Abstract
Affinity maturation is a Darwinian process in which B lymphocytes evolve potent antibodies to encountered antigens and generate immune memory. Highly mutable complex pathogens present an immense antigenic diversity that continues to challenge natural immunity and vaccine design. Induction of broadly neutralizing antibodies (bnAbs) against this diversity by vaccination likely requires multiple exposures to distinct but related antigen variants, and yet how affinity maturation advances under such complex stimulation remains poorly understood. To fill the gap, we present an in silico model of affinity maturation to examine two realistic new aspects pertinent to vaccine development: loss in B cell diversity across successive immunization periods against different variants, and the presence of distracting epitopes that entropically disfavor the evolution of bnAbs. We find these new factors, which introduce additional selection pressures and constraints, significantly influence antibody breadth development, in a way that depends crucially on the temporal pattern of immunization (or selection forces). Curiously, a less diverse B cell seed may even favor the expansion and dominance of cross-reactive clones, but only when conflicting selection forces are presented in series rather than in a mixture. Moreover, the level of frustration due to evolutionary conflict dictates the degree of distraction. We further describe how antigenic histories select evolutionary paths of B cell lineages and determine the predominant mode of antibody responses. Sequential immunization with mutationally distant variants is shown to robustly induce bnAbs that focus on conserved elements of the target epitope, by thwarting strain-specific and distracted lineages. An optimal range of antigen dose underlies a fine balance between efficient adaptation and persistent reaction. These findings provide mechanistic guides to aid in design of vaccine strategies against fast mutating pathogens.
Highlights
Upon infection or vaccination, antibodies (Abs) are generated through affinity maturation (AM), a Darwinian process occurring in a short time (Fig 1)
Aiming to design vaccination strategies to favor HIV broadly neutralizing antibodies (bnAbs) evolution, we extend our previously developed model of AM driven by variant Ags to explicitly account for the process of germinal centers (GCs) reseeding upon immunization with new variant Ags, and the existence of distracting epitopes
We describe how different temporal arrangements of selection forces shape evolutionary dynamics of competing B cell lineages that in turn determine the predominant mode of Ab responses that emerge
Summary
Mutable pathogens pose significant challenges to vaccine design, mainly owing to the vast antigenic diversity they present to the immune system. An increasing variety of broad antibodies that can recognize diverse strains have been isolated from. Patients, but how to induce them by vaccination is largely unknown. How affinity maturation, the Darwinian process that evolves potent antibodies, proceeds under multiple stimulations by distinct antigen variants is not well understood. We use computer simulations and evolutionary models to examine realistic new aspects important for vaccine development: loss of B cell diversity in between immunization periods and the existence of distracting molecular features that do not contain conserved elements. Our findings provide guides for optimal vaccination strategies and reveal their evolutionary basis
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
