Heterologous immunization modulates B-cell epitope competition between helper peptides and the MPER segment in MPER/liposome vaccines

Subdominant B-cell immune responses to conserved epitopes are major obstacles in eliciting broadly neutralizing antibodies (bnAbs) against HIV-1 through natural infection or vaccination. Although the sequence conserved membrane proximal external domain (MPER) of HIV -1 gp41 is partially occluded on the virion surface, epitope-focused immunogens could mitigate access limitations. Here, we found that a MPER/liposome vaccine delivered with single CD4 T cell helper epitope results in a post-priming response hierarchy, eliciting low affinity MPER-specific B cells. Heterologous boosting, however, promotes MPER-specific B cell clonal expansion with greater functionality of plasma antibodies. Enhancement correlates with increasing B cell MPER-directed affinity and reduced germinal center B cell helper antigen competitive advantage. While helper peptide co-delivery increases affinity of serum antibodies, the outcome of subsequent MPER antibody responses is shaped by the priming antigen. Our results offer insights into heterologous immunization strategies to potentiate subdominant B cell responses against frequently mutating viruses.