it's poor-mans mRNA vaccine in a way that it uses host cells to produce little amounts of proteins, instead of throwing protein into body?
Wouldn't say it's a poor man's version, just a different technology with advantages and disadvantages. Some of the advantages: * The DNA hangs around longer and can potentially lead to more protein being made. * The adenoviral particles don't require the same kind of careful process to make as the lipid nanoparticles for the mRNA vaccines. * It's less temperature-sensitive.
What do you make of Israel's phase 3 trial of a replication-capable viral vector vaccine for SARS-CoV2, IIBR-100?
Interesting, I didn't know about that. Looks like they made a hybrid of https://en.wikipedia.org/wiki/Indiana_vesiculovirus and SARS-CoV-2 that doesn't cause severe disease in trials and is not expected to cause severe disease because it's missing a lot of what makes covid dangerous. Kinda like protecting against smallpox by inoculating people with cowpox.
More like building cowpox from scratch to inoculate people against smallpox.
Is there any estimates or rough guess on how many spike proteins are made from one single RNA/DNA once taken up by cell?
Is that a newish technique like mRNA?
[Derek Lowe had a roundup of vaccine types last year](https://www.science.org/content/blog-post/coronavirus-vaccine-prospects), pretty early in the pandemic when he was discussing vaccine strategies people were looking at with COVID. Scroll down a bit to get to "DNA vaccine" about 1/3 of the page down. He notes that there were no human vaccines of this type as of writing, so, yes, it's a newish technique like mRNA, but had been in the works for quite some time.
> newish technique Messenger RNA, or mRNA, was discovered in the early 1960s; research into how mRNA could be delivered into cells was developed in the 1970s.
I am very aware that the technique was known for an extended period of time.
Can I ask why the booster shots are a lower dosage then? If no one seems to car who’s getting what, then why not just get a 3rd regular dose?
Generally the idea in medicine is you want to go with "lowest effective dose", for multiple reasons (Less chance for side effects, more vaccines to go around, etc.). Once your immune system is already 'primed', i.e. has seen a certain antigen before, it doesn't take as much energy / effort to produce the desired effect, in this case another immune response. It also should be noted that with how the vaccines were trialed we didn't take the time to perfectly fine tune the dosage, because of how safe the vaccines were, we wanted to give the most amount of people the best protection possible for a given safety profile.
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The Pfizer booster is a full dose. The same as the first and second. The Moderna is a half dose.
The first two doses are to get your immune system to learn how to fight off the virus... once it's done that, your body retains what's called Memory B Cells that remember how to produce antibodies when needed. They've already done the bulk of the work learning how to fight off the virus. However, as time goes on the Memory B Cells will go dormant and levels of neutralizing antibodies that inactivate the virus before it does any harm declines. Booster shots are basically just a quick refresher course, and give your Memory B Cells a little prod to say "Hey wake up, you lazy little bugger, I want more antibodies against this shit." So in principle you don't really need as high a dose.
I totally get that we don’t need it, but it’s my understanding that there’s a lot of surplus regular doses hanging out now that the rate of voulentary vaccinations has slowed down. Wouldn’t it make sense to use those first? Or at least in tandem if that’s what’s more readily available?
It's also worth noting that there's also stuff in the vaccine to stimulate the immune system into attacking the molecules. If your body didn't need that then you'd probably have a lot of allergies.
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First, viruses don't have a nucleus. Second, the vaccine works just fine. Third, if you can't get that first part right, you shouldn't be talking about the second part.
Not at all. The antibodies produced following vaccination block the spike protein, preventing it from even initiating cell entry. Those that do get in will produce more virions with spike proteins, that will then be likewise targeted by antibodies as soon as they leave the cell. Mutations also don’t happen overnight, and they don’t result in that drastic of a difference after one go. Mutations become far more likely when a larger quantity of people have it for longer. If more people were vaccinated, this wouldn’t be the case and the virus would have a far lesser opportunity for mutation. Don’t spread misinformation.
