Thread by @ENirenberg

IMPORTANT: Imprinting does NOT mean that you are worse off taking a vaccine than not taking it- a thread 🧵

If you're following COVID discourse still there's been a lot of discussion basically since the time Omicron emerged about imprinting (you may know it by the term "Original Antigenic Sin" or OAS).

This is really not something that needs to be anywhere on the list of...

concerns for the average layperson but for the interested, this is basically a special case of immunological memory where our first encounter with a particular antigen has an effect on future encounters with related antigens.

Here's an analogy to try to clarify this: imagine you have a bunch of differently shaped blocks. You are given an assignment to make a cube out of those blocks, so you do. Then you're given an assignment to make a rectangular prism from those blocks which is...

different from the cube, but still has similarities. Also it's in your best interest to complete all of these assignments as quickly as possible. Do you (a) recycle bits from the first shape and try to fit them to the new shape even if they don't fit perfectly or...

(b) do you go through the expensive process of ordering new blocks, waiting for them to be delivered, then assembling them? In basically every instance, given that getting this done as quickly as possible is key, you are better off choosing (a) over (b). That's basically...

what imprinting is: you encounter one strain of a microbe, make an immune response to it, and then encounter a second strain where instead of making a brand new antibody response, you evolve your old antibodies to counter that new strain by concentrating on the bits...

that are shared between the two strains. The priority is to clear the infection as quickly as possible to be able to minimize the damage it does to the body, and it's much faster (and you get a much bigger response) by using memory responses than by using new cells.

In some cases this is really dramatic as some amazing recent papers have shown:


When encountering the same antigen for a second time, nearly 100% of the antibody response comes from memory cells made from the first exposure.nature.com/articles/s4158…

However, as the antigen looks more different from the first exposure, the memory cells will not be able to bind it as effectively, so it makes it easier to recruit new cells specific to the new antigen.

So, what does this have to do with vaccination?

There things get a bit controversial and there are different schools of thought on this point. With the Original Antigenic Sin idea, you would expect that someone who has seen strain A of a microbe and then sees strain B will have a worse response than someone who sees strain...

B for the first time. Note however that you CANNOT claim OAS from someone who sees B first and then encounters B again having a better response than someone who sees A and then B- you are comparing someone with 2 exposures to B vs. someone with 1 exposure- of course...

the one with 2 exposures will be better! Anyway, the basic point is that the exposure to strain A interferes with giving you the best response to strain B.

When Thomas Francis Jr. first described OAS, however, the "sin" was in that people could not be exposed...

to multiple strains of influenza at the same time for their first exposure as this would give them broad protection:


Put in more concrete terms, this argues that people who first see the ancestral spike protein will have more...perspectivesinmedicine.cshlp.org/content/10/10/…

difficulty making a good response against Omicron spike than people who have not been exposed at all (and similarly people who see Omicron first may struggle more with responses to ancestral spike). This, however, is fundamentally not the same thing as saying you are worse off..

getting a vaccine than not getting a vaccine! Even with ancestral spike, you will have antibodies that can crossreact with Omicron and there are ZERO well-designed studies showing negative vaccine effectiveness with SARS-CoV-2 vaccines! All of them show that the person...

who has experience dealing with SARS-CoV-2 spike proteins will fare better than the person who doesn't, and more experienced people fare better than less experienced people.

This begs the question of whether or not imprinting is ever explicitly harmful- the answer is yes.

Dengue (DENV) and some closely related viruses (flaviviruses) can take advantage of a phenomenon called antibody-dependent enhancement. This is often explained as the virus exploiting antibodies to infect additional cells but that's only part of the picture.

Our immune cells have receptors called Fc receptors that sense antibodies and these Fc receptors can deliver messages to our immune cells like "eat this thing" or "make inflammation here." For basically every virus, there exists some sweet spot of antibody levels where...

the antibodies cannot block infection (their levels are too low), but Dengue has a unique biology where the signaling through the Fc receptors enhances its replication (normally this would make immune cells resistant to viral infection).
science.org/doi/10.1126/sc…

In the case of Dengue, there are 4 strains (or 5 depending on who you ask) and they all look different to the immune system. If you first see DENV1 for example and then encounter DENV2, you may have antibodies that bind DENV2 but at levels too low to effectively block...

infection. The result from there is that your second infection with Dengue is more severe than your first (nb- while this is important to the biology of Dengue, even this is not a universal occurrence). This means that any Dengue vaccine must give strong immunity against all..

strains of Dengue at the same time, which has historically been (and continues to be) a serious challenge. For this reason, the first Dengue vaccine, Dengvaxia, was intended only to be given to those who had antibodies against Dengue already- this would ensure that the boost...

from the vaccine kept their antibody levels high- well above the levels that put you at risk for ADE. Unfortunately, this advice was not heeded and it resulted in Dengvaxia causing more severe cases of Dengue when it was used in the real world:
science.org/content/articl…

To be clear- Dengvaxia is a safe and effective vaccine but it has to be given specifically to those who have already encountered Dengue (it cannot give high enough antibody levels for long enough otherwise)

Note that while there are examples here and there in the literature...

reporting ADE for viruses other than Dengue, overall, it is only well established that it has an important role for Dengue. We don't see this sort of thing for flu, COVID, etc.

To summarize: memory cells are your friends and even with imprinting, you are better off vaccinated.

Addendum: imprinting in general refers to a B cell phenomenon- this says nothing about the contribution of T cells. For example, one reason an experienced immune system might make a lower response to a new antigen than an inexperienced immune system is that...

the T cells are recognizing shared regions between the new antigen and the old one and initiating a program to clear it immediately, effectively reducing the "dose" of antigen that the experienced immune system sees relative to the inexperienced one. Lower dose = lower...

antibody response. HOWEVER- this does not translate to worse protection! Indeed, when you look at post-vaccine infections, the T cell response is faster than the B cell response because it takes a minute to evolve the adapted antibodies:
sciencedirect.com/science/articl…