Multiple broadly neutralizing antibody lineages can co-exist and mature in the same germinal centers.

An efficacious HIV vaccine will need to generate broadly neutralizing antibodies (bnAbs) against distinct viral epitopes. To facilitate this, immunogens targeting precursor B cells of bnAbs have been developed. With this strategy, individual immunogens can even target multiple lineages, thereby beneficially limiting the number of immunogens needed for a multi-bnAb-generating vaccine. However, it is unclear whether this approach diminishes the responses compared with isolated targeting of lineages with distinct immunogens. Here, we address this using an in silico model of naive B cell activation and affinity maturation in germinal centers. By incorporating the (1) precursor properties and (2) epitope masking by antibodies obtained from germinal center-derived plasma cells, the model recapitulated features of bnAb lineage evolution as seen in pre-clinical mouse models. Our model predicts that under physiologically relevant conditions, priming of multiple bnAb lineages with a single immunogen can be additive, thus having implications for further testing and development of multi-lineage-targeting immunogens.