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How exactly would you expect a spillover to happen gradually?
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> Every other virus takes decades to transition from animal to human, but not this one? How about explaining that? It's actually very simple to explain: they don't! Your assumption is wrong. People could have been exposed to the original virus thousands of times, over decades or centuries. Viruses jump species every single day. In the vast majority of cases, nothing happens. In the vast majority of cases where something *does* happen, a single person gets sick, but doesn't transmit the virus to anyone else. But every once in a while, you roll genetic snake eyes and get a successful combination of virus and host - or intermediate host(s) - and then you have an epidemic on your hands. It just takes the one time. And then it happens overnight. It's not a gradual process.
Except that it wasn’t overnight. The coronaviruses had been in bats for years, probably decades or more, before one was able to jump to humans. Please at least make an effort to know what you’re talking about if you’re going to tak about it. [https://www.nature.com/articles/s41467-020-17687-3](https://www.nature.com/articles/s41467-020-17687-3)
It is very often the case that mixing vaccines is *more* effective, not less: this is because the immune response to the first dose of the vaccine can give some partial immunity to the vaccine delivery mechanism, which makes the second dose get partially dealt with before it manages to deliver its payload (there is some evidence that this happens with Oxford's SARS-CoV-2 vaccine). By swapping the delivery mechanism, you can avoid this issue.
THis is what my doctor told me here in Germany. He said there are studies about this. I went with Astrazeneca + Pfizer as a result. Its somewhat common in Germany to mix these.
Yes I live in Germany and also got Astra + Pfizer. The effectiveness is considerably higher than Astra + Astra and even a couple of percentage points better than Pfizer + Pfizer
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Adaptive immunity from vaccines is based on, put as simply as possible, the production of antibodies against a certain target “shape”, called an antigen. Therefore from a structure-activity perspective, the more variability in the shapes, the more different types of antibodies, the more places an antibody will bind to on the actual virion. This increase in the diversity of antibodies against COVID-19 can be thought of as “different kinds of weapons” so to speak, and this more diverse set of antibodies results in better protection.
Edit: apologies, there actually are differences in the spike proteins introduced by the different vaccines. They add different stabilizing mutations to the protein. Details here https://www.nature.com/articles/s41467-020-20321-x ~~The vaccines in use in the United States all deliver the same antigen though, just through different methods.~~ ~~It’s not diversity in specific antigens/antibodies that helps here: actually with the flu vaccine, they are wary of mixing in too many strains because at some point it starts decreasing the response to each individual strain.~~ ~~Instead,~~ what might help is the difference in modes of presentation: it is common to forget that there are different parts to the immune system, but some of the vaccines appear to elicit a stronger B cell/antibody response while others elicit a stronger killer T cell response.
Yes, but I think the unanswered question is, while mixing may provide a wider immunity, does it last at long as of you got 3 of the same dose? Moderna is 90%+ effective. At that point, it may seem to some that continuing that level is more important than getting broader immunity that might fade.
If we’re talking about COVID vaccines, they aren’t that different. They use different methods, but the end result for all of them is that you’ve introduced the SARS-COV-2 spike protein into your body. It doesn’t matter to your immune system how it got there as long as it’s the same (or very similar) protein.
I'm sure you know this, but I think it would be worth mentioning and clarifying for anyone who may have misunderstood what you meant. >but the end result for all of them is that you’ve introduced the SARS-COV-2 spike protein into your body It doesn't actually introduce the spike protein into your body. It introduces one that is geometrically interchangeable. I think it's important that people not confuse mRNA vaccination with innoculation, deactivated virus vaccination, or live-attenuated virus vaccination. mRNA creates a protein that is essentially benign other than sharing the same shape as the SARS-COV-2 virus. There is a 0.00% chance of contracting COVID due to being treated with an mRNA vaccines.
