{"doi":"10.1101/2025.04.23.650289","title":"Heterologous immunization modulates B-cell epitope competition between helper peptides and the MPER segment in MPER/liposome vaccines","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>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 and enhances plasma antibody functionality. This improvement is associated with increased B cell affinity for MPER and reduced competition from B cells targeting the helper epitope. 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.</jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement</jats:title>\n                  <jats:p>A key challenge in vaccination against mutable viruses like HIV-1 is the immune system’s focus on highly variable regions. The conserved MPER segment of gp41 elicits weak antibody responses due to poor B cell accessibility. This study evaluated a liposome-based MPER vaccine strategy. Initial priming generated low-affinity MPER-specific memory B cells, influenced by strong B cell affinity for a dominant T cell helper peptide. However, heterologous boosting overcomes subdominant MPER responses by increasing B cell affinity for booster immunogens while also reducing competition from other helper peptides. Co-delivery of helper peptides enhanced antibody affinity, though the priming antigen was critical in shaping responses. These findings suggest heterologous immunization is a promising strategy to enhance subdominant B cell responses.</jats:p>\n                </jats:sec>","journal":null,"year":null,"id":602505,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":889181,"name":"Junjian Chen","orcid":"0000-0003-2897-5777","position":1,"is_corresponding":false},{"id":1545217,"name":"Luke Donius","orcid":null,"position":2,"is_corresponding":false},{"id":622807,"name":"Ellis L. Reinherz","orcid":"0000-0003-1048-5526","position":3,"is_corresponding":false},{"id":889182,"name":"Mikyung Kim","orcid":"0000-0003-2319-9764","position":4,"is_corresponding":false},{"id":1126298,"name":"Rafiq Ahmad Khan","orcid":"0000-0003-4321-5557","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Heterologous immunization modulates B-cell epitope competition between helper peptides and the MPER segment in MPER/liposome vaccines","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>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 and enhances plasma antibody functionality. This improvement is associated with increased B cell affinity for MPER and reduced competition from B cells targeting the helper epitope. 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.</jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement</jats:title>\n                  <jats:p>A key challenge in vaccination against mutable viruses like HIV-1 is the immune system’s focus on highly variable regions. The conserved MPER segment of gp41 elicits weak antibody responses due to poor B cell accessibility. This study evaluated a liposome-based MPER vaccine strategy. Initial priming generated low-affinity MPER-specific memory B cells, influenced by strong B cell affinity for a dominant T cell helper peptide. However, heterologous boosting overcomes subdominant MPER responses by increasing B cell affinity for booster immunogens while also reducing competition from other helper peptides. Co-delivery of helper peptides enhanced antibody affinity, though the priming antigen was critical in shaping responses. These findings suggest heterologous immunization is a promising strategy to enhance subdominant B cell responses.</jats:p>\n                </jats:sec>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"23304386","pmcid":null,"openalex_id":null,"authors":[],"funders":[{"funder_name":"","grant_id":"AI145509","title":null},{"funder_name":"","grant_id":"AI181597","title":null},{"funder_name":"","grant_id":"AI126901","title":null}],"total_grants":3,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"green","license":"https://www.biorxiv.org/about/FAQ#license","oa_locations":[{"url":"https://www.biorxiv.org/content/biorxiv/early/2025/04/26/2025.04.23.650289.full.pdf","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.1101/2025.04.23.650289","host_type":"publisher"}],"fields_of_study":[],"mesh_terms":[],"keywords":[],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-29T19:34:17.102589Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}