Quality-quantity trade off during antibody production and the design of optimal passive immunization protocols

Abstract

Passive immunization has been used classically to rapidly clear antigen and reduce disease burden. Surprisingly, recent studies have found passive immunization to induce lasting improvements in the humoral response, pre- senting a novel strategy to elicit potent antibodies against pathogens includ- ing HIV-1. How passive immunization alters the humoral response is poorly understood. Here, we hypothesized that administered antibodies raise the selection stringency in germinal centres (GCs) by preferentially forming im- mune complexes with antigen and letting only B cells with higher affinities acquire antigen and survive. We performed stochastic simulations of the GC reaction based on this hypothesis. Our simulations recapitulated sev- eral independent experimental observations, presenting successful tests of the hypothesis. Further, the simulations unravelled a quality-quantity trade- o constraining the GC response. Greater selection stringency yielded fewer surviving B cells but with higher affinity for antigen. Increasing antigen avail- ability relaxed the constraint. Comprehensively exploring parameter space, our simulations identi fied passive immunization protocols that exploited the quality-quantity trade-off and maximized the GC output. Together, our study presents a new conceptual understanding of the GC reaction and a robust computational framework for the rational optimization of passive im- munization strategies.