Thread by @markmpainter

Our study on T cell responses to SARS-CoV-2 mRNA vaccines is up!

Are T cells primed by the vaccines?
Do they have features of long-lived memory cells?
Do they contribute to the overall immune response?

A thread on the key findings below 🧵

biorxiv.org/content/10.110…

First of all and most importantly, this was a great team effort alongside co-first authors @divijmathew, @rishirajgoel, and @s_apostolidis. It is a thrill to work with such brilliant and dedicated scientists every day.

So, do T cells that specifically respond to SARS-CoV-2 get activated by the vaccine? Yes! We saw priming of both CD4+ and CD8+ T cells with mRNA vaccination. The CD4 response was rapid and universal - everyone responded after one dose, regardless of prior SARS-CoV-2 infection.

The CD8 response developed more gradually and was more variable, but overall 85% of people who never had COVID had detectable SARS-CoV-2-specific CD8+ T cells after the boost. No significant boosting of CD8s for recovered people.

Overall, recovered people see no benefit to T cells from the second dose, whereas naive people clearly benefit.

We also didn't see any decline in T cell responses with increasing age, in contrast with what we and others have shown for antibodies and memory B cells. Great news!

Now that we found these SARS-CoV-2-specific T cells, what can we learn about them? First, they seem to have characteristics of long-lived memory cells (CD45RA- CD27+), falling in central memory and EM1 subsets, which resembles the memory response to SARS-CoV-2 infection.

Given the robust CD4+ T cell response, we also looked at T helper subsets. We observed clear induction of SARS-CoV-2-specific Th1 and T follicular helper (Tfh) cells by the vaccine, which were the same helper cells activated during natural SARS-CoV-2 infection. Does this matter?

It turns out, yes! Th1 and Tfh cells help the maturation of CD8+ T cell and B cell/antibody responses, respectively. We observed that Th1 cells primed by the first dose strongly correlated with CD8 responses to the second dose, and the same for Tfh with neutralizing antibodies.

This suggests that the CD4+ T cell response to the first dose plays a key role in the developing immune response to the second dose. Early priming of CD4+ T cells may be very important to the overall immunity generated by vaccination. Look at all of those correlations!

Lastly, we compiled 26 antigen-specific measures of T cell, B cell, and antibody responses into high-dimensional UMAP space to visualize the dynamics of the vaccine-elicited immune response. The UMAP1 coordinate captures the overall immune response against SARS-CoV-2.

This analysis revealed a dynamic and coordinated immune response to vaccination. It also highlights the importance of both doses of vaccine in people who haven't had COVID-19 to achieve optimal immunity, while only a single dose is needed for those who have recovered from COVID.

So, here are the key takeaways:
- T cells are activated by the vaccines
- They should be good, long-lived memory cells
- The universal CD4 response to the first dose (Th1 and Tfh) may be critical to overall immunity
- Two doses for naive, one for recovered

Huge shoutout to the whole @PennMedicine and @Penn_IFI team led by @EJohnWherry and the whole Wherry lab, and thanks for critical contributions from the @ljiresearch team @SetteLab @Alba_Grifoni @Dani6020.

Check out the full article for more: biorxiv.org/content/10.110…