How slow delivery antigen modulates immunodominance upon immunization for difficult pathogens

Immunodominance hierarchy of B cell epitopes on highly mutable pathogens such as HIV and influenza poses a hurdle for developing universal vaccines. Upon conventional immunization for these pathogens, most antibodies target highly-mutable distracting epitopes rather than the conserved target epitopes of broadly-neutralizing antibodies. Recent studies showed that slow delivery of immunogen via several closely-spaced injections modulates this hierarchy and boosts neutralizing antibody response against the subdominant epitopes. We developed a computational model to study the competition of B cells targeting two different epitopes on the same antigen, with immunodominance hierarchy imposed by the differences in naive B cell precursor frequency and affinity. Our model reveals potential mechanisms for how slow delivery of antigen boosts B cell response against the subdominant epitope. It can allow the recruitment of low-affinity or rare precursors during the early phase of the germinal center response. Alternatively, it can lead to a strong epitope-masking effect that modulates competition in the germinal center later. We identify conditions required for these mechanisms to be dominant. Moreover, using our model we evaluate the effect of changing the number, interval, and dosing profile of the injections to maximize the neutralization while minimizing the number of injections required. We find that even a small number of injections may recapitulate the beneficial effects of slow delivery.