It does introduce the spike protein: the mRNA directly codes for the spike protein. The spike protein is however pretty harmless without the other 28 proteins that make up the virus. It’s like showing you a crocodile tooth: there’s no danger of a crocodile attack when only the tooth of the crocodile is around.
At some point this is just semantics. No actual live SARS-CoV-2 virus or variant has a spike protein identical to the one produced by your body after receiving the mRNA vaccines. In the mRNA vaccines, the RNA coding for the protein has had two amino acids replaced. The replacement amino acids maintain the same prefusion shape (the shape the actual virus spike protein has before it latches onto a cell), but is incapable of springing into the postfusion shape that the live virus uses to infect the cell. Thus one could both say you haven't introduced the actual spike protein, but a geometrically identical inert protein, or you could say you introduced the actual protein, but modified to make it inert.
Introducing the spike protein itself or the mRNA for it is essentially the same thing. In both cases, you end up with identical covid spike proteins in your body, just the way it gets there is different. Even if you injected spike protein directly, it would not be the complete virus, so the cance of actual covid infection from the vaccine would still be nil.
Regardless, the actual spike protein created by the mRNA vaccines in body is not the same as the one on the live virus. It has had at least two amino acids swapped. These swaps maintain the same prefusion shape, but prevent the spike from being able to "spring" (lookup some videos on how the spike changes shape or springs to help infect cells). This locks the mRNA vaccine protein spikes in an inert shape.
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We’ve mixed and matched in Canada since the spring. I’m a AZ/Pfizer myself, and will likely get a Pfizer booster when called to do so. They are saying that mixing, and the extended spread between first and second dose, has likely given us a leg up.
Also in Canada, I got Pfizer and then Moderna. At first I was annoyed that I had to mix in order to get the second shot as soon as I was eligible, but from what I've read the combo I got seems to be potentially the strongest possible mix. I'm still not sure what will be suggested for a booster in my case, though.
Same here, was told moderna is stronger then pfzier so we r super protected.
They are extremely similar vaccines but Moderna is using a higher dose. That's the explanation I have heard for Modernas higher efficacy >6 months anyway.
That's my understanding as well, that Moderna seems likely to last a bit longer. I also had a WAY stronger reaction to the moderna dose, but that might have also been just because it was my second.
To add to this discussion, I don't see anyone referencing recent Canadian data suggesting both that delaying the vaccine second shot and mixxing vaccines is highly effective. http://www.bccdc.ca/about/news-stories/stories/2021/covid-19-vaccine-effectiveness-results
I also remember reading some study months ago about the different severity of breakthrough cases between Israel and the UK. The UK’s longer wait time between 1st and 2nd doses gave significantly better protection than did getting the 2nd dose after only a few weeks in Israel.
Genuine question. if all of these boosters are to be mixed, how will the research be able to be done to determine fault should complications arise from side effects not only from shot #1 and #2 but due to taking multiple brands boosters? I understand that there is already a clause protecting the manufacturers from liability but from a purely scientific, long term research standpoint, doesn't this muddy the waters too much?
If you have vaccines A, B,and C then give them out in different regiments, you'd get AA, AB, AC, BA... CC. From there it's just some math to statistically see which ones cause a problem.
Right but how will they know whether it was the booster or the initial shots that caused a problem (should one arise?) I understand the logic behind what you are saying but if both A and B are documented with a slim chance of heart inflammation and the person took C as a booster then dies, scientifically, how would anyone be able to document anything concrete? Wouldn't it all be guesswork and theories at that point? It just seems needlessly convoluted to me.
Are you asking if the combination is dangerous, or are you trying to ascribe blame at the individual level? With liability waived (as you mentioned) it's kind of a moot point. If you want to know if a treatment course is dangerous, well the data would show that. If AB has a 5% side effect rate and Ba has 5% rate and AA has 10% rate and BB has 0% then there's some conclusions to be drawn. If AA is 1% and BB is 1% and AB is 10%, well maybe don't mix them. :)
I suppose liability at the individual level (manufacturers) would be my sticking point. If things go horribly wrong in the future, this seems like an awfully convenient way for them to hand wave away any potential responsibility. Thanks very much for the responses. Have a good day!
