{"doi":"10.1101/2021.12.07.471543","title":"Design of a <i>Streptococcus pyogenes</i> M protein immunogen to elicit M type cross-reactivity","abstract":"Abstract Coiled coil-forming M proteins of the widespread and potentially deadly bacterial pathogen Streptococcus pyogenes (Strep A) are immunodominant targets of opsonizing antibodies. However, antigenic sequence variability into &gt;220 M types, as defined by the M protein hypervariable region (HVR), has been considered to limit its utility as a vaccine immunogen due to type-specificity in the antibody response. Surprisingly, a multi-HVR immunogen in clinical vaccine trials elicited M type cross-reactivity. The basis for this cross-reactivity is unknown but may be due in part to antibody recognition of a three-dimensional (3D) pattern conserved in many M protein HVRs that confers binding to human C4b-binding protein (C4BP). To test this hypothesis, we asked whether a single M protein immunogen carrying the 3D pattern would elicit cross-reactivity against other M types carrying the 3D pattern. We found that a 34-amino acid sequence of M2 protein bearing the 3D pattern retained full C4BP-binding capacity when fused to a coiled coil-stabilizing sequence from GCN4. This immunogen, called M2G, elicited cross-reactive antibodies against a number of M types that carry the 3D pattern but not against those that lack the 3D pattern. The M2G antiserum recognized M proteins as displayed natively on the Strep A surface, and promoted the opsonophagocytic killing of Strep A strains expressing these M proteins. As C4BP-binding is a conserved virulence trait of Strep A, targeting the 3D pattern may prove advantageous in vaccine design.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":228063,"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":0.955,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":832839,"name":"Eziz Kuliyev","orcid":"0000-0003-4133-8772","position":1,"is_corresponding":false},{"id":225262,"name":"Victor Nizet","orcid":"0000-0003-3847-0422","position":2,"is_corresponding":false},{"id":379318,"name":"Partho Ghosh","orcid":"0000-0003-0254-5218","position":3,"is_corresponding":false},{"id":833326,"name":"Kuei-Chen Wang","orcid":null,"position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-18T23:54:50.414605Z","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":[]}