SARS-CoV-2 sculpts the immune system to induce sustained virus-specific naïve-like and memory B cell responses

Abstract

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. Here, we longitudinally studied moderate to severe COVID-19 patients to dissect SARS-CoV-2-specific B cell responses overtime. We found a broad virus-specific antibody response 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 that 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. 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.

The mRNA-1273 Vaccine Induces Cross-Variant Antibody Responses to SARS-CoV-2 With Distinct Profiles in Individuals With or Without Pre-Existing Immunity

“…Following primary immunization, individuals with preexisting immunity showed increased titers of all antibodies except IgG3 against WT and VOCs, when compared to SARS-CoV-2 naïve subjects. Our data were consistent with recent studies that reported the presence of pre-existing SARS-CoV-2-specific and cross-variant specific-memory B cells in COVID-19 recovered subjects (16,17,19,20,35). In line with our results, a recent report showed a strong correlation between the frequency of SARS-CoV-2-specific memory B cells at baseline and the antibody concentrations following vaccination (6).…”

“…Following the first vaccine dose, COVID-19 recovered individuals show significantly higher Sand RBD-specific IgG titers, superior serum neutralization activity (7,(12)(13)(14), and increased S protein-specific memory T and B cell responses than naïve individuals (4)(5)(6)15). This enhanced response is consistent with the persistence of humoral and cellular immunity against SARS-CoV-2 in convalescent individuals, as previously reported (16)(17)(18)(19)(20).…”

“…Recent studies have shown that IgG1 and IgG3 subclasses are strongly induced soon after SARS-CoV-2 infection, whereas IgG2 and IgG4 subclasses are induced to a much lesser extent (10,16,21). In recovered individuals, humoral and B cell memory responses appeared to be IgG1-dominated (16,19). SARS-CoV-2 infection also induced virus-specific IgM, IgA1 and, to a lesser extent, IgA2, which all wane during convalescence (16).…”

“…In recovered individuals, humoral and B cell memory responses appeared to be IgG1-dominated (16,19). SARS-CoV-2 infection also induced virus-specific IgM, IgA1 and, to a lesser extent, IgA2, which all wane during convalescence (16).…”

SARS-CoV-2 naïve and recovered individuals show qualitatively different antibody responses following mRNA vaccination

“…Following the first vaccine dose, COVID-19 recovered individuals show significantly higher S-and RBD-specific IgG titers, superior serum neutralization activity 7,11–13 , even against SARS-CoV-2 variants 8,14,15 , and increased S protein-specific memory T and B cell responses than naïve individuals 4–6,14 . This enhanced response is consistent with the persistence of humoral and cellular immunity against SARS-CoV-2 in convalescent individuals, as previously reported 16–20 . Because a recall immunization does not seem to provide any quantitative benefit in subjects with pre-existing immunity to SARS-CoV-2 6,7,13 , it has been proposed that COVID-19 recovered people may only require a single vaccine dose to achieve optimal immune protection 6,7,13 .…”