Thread by @virusmonologues

We have new results on T cell responses to #Omicron, and its good news!
Paper submitted for peer review & preprint:
medrxiv.org/content/10.110…

📢TL;DR: Most of your T cell responses from vaccination or previous infection still recognise Omicron.
#Getvaccinated #GetthoseTcellsnow

We describe T cell responses to #Omicron compared to original SARS-CoV-2 in ppl vaxxed with JnJ (1x and 2x) and Pfizer (2x). We also studied Omicron-infected patients and compared their T cells to patients hospitalised in previous waves (n=138 participants in total).

Why did we do this study?
Omicron has >30 mutations in its Spike protein, and many studies now show that this knocks out a lot of the neutralising antibody binding sites. 💩
We wanted to check if other parts of the immune system - T cells - still recognise Omicron Spike. 🎯

Unlike antibodies, which bind in hotspots, T cells can target the whole of Spike - shown as a mountain range, with Omicron mutations in red.
So we expect that T cells would still be able to target Omicron- even though it has lots of changes, there is lots of Spike NOT mutated.

Why is this important?‼️👇🏾
While antibodies block infection, T cells come in and kill infected cells, preventing the virus from growing & spreading more & causing worse disease
They can't prevent you from getting infected, but they can minimise the damage that comes afterwards..

How did we do this study?
We measured T cell responses using peptides -small chopped up bits of proteins that T cell recognise.
We compared a pool of peptides based on the original (“Ancestral”) SARS-CoV-2 and Omicron spike protein.

🙏🏾🙏🏾 @SetteLab for sending us the peptides

We isolate white blood cells from patient samples,
mix the cells with the peptides, and then use a technique called intracellular cytokine staining and flow cytometry, to check for a T cell response.
We measured both CD4 ‘helper’ cells and CD8 ‘killer’ cells.

Results - First CD4 T cells:
Compared to ancestral virus, there was a small decrease when tested against Omicron spike.
This was a consistent decrease across all study groups.
However, most of the CD4 T cell response was still there and cross-recognised Omicron.

Next, CD8 T cells:
Here too, compared to ancestral virus, there was a small decrease when tested against Omicron spike for some of the groups, no major change for most people.

If we plot fold-change of Omicron responses compared to ancestral, we see that 70-80% of T cell responses are preserved.
This means that most people who were vaccinated with 1x / 2xJnJ, 2xPfizer & those who had COVID 1-6 mo ago, still have T cells that can recognise Omicron.

Important to point out - there were a minority of CD8 T cell “knockouts”.
These represent people who may have had a narrower response targeting only a few regions in Spike, that happened to coincide with mutations in Omicron and a specific HLA bkg – we’ll be following up on these

When we compared the cross-reactivity of T cells to Omicron with Beta and Delta variants, we found that they were very similar, even though Omicron has 3-4x more spike mutations than Beta and Delta.
This emphasises just how robust the T cell response is.

This is consistent with what we recently published on cross-reactivity of the T cell response to the Beta variant:
science.org/doi/epdf/10.11…

To get a full picture of immunity, @sigallab and @PennyMo70026063 measured neutralising antibody responses in the same participants.
You can see that while neutralisation is substantially decreased in most people, overall their T cell responses are only impacted in a small way.

South Africa’s COVID epidemic is characterised by virologically distinct waves, each dominated by a different form of the virus – first original, then Beta, Delta and now Omicron.
Next we tested blood samples from each wave & compared them to patients from the 4th wave (Omicron)

We measured T cell responses to Spike, Nucleocapsid and Membrane proteins (viral proteins most targeted by T cells when you become infected).
Omicron-infected patients had T cell responses in the same range as patients hospitalised with ancestral, Beta or Delta virus infection.

Finally, we also tested some Omicron-infected patients with ancestral and Omicron Spike, and there was hardly any difference between them, showing that most of the parts of Spike that people make T cell responses to are conserved - parts that are not affected by the mutations.

Conclusions:
Despite Omicron having so many mutations, and lower antibody activity, the majority of T cell responses, from vaccination or infection, cross-recognise the new variant.

The limited effect of Omicron’s mutations on the T cell response suggests that vaccination or prior infection may still provide protection from severe disease

Well-preserved T cell immunity to Omicron is consistent with early clinical observations from South Africa, UK and Scotland of lower severity - a decoupling of case loads from hospitalisations, and shorter hospital stays, which may be due to this remaining T cell immunity

Finally: The resilience of the T cell response demonstrated here also bodes well in the event that more highly mutated variants emerge in the future.
We still need to see how long T cell immunity lasts, but after SARS1 it was still detectable after 17yrs..
nature.com/articles/s4158…

Who did the work? 🔬🧪🩸😓
Dr Roanne Keeton is the amazing researcher who generated much of the T cell data, along with my lab team, and I co-led this work with the brilliant Dr Catherine Riou.

This work was also made possible by wonderful collaborators, esp. @Ntobekon and @SetteLab, @VreemdeSiekteDr, @sigallab, @PennyMo70026063, @tuliodna, @Alba_Grifoni, @BhimanJinal, @LindaGailBekker, @houzhou, @just_Thande, @KhadijaKhan24 and many others who contributed to this work

Thank you to all the volunteers and patients who made this work possible, and our funders @MRCza @EDCTP @CIDRI_Africa @UCTIDM @UCT_news @wellcometrust

Shout out to @Biocair for all their efforts in getting critical reagents to us when they were stuck in Dubai because of NONSENSICAL TRAVEL BANS

And for those who may be interested in our work:
@GuptaR_lab @EricTopol @apoorva_nyc @GretchenVogel1 @Williams_T_C @KatherineJWu @krisp_news @jessbreadman