Thread by @MonicaGandhi9

Antibodies wane (major line of defense in nasal passage); may be more susceptible to mild re-infections (omicron); enduring immunity of T cells, ability of B cells to kick in, produce adaptive antibodies toward variants protects against severe disease
leaps.org/how-long-do-co…

Because Omicron variant is latest, we have to examine whether T cells from vaccine or prior infection work well against it and this paper shows us they do! From NIAID & other institutions. Literally only ONE T cell epitope affected by the 32 mutations
biorxiv.org/content/10.110…

"Virtually all individuals with existing anti-SARS-CoV-2 CD8+ T-cell responses should recognize Omicron". This study done in recovered but work in "vaccinees has demonstrated a strong CD4+ and CD8+ T-cell responses suggesting that similar trends" will be seen among vaccinated

Study from Pfizer verifying T cells from vax remain active against Omicron. When antibodies down "virus breaches defenses, cells become infected, that’s when T-cells come in, clear infected cells so they don’t keep replicating and become viral factories"
theguardian.com/world/2021/dec…

An attempt to explain cellular immunity by @MichaelDaignau3 and me from real-world perspective on the ground. Cellular immunity will not prevent re-infections (mild) though; its impact is deeper
washingtonpost.com/outlook/2021/1…

T cell paper: n=70 with J&J vs Pfizer vax vs those with COVID recovery. T cells provide protection across the Omicron spike protein (70-80% of CD4 & CD8 T cell response to spike maintained), same protection as with beta AND delta (despite more mutations)
medrxiv.org/content/10.110…

Today a very nice article in Vox explaining T cells and B cells and antibodies; worth a read if you don't want to read the papers above since summarized really well
vox.com/22878133/omicr…

Important paper to add to this thread. If you got Omicron on top of vaccine, you get broadly neutralizing antibodies but also T cells across whole virus so protects you against alpha, beta, gamma, delta (and zeta in future, immunity across whole virus)
biorxiv.org/content/10.110…

Although have many said "we will all be exposed to Omicron" now since so transmissible, not everyone will; Covaxin booster great for those who didn't get during this time as 1) EUA pending, FDA; 2) whole inactivated virion virus so see whole virus

https://twitter.com/mikalche/status/1483106055328518152

Why would whole inactivated virion (via Covaxin) booster be good if we don't get Omicron during this time of high transmission? Because you then form T cells across the entire virus - more than 1400 - so can combat variants in future
sciencedirect.com/science/articl…

Breakthrough infections induce serum binding/ neutralizing antibody responses markedly more potent, durable and resilient to spike mutations observed in variants than those who received 2 doses of spike protein vax (may need whole virus vax)
sciencedirect.com/science/articl…

Explains cellular immunity in a quick and thorough way. "The cells will save us". We expect antibodies to wane from vax (which is why boosters during Omicron surge helped) but the cellular memory stable at 450 days & counting and, importantly, adaptive
nature.com/articles/d4158…

Good explanation of T cell response to SARS-CoV-2 from recent Nature Immunology article
nature.com/articles/s4159…

Excellent recent article to add to cellular immunity vs antibody response to Omicron. Booster increased antibody responses which was needed in those who can't wait for memory B cells to make antibodies (older) but SARS-CoV-2-specific T-cells
science.org/doi/10.1126/sc…

6 months after all vaccination regimens, with more consistent detection of specific CD4+ than CD8+ cells. No significant differences were detected between wild type & variant-specific CD4+ or CD8+ T-cell responses, including Omicron, indicating minimal escape at the T-cell level

Great article Science on cellular immunity, may help US on booster strategy "much focus in.. immunity surveillance has been on role of neutralizing antibodies..less emphasis on understanding role of T cells, memory B cells and non-neutralizing antibodies"
science.org/doi/10.1126/sc…

"Mounting evidence (I would argue we have known about T cells for long time!) suggests T-cell contributions to the host immune response are required for early, broad, and durable protection from SARS-CoV-2, especially in the setting of new variants of concern"; T cells provide

durable protection Want T cells across whole virus? Give whole virus vaccine. "Because Covaxin shows immune system the entire virus, the vaccine elicits a broad immunologic response not only against spike, but also against the receptor-binding domain, the
medpagetoday.com/opinion/second…

nucleocapsid protein of SARS-CoV-2, other parts of the virus. The vaccine also elicits strong cellular T-cell mediated immune responses, vital for long-term protection". Excellent tweet @profshanecrotty -multiple layers of protection in immune system

https://twitter.com/profshanecrotty/status/1509543057145819139

Cell paper focuses on durability of memory B cells: NO evidence of decay >9 months post vaccination. Boost will reactivate B cells to make antibodies, not needed if you already have high antibodies (eg 4th dose); breakthrough- same increase in Abs as boost
cell.com/cell/fulltext/…

