Abstract
OBJECTIVES: SARS-CoV-2 infection induces virus-reactive memory B cells expressing unmutated antibodies, which hints at their emergence from naïve B cells. Yet, the dynamics of virus-specific naïve B cells and their impact on immunity and immunopathology remain unclear. METHODS: We longitudinally profiled SARS-CoV-2-specific B-cell responses in 25 moderate-to-severe COVID-19 patients by high-dimensional flow cytometry and isotyping and subtyping ELISA. We also explored the relationship of B-cell responses to SARS-CoV-2 with the activation of effector and regulatory cells from the innate or adaptive immune system. RESULTS: We found a virus-specific antibody response with a broad spectrum of classes and subclasses during acute infection, which evolved into an IgG1-dominated response during convalescence. Acute infection was associated with increased mature B-cell progenitors in the circulation and the unexpected expansion of virus-targeting naïve-like B cells. The latter further augmented during convalescence together with virus-specific memory B cells. In addition to a transitory increase in tissue-homing CXCR3(+) plasmablasts and extrafollicular memory B cells, most COVID-19 patients showed persistent activation of CD4(+) and CD8(+) T cells along with transient or long-lasting changes of key innate immune cells. Remarkably, virus-specific antibodies and the frequency of naïve B cells were among the major variables defining distinct immune signatures associated with disease severity and inflammation. CONCLUSION: Aside from providing new insights into the complexity of the immune response to SARS-CoV-2, our findings indicate that the de novo recruitment of mature B-cell precursors into the periphery may be central to the induction of antiviral immunity.