Deep immune profiling of COVID-19 patients reveals distinct immunotypes with therapeutic implications

Immune profiling of COVID-19 patients Coronavirus disease 2019 (COVID-19) has affected millions of people globally, yet how the human immune system responds to and influences COVID-19 severity remains unclear. Mathew et al. present a comprehensive atlas of immune modulation associated with COVID-19. They performed high-dimensional flow cytometry of hospitalized COVID-19 patients and found three prominent and distinct immunotypes that are related to disease severity and clinical parameters. Arunachalam et al. report a systems biology approach to assess the immune system of COVID-19 patients with mild-to-severe disease. These studies provide a compendium of immune cell information and roadmaps for potential therapeutic interventions. Science, this issue p. eabc8511, p. 1210 Immune responses of COVID-19 patients are cataloged and compared with those of healthy individuals. INTRODUCTION Many patients with coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, present with severe respiratory disease requiring hospitalization and mechanical ventilation. Although most patients recover, disease is complex and case fatality can be as high as 10%. How human immune responses control or exacerbate COVID-19 is currently poorly understood, and defining the nature of immune responses during acute COVID-19 could help identify therapeutics and effective vaccines. RATIONALE Immune dysregulation during SARS-CoV-2 infection has been implicated in pathogenesis, but currently available data remain limited. We used high-dimensional cytometry to analyze COVID-19 patients and compare them with recovered and healthy individuals and performed integrated analysis of ~200 immune features. These data were combined with ~50 clinical features to understand how the immunology of SARS-CoV-2 infection may be related to clinical patterns, disease severity, and progression. RESULTS Analysis of 125 hospitalized COVID-19 patients revealed that although CD4 and CD8 T cells were activated in some patients, T cell responses were limited in others. In many patients, CD4 and CD8 T cell proliferation (measured by KI67 increase) and activation (detected by CD38 and HLA-DR coexpression) were consistent with antiviral responses observed in other infections. Plasmablast (PB) responses were present in many patients, reaching >30% of total B cells, and most patients made SARS-CoV-2–specific antibodies. However, ~20% of patients had little T cell activation or PB response compared with controls. In some patients, responses declined over time, resembling typical kinetics of antiviral responses; in others, however, robust T cell and PB responses remained stable or increased over time. These temporal patterns were associated with specific clinical features. With an unbiased uniform manifold approximation and projection (UMAP) approach, we distilled ~200 immune parameters into two major immune response components and a third pattern lacking robust adaptive immune responses, thus revealing immunotypes of COVID-19: (i) Immunotype 1 was associated with disease severity and showed robust activated CD4 T cells, a paucity of circulating follicular helper cells, activated CD8 “EMRAs,” hyperactivated or exhausted CD8 T cells, and PBs. (ii) Immunotype 2 was characterized by less CD4 T cell activation, Tbet+ effector CD4 and CD8 T cells, and proliferating memory B cells and was not associated with disease severity. (iii) Immunotype 3, which negatively correlated with disease severity and lacked obvious activated T and B cell responses, was also identified. Mortality occurred for patients with all three immunotypes, illustrating a complex relationship between immune response and COVID-19. CONCLUSION Three immunotypes revealing different patterns of lymphocyte responses were identified in hospitalized COVID-19 patients. These three major patterns may each represent a different suboptimal response associated with hospitalization and disease. Our findings may have implications for treatments focused on activating versus inhibiting the immune response. High-dimensional immune response analysis of COVID-19 patients identifies three immunotypes. Peripheral blood mononuclear cell immune profiling and clinical data were collected from 60 healthy donors (HDs), 36 recovered donors (RDs), and 125 hospitalized COVID-19 patients. High-dimensional flow cytometry and longitudinal analysis highlighted stability and fluctuations in the response. UMAP visualization distilled ~200 immune features into two dimensions and identified three immunotypes associated with clinical outcomes. cTfh, circulating T follicular helper cells; EMRA, a subset of effector memory T cells reexpressing CD45RA; d0, day 0. Coronavirus disease 2019 (COVID-19) is currently a global pandemic, but human immune responses to the virus remain poorly understood. We used high-dimensional cytometry to analyze 125 COVID-19 patients and compare them with recovered and healthy individuals. Integrated analysis of ~200 immune and ~50 clinical features revealed activation of T cell and B cell subsets in a proportion of patients. A subgroup of patients had T cell activation characteristic of acute viral infection and plasmablast responses reaching >30% of circulating B cells. However, another subgroup had lymphocyte activation comparable with that in uninfected individuals. Stable versus dynamic immunological signatures were identified and linked to trajectories of disease severity change. Our analyses identified three immunotypes associated with poor clinical trajectories versus improving health. These immunotypes may have implications for the design of therapeutics and vaccines for COVID-19.