Rishi Goel
@rishirajgoel
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PGY-1 @mghmedres @HMSCombinedDerm via @Penn @WherryLab @PDSoros | Previously @NIH @UniofOxford @UMich | @UMichFootball fan 〽️🏈
Ann Arbor, MI
Joined January 2017
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Pinned Tweet
Some big news - I’m headed to
@MassGenBrigham
@HMSCombinedDerm
for my residency training!
I owe everything to the amazing people at
@PennMedicine
(s/o
@EJohnWherry
lab),
@PDSoros
, and my family + friends who made this possible
#Match2024
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Antibodies come and go, but memory cells are forever (maybe not forever, but at least 6 months). Our latest in
@ScienceMagazine
:
How long does immune memory last after
#mRNA
vax? Is it effective vs. variants? What about “boosted” responses?
Full 🧵⬇️...
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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: . Antibodies, memory B/T cells, & more. Full thread below 💉👨🔬
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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 👇
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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?
Our latest on immune memory to SARS-CoV-2: . 🧵👇
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Our paper on antibody & memory B cell responses to SARS-CoV-2
#mRNA
vaccines is out
@SciImmunology
- 1 vs. 2 doses?
- What about age & side effects?
- Relationships btw/ antibody & memory cells?
We look at all that & more... full
#Tweetorial
below 💉🧵
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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. . Full tweetorial below 💉🧵
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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
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Boosting is more complicated. Antibodies definitely go up, but no change in their decay rate + no long-term increase for memory B/T cells. The temporary ⬆️ in protection from antibodies may work on an individual level, but unclear if we can just boost our way out of this pandemic
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To recap - immune memory vs. SARS-CoV-2 (including variants) looks durable for at least 6 months after mRNA vax. Memory cells do the heavy lifting when antibodies start to go down - this may explain the increase in "breakthrough" infections but good efficacy vs. severe disease
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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
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Memory B cells - also efficiently generated by 2 doses of mRNA. But unlike antibodies, these actually continue to INCREASE over time. And when you re-activate these memory B cells, they can rapidly respond to produce more antibodies that can bind/inhibit SARS-CoV-2
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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...
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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)
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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)
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We also looked at memory B cells against different variants and compared w/ natural infection. Turns out the majority of memory B cells induced by mRNA vax can bind Alpha, Beta, AND Delta… mRNA vax also slightly better against variants than mild COVID-19 (panels E/F)
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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
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#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
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Finally, mRNA vax in folks w/ prior immunity from COVID allowed us to study what “boosted” responses might look like… Boosting here increased antibodies likely through recall from memory B cells. But decay rates over time are similar & no long-term benefit to cellular immunity
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With all this data we could construct an “immune landscape” of mRNA vaccination. Note how all the 6-month samples cluster away from pre-immune baseline samples! Suggests that mRNA vax generates durable, multi-component immune memory to SARS-CoV-2
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There is no evidence that boosters will "exhaust" the immune system.
@EJohnWherry
lab studies T cell exhaustion for a living... transient re-exposure to antigen w/ mRNA vaccine =/= chronic infection or cancer where persistent antigen drives exhaustion
do I need to make a thread about how boosters exhausting the immune system isn't a thing or do people know it's nonsense
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Full text available here if you want to read all the details:
Happy to discuss/share any of the data
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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
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To summarize - mRNA vaccines are awesome... 2 doses generate amazing B cell memory that likely lasts for years. A 3rd dose of OG Spike vaccine (or a breakthrough infection) re-activates that memory to produce primo antibodies that work vs. Omicron and other variants
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These variant binding memory B cells evolve from variant non-binders through somatic hypermutation in immune structures called germinal centers (GCs). Amazing work from
@TheBcellArtist
shows that GCs persist for months after vax. See full text for our sequencing data on this
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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
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What about T cell responses? CD4+ T cells strongly induced after 2 mRNA vax doses w/ slight contraction from peak (again, expected for a normal immune response), then very stable from 3-6 months. CD8s also strong after 2 doses w/ a bit more variability at memory timepoints
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Key take-home messages: 1) SARS-CoV2 recovered people don’t benefit from the 2nd dose by multiple parameters. Might be ok to skip/delay 2nd dose. 2) Age is something to keep an eye on… 3) Memory is important! Especially w/ variants that might escape initial antibody responses
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Some cool human immunology findings led by
@markmpainter
- antibody levels at later time points are highly correlated w/ early CD4+ T cell responses, suggesting that these cells are essential for coordinating the long-term immune response
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Thanks to all the authors and collaborators. Co-first authors
@markmpainter
@s_apostolidis
@divijmathew
have done a lot of the work here w/ constant feedback/support from all of
@WherryLab
@Penn_IFI
. And of course
@EJohnWherry
for his mentorship over the past 8 months
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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:
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Rishi's terrible, horrible, no good, very bad Saturday in lab:
Months of planning, >1 BILLION cells used, 18 hours of pipetting/sorting super rare cells (with excellent purity s/o
@amylizbaxter
@facts___matter
)
Only to get a wetting failure on the
@10xGenomics
chip... 😐
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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
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#2
- Memory B Cells:
These are the backup plan when circulating antibodies go down. They are also harder to measure...