As US debates 4th shot, ? comes up whether even 3rd shot makes B cells longer lasting; above paper did not show that. Below paper on T cells >80: 3rd shot increases antibodies but "CD4 T-cell frequencies reached similar levels after two and three doses "
thelancet.com/journals/lanin…

Important article that shows that every vaccination or exposure to COVID-19 expands and diversifies T cells
nature.com/articles/s4159…

Recent article about Omicron (>=32 mutations in spike) in vax'd: "despite mutations in spike protein, Omicron recognized by cellular component of immune system.. reasonable to assume protection from hospitalization and severe disease will be maintained"
jamanetwork.com/journals/jaman…

Please remember cellular immunity is not just T cells but also B cells- they produce antibodies if virus seen again aided by T cells but the antibodies are adapted to the variant they see in front of them

https://mobile.twitter.com/monicagandhi9/status/1443016556460470272?s=10

Question on whether variant-specific booster needed in future; study in above thread in macaques showed 3rd shot with "old" vaccine stimulated B cells & protected macaques to same extent as getting Omicron-specific booster due to B cells. New paper here:
nature.com/articles/s4158…

3rd shot (boost) increases frequency of Omicron-receptor binding domain (RBD) binding memory B cells, a site on spike protein that is more conserved across variants (part that sticks to cell). So, 3rd shot stimulates B cells that work across parts of virus same in all variants

Epidemiologically, we saw 3rd shot of great benefit to older individuals in terms of protection against severe disease during Omicron in this large VA study

https://twitter.com/MonicaGandhi9/status/1523153566340321280

This is why 4th shot likely will be needed for older individuals (and immunocompromised) in late summer to prepare for seasonal fall/winter respiratory pathogen season to protect these populations against severe disease
washingtonpost.com/outlook/2022/0…

If you read these long threads on cellular immunity, the ability of vaccines to prevent severe disease with COVID will become more clear; which is a HUGE benefit of vaccines

https://twitter.com/MonicaGandhi9/status/1524038482565353472

Amazing paper @SetteLab Cell today comparing cohorts Pfizer, Moderna, AztraZeneca, Novavax
1) 100% mRNA/Novavax vaccinees made CD4 cells
2) mRNA/AZ vaccinees similar % CD8 cells
3) Infection or AZ inc memory B cells
4) Antibodies wane; B/T cells stable
cell.com/cell/fulltext/…

CD4 and CD8 are T cells against SARS-CoV-2 and memory B cells being stimulated help produce more antibodies. Antibodies waning (or not working as well against variants) happening but preservation of B/T cells generated by vaccination very heartening
leaps.org/how-long-do-co…

Saw article yesterday -those with previous infection didn't have T cell response broadened by Omicron?Sample size tiny (6 prior Wuhan Hu-1 infection). Doesn't negate huge body of research on cellular immunity above. New test for cellular immunity below!
nature.com/articles/s4158…

The profound decoupling between cases & severe disease at this stage of the pandemic is mainly due to cellular immunity (for instance, Chicago has had zero COVID deaths June 6-10: chicago.gov/city/en/sites/…; Marin none since March) - B cells
T cells here:

https://twitter.com/MonicaGandhi9/status/1505928423553699843

Nice review why T cells so important to combat variants: "As we adapt to coexist with SARS-CoV-2"..need T cell assays. 1 large study (n=3000) w/ T-SPOT Discovery SARS-CoV-2 assay shows SARS-CoV-2–reactive T cells protect from COVID & last long time
science.org/doi/10.1126/sc…

This article explains why - even with BA4/BA5- rates of severe disease staying lower than any time since March '20 across much of the world due to cellular immunity @Medscape
medscape.com/viewarticle/97…

Although above cellular immunity thread has good papers, this review @profshanecrotty great (see figure). 1) Hybrid immunity strongest of all (if haven't had covid, hopefully #covaxin whole virus vax coming; 2) T/B cells last long from infection or vax
onlinelibrary.wiley.com/doi/10.1111/im…