How long does immune memory last after #mRNA vax? Is it effective vs. variants? What about “boosted” responses?
Full 🧵⬇️...
Antibodies are important for protection, but our immune system can also remember viruses through memory B and T cells
We measured all components of immune memory for 6 months after #mRNA vax. Vaccination in people w/ prior immunity also let us study "boosted" responses
#1 - Antibodies:
2-dose mRNA induces high levels of antibodies (blue). Even higher in "boosted" responses (red)
Antibodies decline over time (THIS IS NORMAL AND EXPECTED). But neutralization declines more slowly than binding antibody, suggesting higher quality antibody persists
What about Delta (B.1.617.2)?
We observe that almost everyone in our study still had neutralizing antibodies to Delta at 6 months. Maybe some decrease relative to wild-type D614G spike, but Delta is clearly not as immune evasive as the Beta (B.1.351) variant
#2 - Memory B Cells:
These are the backup plan when circulating antibodies go down. They are also harder to measure...
Unlike antibodies, memory B cells targeting Spike and the Spike RBD actually INCREASE over time
And 2 doses of mRNA vaccine get you to similar levels of B cell memory as the much-hyped "hybrid" immunity. We think this is pretty remarkable...
These memory B cells were able to rapidly produce functional anti-Spike antibodies after re-activation that inhibited RBD binding and neutralized Beta/Delta pseudovirus
We then expanded this approach to study memory B cell responses to different variant RBDs and also non-RBD parts of Spike. We included mild COVID-19 samples here to compare vaccine w/ infection
2-dose #mRNA induced memory to all components of Spike, w/ S2 clearly immunodominant
Here is the kicker - we found #mRNA vax generates memory B cells that are better at cross-binding variants than infection at 6 months
Memory from infection evolves more over time compared to vax but doesn't seem to generate as good of an endpoint response vs. Beta (B.1.351)
For a subset of these memory B cells, we could observe their evolution from binding only wild-type RBD to also binding variant RBD. This evolution was associated w/ higher somatic hypermutation, a process that happens in immunological "boot camps" called germinal centers
Vaccination generated durable CD4+ T cell memory at 6 months. CD8+ T cells were also detectable but a bit more variable at memory timepoints in this assay
With all of this data, we constructed an "immunological map" of vaccine responses
Notice how samples at 6 months cluster far away from baseline pre-immune samples! Even though antibodies decline from peak levels, mRNA vaccines still generate durable multi-component immune memory
For the aficionados - we also investigated relationships between different components of the immune system
CD4+ T cell responses ~2 weeks after the first dose correlated w/ antibody responses out to 6 months, suggesting these cells are important for coordinating long-term memory
Finally, we analyzed what "boosted" responses might look like
Boosting prior immunity w/ vax increased antibody levels via memory B cells but didn't change their decay rate relative to 2-dose #mRNA. And there wasn't much change in the long-term frequency of memory cells
Boosters are a complicated topic. Based on our data, we think antibody recall will extend protection vs. "breakthrough" infx for a while, but not forever
OTOH memory cells seem durable and may explain continued protection vs. severe disease w/o a boost: theatlantic.com/science/archiv…
To summarize:
- Antibodies decrease but memory B/T cells are stable for ≥6 mo
- Immune memory is still effective vs. variants
- "Boosting" from memory = significant (but temporary) increase in antibodies w/ less impact on already durable memory cells
We think this is mostly good news. Immunological memory after #mRNA vax meets our expectations for long-term immunity. Our data may also provide some information on what to expect from booster vaccines. Lots more discussion in the full paper that doesn't fit a 280 character limit
Additional thanks to folks like @KatherineJWu@ewencallaway@jwgale for highlighting this work. The immune system is complicated and their science communication is more important now than ever. Stay tuned for more vaccine science from the @WherryLab
A few more thoughts on boosters -
Vax is not a one size fits all concept. 3rd dose clearly has benefit for >65, immunocompromised, etc. who did not have an optimal response to the initial vax series: nature.com/articles/s4159…
We looked at mostly young and otherwise healthy folks
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Our work on B cell memory to Omicron + other variants is now online @CellCellPress
How does a 3rd shot of original mRNA vax work vs. variants? Does it increase the durability/quality of immune responses? What happens after a second boost? Key findings 👇
How does original mRNA vax work for Omicron + other variants? Does a 3rd shot increase the durability and/or quality of immune response? What factors predict boosting, and what happens after a second boost?
We previously studied immune memory for 6 months after mRNA vax. In this study, we followed the same individuals out to ~9 months after primary 2-dose vaccination, as well as ~3 months after a 3rd (booster) dose
Remember the headlines about 📉 antibody levels (TOTALLY NORMAL AND EXPECTED)?
Binding/neutralizing antibody levels stabilize between 6 and 9 months post-vax. A 3rd dose (or breakthrough infection) supercharges the antibody response w/ lasting benefit ~3 months post-boost
How long does immune memory last after #mRNA vax?
Immunity vs. variants?
What happens when you “boost” w/ vaccine?
Our work on durability & evolution of memory responses to SARS-CoV-2 vaccines: biorxiv.org/content/10.110…. Antibodies, memory B/T cells, & more. Full thread below 💉👨🔬
Lots of data here so I’ll only focus on the highlights. TLDR: immune memory looks great and improves over time (even against variants). Boosting existing immunity w/ vaccine significantly increases antibody in the short-term but w/o much effect on already durable memory B/T cells
Antibodies - 2 dose mRNA induces high antibodies/neutralization. Even higher for “hybrid” immunity in folks w/ prior infection + vax. Antibodies do come down over time (THIS IS EXPECTED AND TOTALLY NORMAL FOR AN IMMUNE RESPONSE)
As others (including @florian_krammer@Daltmann10 etc) have shown, folks who have recovered from COVID only need 1 dose to get peak antibody responses to full-length spike protein and the RBD. People who are SARS-CoV-2 naive need 2 doses for optimal responses
Similar data for neutralizing ability against wild-type (D614G) strain & the B.1.351 (S African) variant
2nd dose especially important in people w/o prev infx... 50/50 on neutralizing antibody against D614G & very little against B.1.351 after dose 1. Great response after dose 2
Our study on #mRNA vax in #SARSCoV2 naive/recovered individuals is up on medRxiv! Massive team effort btw/ @EJohnWherry lab + others @Penn_IFI to profile both antibodies & antigen-specific memory B cells following 1st/2nd doses. bit.ly/3rlfhwO. Full tweetorial below 💉🧵
1) Consistent w/ what others (e.g. @florian_krammer) have shown: COVID-experienced folks don’t have an increase in antibodies after 2nd dose… clear benefit for people who are COVID-naive
2) We also find the same pattern for antigen-specific memory B cells… COVID-experienced folks have an increase in spike+ and RBD+ memory cells after the first dose, but then plateau w/ no increase in frequency or class switching after the second dose