This includes the phasing of low versus high affinity antibody over time in a process known as affinity maturation, and the development of memory and long-lived plasma cells. First, at the level of an individual organism, spanning timescales of weeks to years, are the temporal dynamics of the antibody repertoire itself. Figure 1 provides a graphical overview representing these different scales. This occurs through a highly dynamic process, whose basic underlying science can be understood at three distinct scales. Addressing this dual challenge of pathogenic and human variation prompts us to ask whether antibody response prediction and the rational development of vaccination strategies are possible – specifically, by leveraging a fundamental understanding of cell biological and immunological processes.Īntibody responses arise from the evolution of precursor B-cells into their effector and memory counterparts. To maximize protective coverage, we further require precision vaccination, through personalized cocktails of co-stimulatory or other pharmacological compounds that act on the molecular scale. This means that antibody responses and vaccine efficacy are both highly variable across the human population, and extremely challenging to predict. Second, human variations in genetic composition, age, gender, antigen and environmental exposure history, tonic inflammatory setpoint, and myriad other physiological parameters drastically vary our immune responses, even to the same pathogen. Here, we need vaccine designs that provide optimal coverage across pathogenic strains – for example, through broadly neutralizing antibodies, or by producing a diverse repertoire, or by minimizing deleterious cross-reactive effects. This is reflected in the difficulty of developing effective vaccines for HIV, malaria, or dengue, despite the urgent need to address these high-mortality public health challenges. First, pathogens with high mutation rates result in multiple and fast-evolving strains, which lead to immune evasion or antigenic drift, hampering responses to chronic infections or development of immunization strategies. There are two main challenges in mounting the appropriate antibody responses to infection or vaccination, arising from the variations intrinsic to both pathogen and human populations. Eliciting repeated, specific, and potent antibody responses to a given pathogen is also a primary goal of vaccination, and the desired outcome of most vaccine development strategies. Antibodies are an important mediator of the immune response to infection, with the ability to bind various pathogens and neutralize their infectivity or accelerate their clearance. We suggest that quantitative multi-scale mathematical models of B-cell and GC reaction dynamics provide predictive frameworks that can apply basic immunological knowledge to practical challenges such as rational vaccine design.Įffective immune responses to pathogens are characterized by antibody production in the short term, and generate immune memory against that specific antigen in the long term. We summarize our current understanding within each of these scales, and identify missing links in connecting them. At the molecular scale, over seconds to days, intracellular signaling, transcriptional, and epigenetic networks modulate B-cell fates and shape their clonal lineages. At the tissue and cellular scale, over hours to weeks, B-cells undergo selection via spatially distributed interactions with local stroma, antigen, and helper T-cells. At the organism scale, over weeks to years, the antibody sequence repertoire formed by various B-cell clonal lineages modulates antibody quantity and quality over time. The regulatory dynamics of B-cells within the GC are complex, and unfold across multiple interacting spatial and temporal scales. In order to grasp and leverage the complexities of the antibody response, we advocate for a mechanistic understanding of the multiscale germinal center (GC) reaction – the process by which precursor B-cells evolve high-affinity antigen-specific antibodies, forming an effector repertoire of plasma and memory cells for decades-long protection. Signaling Systems Laboratory, Department of Microbiology, Immunology, and Molecular Genetics, and Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, Los Angeles, CA, United StatesĪntibody-mediated adaptive immunity must provide effective long-term protection with minimal adverse effects, against rapidly mutating pathogens, in a human population with diverse ages, genetics, and immune histories.Haripriya Vaidehi Narayanan Alexander Hoffmann *
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