Thread by @BenIsraelow

I am excited to share our new preprint detailing our exploration into the adaptive immune determinants of viral clearance and protection from SARS-CoV-2!!
🧵 (1/n)

biorxiv.org/content/10.110…

Translation: Good news!! Antibodies from infection or vaccination protect against reinfection or infection by emerging variants.

Thanks to my mentor @VirusesImmunity, and my coauthors @tianyangmao @sneakyvirus1 @ericsongg @biobridget @SaadOmer3 for all their contributions. (2/n)

The Details: early on in the pandemic questions arose regarding how SARS-CoV-2 is cleared during acute/primary infection and what aspects of the adaptive immune were necessary and sufficient for protection from repeat infection. (3/n)

We wanted to mechanistically address this. So we utilized our recently described mouse model, which allows for infection of mice of any genetic background. (4/n)

rupress.org/jem/article/21…

We had previously shown that mice lacking innate immunity were perfectly competent in clearing acute SARS-CoV-2 infection. We start by showing that mice deficient in adaptive immunity (RAG-/-) are unable to clear infection. (5/n)

However, mice without functional B cells (uMT) and who cannot produce new antibodies, have reduced but not completely deficient clearance capacity, suggesting that T cell immunity plays a role. (6/n)

To assess the T cell component of SARS-CoV-2 clearance during acute infection, we depleted either CD4 T cells or CD8 T cells, or both, and found that depletion of either CD4 or CD8 led to reduced viral clearance. Depletion of both acted synergistically. (7/n)

We also found that anti-SARS-CoV-2 antibody development was significantly hamstrung in CD4 T cell-depleted mice, confirming their importance in anti-SARS-CoV-2 antibody development. (8/n)

To assess the T cell component of viral clearance in the absence of antibody responses, we performed CD4 and CD8 depletion in B cell-deficient 🐭 (uMT). In the absence of antibodies, CD8 T cells were necessary for clearance, while CD4 T cells played only a small role. (9/n)

These results are largely consistent with studies by @profshanecrotty, @SetteLab, @EJohnWherry, and many others, which have shown that defects in one arm of adaptive immunity can slow viral clearance and clinical resolution of COVID-19 in patients. (10/n)

pubmed.ncbi.nlm.nih.gov/33497610/

But, it has been difficult to assess the determinants of protection in patients. To address this, we started by performing adoptive transfer of either T cells or serum from previously infected mice and found that serum provided superior protection. (11/n)

Finally, we wondered if CD8 T cells or antibodies, or both, were required for protection in the setting of vaccine- or infection-induced immunity. We hypothesized that there may be a difference because infection induces lung T resident memory cells, while vaccines do not. (12/n)

To test this hypothesis we infected mice who were either convalescent or vaccinated with either homologous (WA1) strain or VOC (B.1.351) known to evade humoral immunity and performed these infections in the setting of local and systemic CD8 depletion. (13/n)

While B.1.351 was able to replicate better than homologous WA1 strain in either vaccinated or convalescent 🐭 none developed any clinical signs of infection and all of the naive mice succumbed by 4 days. (14/n)

These data suggest that protection is largely mediated by antibody response and not cellular immunity, and highlight the in vivo protective capacity of antibodies generated to both vaccine and natural infection. (15/end)