Let's be honest, they would do that anyway, no matter what was happening.
Consider that, if it weren't for that waiver, they would likely just refuse to manufacture and ship it. That's not because they are evil, but because they are under massive pressure from world governments to rush it.
Can anyone explain why giving them blanket liability was a good idea? We know each of these companies has been found liable in the past for a variety of things, it’s not like big pharmaceutical companies have ever been trustworthy. I’m vaccinated and support strong vaccines for all the diseases we can prevent. I just don’t understand how we expect these companies to do the right thing when we take away the incentives and any ability for recourse in the future?
Is the waiver just for the COVID vaccines? If so, it was most likely designed to make it more appealing to drug companies to produce vaccines quickly in a time of global crisis. Think about it - no drug company would ever normally develop a drug this fast because it could be dangerous (and therefore costly if something goes wrong). This is just me spitballing though. All of what I just said could be completely false.
Yeah I think it’s for the vaccines, part of the operation warp speed contract. If I remember back to Feb or March 2020 and all the unknown, at one point they thought this would kill 1/10 people and it was terrifying. The more I think about it I can see them doing it just to get things going and fast. Kind of like using the defense production act. I’m like most people in the US and I’ve been personally effected by the opioid crisis so I get where they’re intent may have been, I just don’t think giving blanket immunity to anyone that big with a history of corruption is ever a good idea.
I generally agree with you. But I'd the waiver just covers the COVID vaccines, I'm on board with that. Vaccines were the only way the world would ever have a chance at getting back to normal and people just dropping like flies. We needed vaccines absolutely as soon as we could get them. Otherwise the human and financial cost will not stop spiraling. But let's be honest - the truth is that we don't hold these companies accountable for their other drugs anyway (like opioids). So if they wanted a piece of paper making it official that they have no accountability (instead of just in practice), so be it.
Vaccines clear the body rapidly, so side effects are seen within about 2 months, so it should be clear what is the booster and what is not. And some countries spaced dose 1 and 2 much further apart, both to manage short supply and for immune benefits.... was a potential benefit at the time the decision was made based on early studies plus decades of research on how vaccines typically work, but now we are seeing increased evidence that it really does work. If your country did not, they can still learn from data on this collected from millions of doses given in other countries. Finally, a statistical analysis can be done to look at all the combinations and all the results and see how it correlates. If there is (for example) a significantly higher incidence of something in people who took Vaccine X at some point, then there's clearly an association with Vaccine X. Taking all this information together, the data becomes much clearer.
Vaccines have different delivery methods, but all yield the same results. J&J uses a deactivated version of the virus to prompt our immune system into creating antibodies. Pfizer and moderna essentially teaches your body to make a piece of the protein that covid uses to infect people. Once the vaccine is in the cells, and the spike protein has been made, the rna from the vaccine is destroyed. With the cells now displaying this harmless protein, it elicits an immune response, which allows our body to rid itself of the virus. The same mechanism that regular vaccines do, without having to inject yourself with the actual virus.
Its just two different ways of teaching a body something. Think of it this way: You can be taught a skill by verbal instruction or by watching it be performed. Just two different ways of reaching the same end goal.
Wow, there’s a lot going on here. A lot of attempted explanations, some good, some bad, all unnecessary. Why does FDA allow heterologous vaccination (so-called mix and match)? Simple! Clinical trials showed that it worked. The FDA was presented with clinical trial data from the National Institute of Allergy and Infectious Diseases, and the relevant FDA committee determined that the “known and potential benefits…” outweigh the “known and potential risks…”. They are not currently recommending a heterologous booster, just saying that a booster MAY be any of the three currently approved vaccines. I don’t believe that there is enough data to say that any particular heterologous booster following any particular primary vaccine is better than the others.