Inspired by
@profshanecrotty
@PepperMarion
@NussenzweigL
& others, we developed a method to quantify SARS-CoV-2-specific memory B cells in the blood
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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
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Data from
@TheBCellArtist
lab has shown that germinal centers are still active in lymph nodes up to 15 weeks post-mRNA vax:
So it is possible that ongoing germinal center activity after vax may continue to improve the quality of memory against variants
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For folks who are older or have other medical conditions, a 4th dose might have a lot of benefit. These folks tend to have lower antibody responses after 3 doses, and our data suggest that the relative benefit of boosting is greatest for individuals with lower pre-boost antibody
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Success is best when it is shared. Celebrating the
@PDSoros
announcement with
@EJohnWherry
and the fam 🥳🥂. Thank you for supporting my medical training and research, and for honoring our New American journey
Rishi Goel (left), a student at
@PennMedicine
, & Kingson Lin, who graduated with degrees from
@PennSAS
, have each received a Paul & Daisy Soros Fellowship for New Americans, providing grad school funding for immigrants & children of immigrants to the U.S.
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--- MEMORY B CELLS ---
Memory B cells are durable after 2 doses w/ no evidence of decay for 9+ months
~50% of memory cells after 2 doses can bind ALL variants (including Omicron)
A 3rd dose of original vaccine efficiently re-activates Omicron-reactive memory cells
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This was team science from the start
@markmpainter
@divijmathew
@s_apostolidis
co-led this work w/
@Bad2theBeaker
@EJohnWherry
. Collabs w/
@Penn_IFI
@SCOTTeHENSLEY
@PaulFBates
@SetteLab
@KirbyInstitute
also critical.
@amylizbaxter
@facts_matter
@OldridgeDerek
helped build methods
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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
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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
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So what does this mean for a 4th dose? That's a lot more complicated... For young, healthy folks a 4th dose might not change the game because they already have high antibody levels after 3 doses and good immune memory
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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
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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
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--- ANTIBODIES ---
Antibody levels stabilize somewhere between 6 and 9 months after primary vaccination
Antibody QUALITY (neutralization potency) continues to increase for 6+ months after primary vaccination
A 3rd dose supercharges the amount and quality of antibody response
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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
These data are consistent w/ findings from
@Dani6020
summarized here by
@profshanecrotty
:
Our newest study is out in Science!
It cover 5 COVID-19 RNA vaccine topics. Using samples from the "low dose" 25mcg Moderna RNA COVID-19 vaccine clinical trial 🧵👇🏼
By the LJI team!
@Dani6020
@SetteLab
@jmateust
@ljiresearch
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Wonderful summary of anti-SARS-CoV-2 immunity by
@profshanecrotty
@SetteLab
Our extensive scientific review of SARS-CoV-2 immune memory is published. Antibodies, CD4 T cells, CD8 T cells, memory B cells, and tissue resident cells. After vaccination, infection, or both, ready to battle COVID-19. Open access:
@SetteLab
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#3
- Memory T Cells:
What about T cells? CD4+ T cells are important for helping antibody and B cell responses. CD8+ T cells are important for killing virus-infected cells
Working with
@SetteLab
,
@markmpainter
@divijmathew
developed an assay to detect SARS-CoV-2 specific T cells
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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
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In summary - mRNA vaccines are awesome... they generate durable B cell memory and a 3rd dose of OG Spike re-activates that memory to produce primo antibodies that work vs. immune-evasive variants like Omicron. We owe a lot to
@kkariko
@WeissmanLab
@KizzyPhD
@BarneyGrahamMD
et al.
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Disagree with this conclusion
@EricTopol
. These data are very consistent with our recent paper:
Antibodies start higher & end higher in hybrid/boosted immunity but the decay rate compared to 2-dose mRNA looks the same. Memory cells more stable over time
Considerable neutralizing antibody decline after both Pfizer and Astra Zeneca vaccines over 3-7 months in over 500 healthcare workers, but much less so in those with prior Covid
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And it's not just quantity - antibody QUALITY also seems to get better for at least 9 months after primary 2-dose vax and improves further after a 3rd dose
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Memory B cells are also VERY effective against variants
After 2 doses of mRNA vax, ~55% of RBD-specific memory B cells recognize Omicron. Most Omicron-reactive memory cells also bind Alpha, Beta, and Delta
We think this is good news for protection against future variants
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Dysregulated type I
#interferon
responses are strongly associated with autoimmune disease. But what about type III interferons?
