Thread by @MonicaGandhi9

Another paper showing the durability of memory B cell responses after vaccination despite waning of antibodies (latter natural part of immune system) and ability of those memory B cells & triggered antibodies to respond to variants. 342 samples collected
biorxiv.org/content/10.110…

from 61 participants who got Moderna or Pfizer vaccines. Measured our 2nd favorite memory cell after T cells- memory B cells and found increasing enduring concentrations over the 6 months studied. Assessed places memory B cells bound to antigens (little pieces) on spike protein

to ensure they bind to places OTHER than the mutations present in variants. Memory B cells bind to conserved regions of the spike protein that are common to all variants- they will react to and produce antibodies to places on the spike protein that are the SAME across variants.

In terms of natural immunity, authors specifically note: "boosting previous immunity with mRNA vaccine in SARS-CoV-2 recovered individuals provides little long-term benefit to the frequency or proportions of memory B cells binding different SARS-CoV-2 Spike antigens". Amazing

experiments then showed that memory B cells can EVOLVE to bind new variants - "variant binding capacity can evolve from clones that initially bound to wild type receptor binding domain" (latter is part of the spike protein that connects to host cell). Also showed strong memory T

cell responses to vaccination. Strong memory B/T cells formed by natural infection - boosting just increased antibodies then came down. "Overall, the benefit of booster vaccination in this setting may be limited to a significant but transient increase in antibody". Great study

showing
1) SARS-CoV-2-specific memory B cell responses
robustly induced by mRNA vaccination and continued to increase in frequency for at least 6 months, even as circulating antibody levels declined in the same individual
2) Vaccines generated memory B cells that evolve and can

cross bind variants including alpha, beta, and yes, delta
3) Memory B cells formed by natural infection but you may want to get a booster vax if you had mild infection
4) Strong T cell memory formed by vax (with long half-life suggesting durability)

Please follow @mugecevik who explains cellular immunity beautifully & why vaccine effectiveness complex (her picture below). When SARS-CoV-2 circulating at lower rates (delta brings down with more immunity), less susceptibility to breakthroughs which is why #globalvaxequity key

Finally, here is an article where I try to put all the references and links together so you can download & read them yourselves.
leaps.org/how-long-do-co…

Another nice paper on cellular immunity showing why a 3rd shot ("booster") is so important among those who are immunocompromised (but that immunocompetent form very nice B cell immunity). B cells hang out in "germinal centers" in secondary lymphoid tissues
medrxiv.org/content/10.110…

like lymph nodes (& bone marrow). These investigators biopsied lymph nodes and found same finding as Nature paper above- strong formation of B cells after 2 doses in those who are immunocompetent but need more stimulus in those who are immunocompromised (at least 3rd dose)

when you look at the beauty and complexity of the immune system, you realize that immunity is the only way to get through a pandemic

Beyond data that shows biopsy of lymph nodes reveal ongoing and increasing concentrations of memory B cells in vax'd & data of biopsies of bone marrow showing same thing in recovered, this paper shows the memory B cells are there 15 months & counting
biorxiv.org/content/10.110…

Never done for other vaccines when we decide whether they are 1 dose (rare; yellow fever and get booster if going to place with high circulation), 2 dose (common), 3 dose (common), etc. is biopsy LYMPH NODES to show formation of strong B cells after 2 dose vax like COVID!

This paper is spectacular ( full Science paper of a preprint above) which looks at the formation of cellular memory after vax. We know that antibodies decline but "vaccine-induced immunity remains highly effective at preventing severe disease"
science.org/doi/10.1126/sc…

So, even as your antibodies wane "memory B and T cells can be rapidly re-activated, resulting in enhanced control of initial viral replication and limiting viral dissemination in the host" (which should limit the infection & lingering symptoms). We know memory B/T go on for 8

months & counting (Dan et al Science) with natural infection, what about vaccine? And also vaccine going into delta era? So, even as antibodies decline after Pfizer/Moderna vaccines, memory B cells continue to increase in this study (they are blueprints to make more antibodies)

And, of note, the memory B cells can easily cross bind VARIANTS OF CONCERN: alpha, beta, delta. "the memory B cells are capable of mounting rapid recall responses, providing new source of antibodies upon infection or booster vaccination". So if you see virus, make more antibodies

If you had mild COVID, there is a benefit of vaccination s "as memory B cells 6 months post-vaccination were qualitatively superior at binding variants of concern compared to memory B cells 6 months after recovering from mild COVID-19". Strong T cell immunity developed after vax

and helps B cells make more antibodies when needed. However, authors also note "boosting of pre-existing immunity from prior infection with mRNA vaccination mainly resulted in a transient benefit to antibody titers with little-to-no long-term increase in cellular immune memory"

And this is a key point when we think of boosters: "boosters will temporarily prolong antibody-mediated protection without fundamentally altering the underlying landscape of SARS-CoV-2 immune memory". So you can get a booster but it will just raise antibodies which will come

right down but your memory cells are there for a long time to make more antibodies if you see the virus again in the future. So your protection from severe disease should be durable & your antibodies will adapt to the variant they see (although you could have mild breakthrough)

Think it is important to add this paper to the cellular immunity thread showing that giving Pfizer doses 6-14 weeks apart instead of 3-4 weeks both increases antibody response AND CD4 (T cell) response so we should rethink our spacing interval in US
cell.com/cell/fulltext/…

Probably good paper to put at the end of a cellular immunity thread by my friends @jakescottMD, @AaronRichterman, @mugecevik
bmj.com/content/374/bm…

CELLULAR IMMUNITY: If we want vax induced immunity to be at its "strongest", most safe, suggest 7-8 weeks between shots as Canada did because of Cell study in this thread showing increasing duration between doses increases Abs and CD4 (T) cells (cellular)

Pretty amazing graphic that speaks to the power of cellular immunity more than any I've seen!

And how do we know T cells will last a long time from vaccination? Because of papers like this (just 3 days ago in Science) showing the T cells generated are the types that persist, go into memory, last for very very long time
science.org/doi/10.1126/sc…

And how do we know B cells will last a long time from vaccination - because of paper like this that show they mature and go into germinal centers (lymph nodes, for example) where they last a long long time
biorxiv.org/content/10.110…

Important paper to add to this thread on cellular immunity on what happens if you see the virus AFTER vaccination ( P-town breakthroughs) - you do not boost just antibodies, but strengthen cellular immunity with broad T cell response
medrxiv.org/content/10.110…

Figures from paper here so don't likely need booster if infection occurs after vaccination. Antibodies declining mean re-infection possible but strong cellular immunity keeping many vaccinated from severe disease; boost J&J, older, immunocompromised

Nice video from the Vaccine Makers project that shows the concepts of adaptive immunity (cellular immunity) well

And this one explains B and T cell immunity to one of the vaccine types (adenoviral vector vaccines) really well

Interesting paper that adds to our understanding of the vaccine response even in patients on B cell depleting therapy - with a REDUNDANT and complex immune system, T cells are still there to protect
nature.com/articles/s4158…