Adjuvants and MHCII modulate the immunogenicity of subdominant epitopes in Plasmodium vivax Duffy binding protein

Antibody responses to protein antigens are driven by epitope hierarchies that promote the immunogenicity of select epitopes. For antigenically variable pathogens, immune responses toward conserved epitopes are critical to elicit strain-transcending antibodies, yet these epitopes are often subdominant. Designing vaccines that focus immune responses to these epitopes requires an understanding of which components can overcome subdominance. Using the <i>Plasmodium vivax</i> Duffy binding protein with a defined subdominant region, we investigated how immunization strategies affect the immunogenicity of this region. We demonstrated that antigens with mutations in immunodominant epitopes, combined with the adjuvants GLA-SE or alum, overcame the subdominance of this region. However, these effects were largely negated by MHCII restriction. Further, robust antibody responses toward subdominant epitopes depend on boosting, which alters the epitope hierarchy and enables the recruitment of germinal center B cells specific to the subdominant epitopes. Our study provides valuable insights for designing subunit vaccines targeting subdominant epitopes.