Our review on the possible effects of interferon lambda (IFNλ) in inflammation & autoimmunity is now online
@NatRevRheumatol
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Lots of talk recently about variant-specific vaccines... But does a 3rd dose of OG vaccine efficiently re-activate Omicron-binding memory B cells?
YES! Omicron-binding memory B cells were boosted/activated as well if not better than cells that did not recognize Omicron
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What about side effects? Turns out you do get some benefit to your antibody response if you had systemic symptoms (i.e fever, chills). No pain, no gain...
But side effects do not impact the generation of memory cells. And even w/o side effects, everybody had a great response
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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
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What about Omicron?
Antibody responses definitely take a hit vs. Omicron and ~20% of people had no detectable neutralization at 9 months post-primary vax. As others have published, boosting does wonders for antibody responses against Omicron
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Will the L452R mutation in new Omicron sub-lineages ruin BA.1-specific vaccines? I don't think so. Most BA.1-binding memory B cells (purple arcs here) in 3x vaccinated individuals also bind Delta which had L452R (orange arcs):
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Check out the full paper for more analysis:
Massive thanks to the whole
@Penn_IFI
@PennMedicine
team led by
@EJohnWherry
@SCOTTeHENSLEY
& co, as well as co-first authors
@s_apostolidis
@markmpainter
@divijmathew
. Nobody does team science better than
@Penn
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How does a 3rd dose compare w/ the much-hyped "hybrid immunity" (infection --> vax)? Antibody potency after a 3rd dose looks similar to the combo of infection + primary vax
Infection + 3X vax does get to higher potency than 3X vax only, so there may be room for improvement still
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What about a potential 4th dose? A 3rd vaccination in individuals with a prior infection let us study what a "second boost" (i.e. 4th dose) might look like...
A 4th exposure resulted in significantly higher neutralizing titers compared to 3X vaccine only
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So what are the take-home points:
1) Probably ok to delay or skip 2nd dose in individuals who previously had COVID
2) 2nd dose important for the quality of immune response in previously uninfected individuals
3) Some association of age & side-effects w/ vaccine response
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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
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Our interpretation of this data - a second boost increases antibodies, but w/ less "bang for your buck" than the 3rd dose. A major factor here is pre-boost antibody levels. High antibody levels before another vax may compete w/ memory cells for antigen and limit boostability
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--- BOOSTABILITY ---
Boosting universally increases antibody titers
A 4th exposure (infection + 3x vax) --> lower fold change in antibodies compared to a 3rd exposure (3x vax only)
Low pre-boost antibodies --> greater fold change in antibodies after boosting (and vice versa)
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Memory B cells - these are the blueprint for making new antibodies on demand if you ever see SARS-CoV-2 again
We tracked the frequency of these cells in the blood and found they remain highly stable over time. A 3rd dose also resulted in an expansion of memory cells
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Finally - this study builds on work from many other labs including
@TheBcellArtist
@profshanecrotty
@SetteLab
@NussenzweigL
@PepperMarion
@sigallab
@deeptabhattacha
@LabTaia
@VirusesImmunity
COVID sucks, but it is remarkable how the community has responded to the challenge
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There is a lot of data in the manuscript not discussed in this thread - check out the full text here for additional analysis:
Happy to answer any questions or share any data/protocols!
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Coolest paper I have read... maybe ever
One of the most impressive T cell papers in the past decades. A truly humbling experiment and incredibly important insights into T cell biology.
@Masopust_Vezys
truly amazing. A must read for all T cell biologist (all immunologists really).
#instantclassic
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So why do we care about measuring memory B cells? As expected, they are associated w/ the magnitude of the recall response...
People with higher frequencies of memory B cells prior to the boost tended to have a greater increase in neutralizing antibodies after the boost
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I summarized a lot of the data in more detail when the pre-print was uploaded:
Happy to answer any questions or share any data with the community
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?
Our latest on immune memory to SARS-CoV-2: . 🧵👇
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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
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We went a step further and mapped out memory responses to different parts of Spike & variants
RBD gets a lot of attention because it is the major target of neutralizing antibodies. OTOH S2 is more conserved w/ other CoVs
mRNA vax generated/boosted memory vs. all parts of spike
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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
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Massive thanks to
@EJohnWherry
@markmpainter
@s_apostolidis
@amylizbaxter
@facts___matter
@SCOTTeHENSLEY
and all our collaborators
@PennMedicine
@Penn_IFI
and other institutions. This is probably my last COVID story, but stay tuned for some very cool T cell data from the lab
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To all the haters that said we don’t have a national testing strategy…
@TheYankeeCandle
thank you for your service
@drewtoothpaste
Here's a plot of the "no smell" complaints for the top three Yankee Candles on Amazon.
