Germinal centers are permissive to subdominant antibody responses

Abstract

A protective humoral response to pathogens requires the development of high affinity antibodies in germinal centers (GC). The combination of antigens available during immunization has a strong impact on the strength and breadth of the antibody response. Antigens can display various levels of immunogenicity, and a hierarchy of immunodominance arises when the GC response to an antigen dampens the response to other antigens. Immunodominance is a challenge for the development of vaccines to mutating viruses, and for the development of broadly neutralizing antibodies. The extent by which antigens with different levels of immunogenicity compete for the induction of high affinity antibodies and therefore contribute to immunodominance is not known. Here, we perform in silico simulations of the GC response, using a structural representation of antigens with complex surface amino acid composition and topology. We generate antigens with different levels of immunogenicity and perform simulations with combinations of these antigens. We found that GC dynamics were driven by the most immunogenic antigen and immunodominance arose as affinity maturation to less immunogenic antigens was inhibited. However, this inhibition was moderate since the less immunogenic antigen exhibited a weak GC response in the absence of other antigens. Less immunogenic antigens reduced the dominance of GC responses to more immunogenic antigens, albeit at a later time point. The simulations suggest that increased vaccine valence may decrease immunodominance of the GC response to strongly immunogenic antigens and therefore, act as a potential strategy for the natural induction of broadly neutralizing antibodies in GC reactions.