Since the beginning of the COVID-19 pandemic the elicitation and persistence of antibody-mediated protection has been a primary area of research focus. Less broadly appreciated has been the development of deep understandings of the B cell responses that underpin antiviral humoral immunity. While evidence has been building for many decades in a broad variety of immunologic subfields in both mouse[1], [2], [3] and human[4], [5] systems, detailed response evaluation in COVID-19 has crystallized the complexity of coordination in the B cell responses underpinning functional antibody response development[6]. Rather than a simple model of B cell activation leading to memory formation and long-lived plasma cell engraftment into the bone marrow, it has become clear that an effector arm of B cell activation, arising during the early phases of infection and which may or may not contribute to the long-term humoral response, is a common and important component of developing humoral immunity (Fig. 1).

The complex mechanisms controlling naïve B cell activation and their differentiation into heterogeneous populations of effector and memory B cells, ultimately contributing to the antibody secreting cell (ASC) pool, has resulted in a growing interest in the identification of new B cell subsets and understanding of their intrinsic properties and functions[7]. Beyond their capacity for antibody secretion, B cell contributions to the overall immune landscape can encompass a breadth of critical functions including cytokine production[8], antigen presentation[9], anti-inflammatory activities[10], and the mediation of innate immune targeting[11]. Although the details of the segregation of naïve-derived effector versus memory B cell responses, alongside their independent contributions to each of these cellular functions remain an active area of investigation, the COVID-19 pandemic has provided a unique opportunity to investigate the early phases of antiviral responses broadly elicited in the general population worldwide. Those investigations have been fruitful; they have solidified important generalized concepts in B cell-mediated immunity such as the rapid expansion of extrafollicular (EF) effectors populations in the early response to severe infection[12], identification of shared (public) clonotypes across human populations[13], Fc-mediated effector activities of circulating Immunoglobulins (Igs) in anti- and pro-inflammatory responses[13], as well as the autoreactive tendencies of B cell responses when tolerance mechanisms are relaxed[14], [15].

Beyond the acute phase of infection, the maturation of the pandemic over years has provided the possibility of understanding how these early responses contribute (if at all) to long term memory and eventual adaptive recall[16]. Rapid development of mRNA vaccines against the Spike protein of SARS-CoV-2 has increased the complexity of the patient population but has also presented an opportunity to compare and learn from different populations of memory B cells formed during infection(s), upon repeated vaccinations, or in the presence of both (hybrid immunity). Initially, the unique opportunity to enroll naïve-to-infection(s) subjects permitted the investigation of the engagement of naïve-derived B cell responses and mapping of their kinetics, thus identifying the initiation of germinal center (GC) activity in secondary lymphoid organs (SLOs) with surprisingly long-lasting activity[17]. This contrasted observations of aberrant GC formation in the context of (severe) infections[18], and the comparison of these distinct developmental environments has provided an opportunity to integrate a growing understanding of effector B cell heterogeneity into the better-established fields of B cell memory and plasma cell biology.

The accomplished gains in understanding in these areas have come, in no small part, from the routine implementation of methods designed to extract high-dimensionality data from limited sample input. From high-dimensional flow cytometry to B cell repertoire analysis to advancements in serological screening, diverse methods have been brought together to provide a systems-level view of emerging B cell immunity in response to both infection and vaccination. Although many questions remain unanswered, technological advancement in these areas has undoubtedly allowed the immunological community to make use of the unique opportunities presented by the pandemic to rapidly advance the B cell field. In this review, we highlight several of the central approaches that now comprise the vast array of new technologies capable of dissecting immune development down to the molecular scale. We discuss how those systems-level technologies have accelerated our understanding of B cell biology in COVID-19, and their ongoing potential to help us identify critical control points of developing humoral immunity in vaccination, autoimmunity, and beyond.