Low-dose IL-2 reduces IL-21+ T cells and induces a long-lived anti-inflammatory gene expression signature inversely modulated in COVID-19 patients (preprint)

Despite early clinical success, the mechanisms of action of low-dose interleukin-2 (LD-IL-2) immunotherapy remain only partly understood. Here, we examine the effects of interval administration of low-dose recombinant IL-2 (iLD-IL-2) using high-resolution, single-cell multiomics. We confirmed that iLD-IL-2 selectively expands thymic-derived FOXP3 + HELIOS + Tregs and CD56 br NK cells, and provide new evidence for an IL-2-induced reduction of highly differentiated IL-21-producing CD4 + T cells. We also discovered that iLD-IL-2 induces an anti-inflammatory gene expression signature, which was detected in all T and NK cell subsets even one month after treatment. The same signature was present in COVID-19 patients, but in the opposite direction. These findings indicate that the sustained Treg and CD56 br NK cell increases induced by our 4-week iLD-IL2 treatment create a long-lasting and global anti-inflammatory environment, warranting further investigations of the potential clinical benefits of iLD-IL-2 in immunotherapy, including the possibility of reversing the pro-inflammatory environment in COVID-19 patients.

Durability of ChAdOx1 nCoV-19 vaccination in people living with HIV.

Duration of protection from SARS-CoV-2 infection in people living with HIV (PWH) following vaccination is unclear. In a substudy of the phase II/III the COV002 trial (NCT04400838), 54 HIV+ male participants on antiretroviral therapy (undetectable viral loads, CD4+ T cells > 350 cells/µL) received 2 doses of ChAdOx1 nCoV-19 (AZD1222) 4-6 weeks apart and were followed for 6 months. Responses to vaccination were determined by serology (IgG ELISA and Meso Scale Discovery [MSD]), neutralization, ACE-2 inhibition, IFN-γ ELISpot, activation-induced marker (AIM) assay and T cell proliferation. We show that, 6 months after vaccination, the majority of measurable immune responses were greater than prevaccination baseline but with evidence of a decline in both humoral and cell-mediated immunity. There was, however, no significant difference compared with a cohort of HIV-uninfected individuals vaccinated with the same regimen. Responses to the variants of concern were detectable, although they were lower than WT. Preexisting cross-reactive T cell responses to SARS-CoV-2 spike were associated with greater postvaccine immunity and correlated with prior exposure to beta coronaviruses. These data support the ongoing policy to vaccinate PWH against SARS-CoV-2, and they underpin the need for long-term monitoring of responses after vaccination.