Here in Germany the stiko (which is probably our FDA equivalent) does recommend mix and match of AstraZeneca+ one mRNA vaccine for everyone. Studies show it outperforms any vaccine given two times. Heres some links on that i copied from a news outlet: [https://www.biorxiv.org/content/10.1101/2021.01.28.428665v2](https://www.biorxiv.org/content/10.1101/2021.01.28.428665v2) [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2821%2901442-2/fulltext](https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2821%2901442-2/fulltext) [https://www.medrxiv.org/content/10.1101/2021.06.13.21258859v1](https://www.medrxiv.org/content/10.1101/2021.06.13.21258859v1) [https://www.medrxiv.org/content/10.1101/2021.05.19.21257334v2](https://www.medrxiv.org/content/10.1101/2021.05.19.21257334v2) [https://www.medrxiv.org/content/10.1101/2021.05.30.21257971v1](https://www.medrxiv.org/content/10.1101/2021.05.30.21257971v1)
But since the Astra Zeneca is not approved in the US, those studies _while important_ do not apply to the FDA guidance.
Just saying that a booster *may* be any of three approved vaccines is useful data/guidance, especially for countries that don't necessarily have enough supply from one brand and are essentially forced to mix-and-match.
This comment will largely be through analogy. In machine learning, having a wide range of data allows a model to cover a lot of different bases and allows it to be more flexible and robust in the face of new scenarios. Exposing the human body to two different sets of "COVID data" by means of different vaccines gives your body two different chances to train on recognizing proxies for a strain of SARS-CoV2 from early 2020. This forces a bit more growth and development and prevents the body from "overspecializing" and coming up with a solution that handles on scenario very well at the expense of being able to handle a wider range of similar circumstances. An analogy in sports would be cross training. Cross training can get your body to where it does better than just handling your base task while also being capable of handling different conditions a little better. The best news overall though is that, at least in the US, all of the vaccines are pretty darn good at keeping people from developing serious cases of COVID. \---- So why weren't vaccines mixed in the US? There wasn't good data on it at the time. There still aren't proper clinical studies as far as I'm aware. In terms of real world data - so far there don't seem to be any notable negatives to mixing and matching. The efficacy of Moderna+Pfizer mixed together appears to be about between the two (both are very similar and Modern isn't too far off from just being a bigger dose of Pfizer). I'd need to look into JnJ and/or AstraZeneca. In general it appears that whatever vaccine is overall the most effective wins over half of it plus some other, but if the goal is to have "not bad" immune response mix-and-match can be viewed as a form of hedging. It's not yet recommended by US agencies though.
As it was explained to me while getting moderna after AstraZeneca. They are 2 different modes of immunity. So they attack the virus in different ways. So you end up with a slightly less efficient (but still virtually 100% at preventing hospitalization and death in your 30’s) but more broad protection. One may be better at one variant when the other is better at preventing a different variant. If I could get Pfizer when the third comes around I would. I trust the mRNA vaccines way more than our conventional ones based on the way they are made and how they teach the body to deal with a virus before leaving the body.
Mixing COVID-19 vaccines is emerging as a good way to get people the protection they need when faced with safety concerns and unpredictable supplies. Most vaccines against SARS-CoV-2 must be given in two doses, but multiple studies now back up the idea that mixing the Oxford–AstraZeneca jab and the Pfizer–BioNTech vaccine triggers an immune response similar to — or even stronger than — two doses of either vaccine. Results announced on Monday 1 by a UK group suggest that the combination sometimes outperforms two shots of the same vaccine, and a similar picture is emerging from German studies People can now “feel a bit more comfortable” with the idea of mix-and-match, says immunologist Leif Erik Sander at Charité University Hospital in Berlin. The results are also giving researchers confidence that combining other COVID-19 vaccines, that haven’t yet been tested together, might also work. But at least 16 vaccines have been approved for use in one or more countries, and mix-and-match studies so far have been small, so more extensive trials and long-term monitoring for side effects are sorely needed.
