Highly mutated memory cells drive an inefficient secondary antibody response to a variant protein

A powerful vaccine against mutable viruses might induce memory antibodies that either strongly bound antigenic variants or that could rapidly undergo secondary affinity maturation to achieve this. We have recently shown after secondary immunization of mice with a widely variant protein (Burton et al. 2018) that IgM+ memory B-cells with few mutations supported an efficient secondary germinal centre (GC) and serum response, superior to a primary response to the same protein. Here, boosting with more closely related proteins produced a GC response dominated by highly mutated B-cells that failed, not efficiently improving serum avidity even in the presence of extra adjuvant, and that was worse than a primary response. This supports a hypothesis that over certain antigenic differences, a cross reactive, mutated, memory B-cell compartment can be an impediment to affinity maturation.