COVID-19 and plasma cells: Is there long-lived protection?

Abstract

Infection with SARS-CoV-2, the etiology of the ongoing COVID-19 pandemic, has resulted in over 450 million cases with more than 6 million deaths worldwide, causing global disruptions since early 2020. Memory B cells and durable antibody protection from long-lived plasma cells (LLPC) are the mainstay of most effective vaccines. However, ending the pandemic has been hampered by the lack of long-lived immunity after infection or vaccination. Although immunizations offer protection from severe disease and hospitalization, breakthrough infections still occur, most likely due to new mutant viruses and the overall decline of neutralizing antibodies after 6 months. Here, we review the current knowledge of B cells, from extrafollicular to memory populations, with a focus on distinct plasma cell subsets, such as early-minted blood antibody-secreting cells and the bone marrow LLPC, and how these humoral compartments contribute to protection after SARS-CoV-2 infection and immunization.

Keywords: COVID-19; SARS-CoV-2; antibody secretion; antibody-secreting cell; long-lived plasma cell.

FIGURE 1

B cell response development in COVID‐19. Primary infection with SARS‐CoV‐2 results in a spectrum of disease severity with differing impacts on humoral response development. (Right) Mild COVID‐19 or vaccination results in a GC‐focused response, allowing normal accumulation of somatic hypermutation, affinity maturation, memory formation, and plasma cell development. The extent of LLPC development in GC‐focused COVID‐19 responses remains a critical open question with important implications in response longevity. (Left) Severe/critical COVID‐19 results in an extrafollicular (EF)‐biased response with the rapid development of low‐mutation effector B cells (DN2) and plasmablasts. While the neutralizing capability of these populations has been confirmed, the impact of EF‐biased responses on memory formation, plasma cell development, and bone marrow engraftment is less clear. Heavy arrows—dominant pathway; Light arrows—secondary pathway; Dotted arrows—unconfirmed pathway. GC, germinal center; aNav, activated naive B cells; DN2, double negative (i.e., IgD⁻CD27⁻ B cells that also lack expression of CXCR5 and are involved in the EF response that is outside the GC but can still have T cell help); ASC, antibody‐secreting cell; SLPC, short‐lived plasma cell; LLPC, long‐lived plasma cell

FIGURE 2

ASC kinetics and Ab effector functions during responses to infection with and vaccination against SARS‐CoV‐2. Initial infection induces ASC that produce virus‐specific, low‐affinity serum Abs. In general, mild infection, priming vaccination, or tertiary vaccination generates a GC response, by which the derived MBC undergo continued clonal evolution over 6‐12 mo, leading to the production of more potent and broader nAbs. The frequency of ASC generally correlates with the magnitude of the serum Ab levels (total binding Ab pool size). Dose 1 vaccine induces a robust GC response resulting in the generation of virus‐specific ASC (and MBC) including in infection‐naive subjects and which is substantially enhanced either by Dose 2 (in infection‐naive subjects) or in previously infected (recovered) subjects—and further enhanced by boosters (in infection‐naive subjects). The highest total binding Ab production is observed in recovered, tertiary vaccinees. Dose 1 ignites potent nAbs (in about half the subjects) that are enhanced by Dose 2 and further enhanced by booters—against the wildtype but less potent against variants (decreasing cross‐variant nAb potency). S‐specific and nAbs wane over 4‐6 mo following infection, although total binding Abs could be detected 18‐20 mo post‐infection. The nAb waning period of time in COVID‐19‐naive vaccinees also are usually 4‐6 mo; it may last longer in previously infected subjects (i.e., 10‐12 mo). Ab, antibody; nAb, neutralizing antibody; ASC, antibody‐secreting cell; EF, extrafollicular; S, spike

FIGURE 3

Mucosal and systemic antiviral responses after SARS‐CoV‐2 infection and vaccination. Mucosal exposure to viral antigen (by natural infection or by intranasal immunization) leads to in situ as well as systemic activation of virus‐specific adaptive immune cells. With intramuscular immunization, mucosal exposure to antigen is not present, therefore, only generating systemic but not mucosal immune responses. With mucosal antigen exposure, there is generation of tissue‐resident memory lymphocytes and ASC that locally prevent infection upon subsequent virus exposures. Without mucosal responses but in the presence of systemic antiviral responses, there is protection against severe disease but less so against the early infection at the mucosal entry site. Ab, antibody; BTI, breakthrough infection

FIGURE 4

Model of autoantibody feedback. B cell activation pathway bias in COVID‐19 is dictated by early viral control. (Right) High‐inflammation microenvironments due to poor viral control drive EF‐biased responses that, while rapidly generating neutralizing Abs, can result in autoantibody production through relaxed tolerance enforcement. These autoantibodies may contribute to inflammation and tissue damage, potentially reenforcing EF‐biased response