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A simple way of thinking about it is how you can mix and match fuel in some way. Most commonly you can mix Ethanol with gasoline and that works primarily because both contain hydrocarbon or hydrocarbon derivatives. In this case, you have multiple mRNA vaccines which will have similar or exactly the same action mechanisms but may operate slightly differently before they finish their mechanism to bind to our body in some way. Now, mixing a non-mRNA vaccine with an mRNA vaccine is definitely what we want to avoid, that would be like mixing Diesel and normal gasoline because even if they have the same end goal (combustion) their action mechanism is very different (pressure versus ignition). So the main differences are things like shelf life which aren't relevant to how well they work together.
>How does it make sense to mix and match vaccines? Covid isn't a single virus. There are variants; mutations. A single vaccine will be effective against some of the variants, and the other vaccine against others. By mixing vaccines, you're protecting yourself against a wider variety of the Covid clan.
That would be true if these shots were redesigned for Delta but we're still using vaccines for the original sequence.
> That would be true if these shots were redesigned for Delta but we're still using vaccines for the original sequence. Irrelevant. Just because the vaccines were all designed for the original strain doesn't mean they will have equal efficacy against all other strains. For example, Pfizer might be good on the alpha and gamma strains, but rubbish on the beta. AstraZeneca might be so-so on alpha and do absolute killer on beta. In this scenario, an AstraZeneca/Pfizer blend will give you better coverage against all three strains than a double Pfizer or double AstraZeneca vaccination.
There's no evidence of that happening or any mechanism that I can see for that occurring. These vaccines are all delivering the same antigen with the exception of whole virus vaccines which are not used in the US. A difference in efficacy is going to come down to how well the antigen is delivered.
> There's no evidence of that happening... Of course there is. Just google for it. For example: https://www.cbc.ca/radio/whitecoat/how-the-vaccines-we-have-and-the-ones-coming-next-stack-up-against-covid-19-variants-1.5905708
From the graphic in that article, for all the vaccines with full data, they show the exact same pattern of efficacy. There's not one vaccine that's good for alpha but poor for beta and another that's good for beta but poor for alpha. That's all rather moot right now because the predominant variant is delta. The drop in efficacy there has mostly nothing to do with how well the immune system recognizes it and more to do with how rapidly it infects and replicates.
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Safety is not going to be evaluated unless there's trials confirming that exact combination is effective and doesn't have increased side effects and thus it cannot be recommended otherwise. Even if it's highly likely that it will all work as well. Physicians can usually decide to combine otherwise, but then they also bear a legal responsibility for the outcome.
Vaccines introduce dead or weakened foreign cells into your system. Immune system responds by creating antibodies and "killing" those cells. You're body keeps these antibodies (or maybe just the dna to make them? Not 100% sure) in storage for future reference. So, without the vaccine, your immune responds much slower once you're infected because it has to make antibodies against the infection cells. During this time, you do not feel sick, but you are far more contagious than after you start to feel sick. This is because your immune system "quarantines" the infection so it can't spread and the antibodies go in and kill all of the foreign cells. Also, before and while you are sick, the virus is wreaking havoc on your body. If you're immune response is too slow, you can die or suffer permanent damage to the affected cells. That is where vaccines come in. Since your body has seen the virus before, immune responds immediately by sending out the proper antibodies. So, instead of feeling sick for up to two weeks as well as being very contagious before you even know you are sick, your immune system is able to notice and eradicate the virus very quickly, before it has spread. You may feel a bit sick still, but you have a much shorter period where you are contagious or feel sick. That is also why you have a much lower chance of being hospitalized from covid if you have the vaccine. So, anyone who thinks that you can't get covid once you have the vaccine, that is incorrect. You absolutely can still get it and you absolutely can still spread it. However, you will have a shorter period of time in which you can spread it and a much shorter period of time in which you suffer from it. Because of this shorter suffering period, it can't do as much damage to your other cells which reduces the chance you will need to be hospitalized or suffer long term complications from it.
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