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TFW you get quoted alongside
@EJohnWherry
@VirusesImmunity
and TONY FAUCI
Fantastic reporting and
#scicomm
on what we know about immunity from vaccine vs. infection by
@KatherineJWu
@TheAtlantic
in advance of the upcoming news on boosters, I wrote about a different way in which we're arguing about how much immunity is "enough": what's the exchange rate between infection and inoculation? should the once-infected count as (partially) vaccinated? 1/
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If you instead look at boosting as a fold-change in antibody responses, you get a slightly different picture
A 4th exposure resulted in a lower fold-change of antibodies compared to 3X vax only and the fold change in antibody was inversely correlated w/ pre-boost antibody levels
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None of this would have been possible without an amazing team. S/o to
@EJohnWherry
@markmpainter
@s_apostolidis
@amylizbaxter
@facts___matter
@SCOTTeHENSLEY
@PaulFBates
and all our amazing collaborators at
@PennMedicine
@Penn_IFI
and
@UNSW
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Epic journey is an understatement. Another remarkable paper on the evolution of B cell responses after mRNA vaccination by
@TheBcellArtist
. The fact that there are still SARS-CoV-2-specific GC B cells doing their GC thing at 6 MONTHS is 🤯
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YES. John and I have been going on about this for months… breakthrough implies failure which really undersells the efficacy of vaccination
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4) For the immunology nerds out there - we also show that taking a snapshot of just antibody levels post-boost is not a good predictor of memory cells. And baseline memory cells in SARS-CoV2 recovered folks correlate strongly with antibody recall responses post-vax
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Politics x Med-Ed. The most important collab of 2020. Our letter is now online
@AcadMed
@nolankavanagh
. We argue that teaching about politics during medical education is necessary to better diagnose and treat structural inequities in health 🩺
#MedTwitter
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These findings build on data from
@TheBcellArtist
@profshanecrotty
@SetteLab
@NussenzweigL
@PepperMarion
@deeptabhattacha
@LabTaia
@SutharLab
@VirusesImmunity
@BioNTech_Group
and others. Will be important to see how variant-specific vaccines activate/reshape the memory response
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Taking a moment to celebrate what we accomplished with
@OneCampaignMI
@MichiganDems
. Working on this campaign for the past 6 months has shown me that
#politics
and
#medicine
are inseparable. The campaign might be over, but our work continues
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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
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Relationships btw these different measures of immunity: do antibodies predict memory (or vice versa)?
Turns out that just measuring post-boost antibodies doesn't tell us much about memory. BUT baseline memory does predict antibody recall upon re-exposure in recovered folks
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I love B cells more than most people (literally work on B cells in a T cell lab), but this is some good stuff by
@KatherineJWu
. We are still figuring out how important T cells are in preventing severe COVID-19, but there are reasons for optimism, even with variants like Omicron
infected cell: help, I've been compromised
T cell: no problem. how would you like to die horrifically
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With all the commentary on Twitter about the omicron neutralization data that just dropped, it’s worth reading this great article from
@KatherineJWu
. I’m usually all about quality > quantity, but sometimes, dips in immunization quality can be rescued with a little extra quantity
1. drops in neutralization are NOT equivalent to drops in vaccine effectiveness
2. vaccinations and boosts raise antibody levels very high, providing a cushion for drops
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Another question we get a lot: how does age affect vaccine response?
There is a slight negative trend btw/ age and antibodies
We do see a stronger association btw/ age and memory B cells post-boost, but everyone is still over baseline so something to keep an eye on longer-term
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@sian8281
@ScienceMagazine
@aaas
@UofPenn
@PennMedicine
@Penn_IFI
@PennMedNews
@gavi
@EJohnWherry
@SciImmunology
@ljiresearch
Quite the contrary! Our data suggest that the vaccine-induced responses are still effective against variants even at 6 months. Additional doses will significantly increase antibody levels in the short-term, but likely not forever (whereas memory cells stick around for longer)
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Nice work by
@deeptabhattacha
and co. on vax response in cancer pts. Also interesting that memory B cells don't predict antibody recall to 3rd mRNA dose in this cohort. Will be super interesting to decode the functional differences in the biology here
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This is the correct framing IMO. 2 dose vaccine is still really good. Booster dose tops up antibodies and pushes VE against symptomatic infx to ridiculous numbers at least in the short-term. Will be important to monitor how long this boosted protection vs. infx lasts
To put into perspective. VE for Pfizer vs. symptomatic infxn @ 11 months from their crossover study is estimated @ ~77%. A 95.6% improvement on that is a VE of ~99%. That's better than the initial RCT. What's that mean? That a really effective 2 dose vax is even better w/ 3 doses
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