{"doi":"10.1074/jbc.ra119.011258","title":"Structure-based group A streptococcal vaccine design: Helical wheel homology predicts antibody cross-reactivity among streptococcal M protein–derived peptides","abstract":"Group A streptococcus (Strep A) surface M protein, an α-helical coiled-coil dimer, is a vaccine target and a major determinant of streptococcal virulence. The sequence-variable N-terminal region of the M protein defines the M type and also contains epitopes that promote opsonophagocytic killing of streptococci. Recent reports have reported considerable cross-reactivity among different M types, suggesting the prospect of identifying cross-protective epitopes that would constitute a broadly protective multivalent vaccine against Strep A isolates. Here, we have used a combination of immunological assays, structural biology, and cheminformatics to construct a recombinant M protein-based vaccine that included six Strep A M peptides that were predicted to elicit antisera that would cross-react with an additional 15 nonvaccine M types of Strep A. Rabbit antisera against this recombinant vaccine cross-reacted with 10 of the 15 nonvaccine M peptides. Two of the five nonvaccine M peptides that did not cross-react shared high sequence identity (≥50%) with the vaccine peptides, implying that high sequence identity alone was insufficient for cross-reactivity among the M peptides. Additional structural analyses revealed that the sequence identity at corresponding polar helical-wheel heptad sites between vaccine and nonvaccine peptides accurately distinguishes cross-reactive from non-cross-reactive peptides. On the basis of these observations, we developed a scoring algorithm based on the sequence identity at polar heptad sites. When applied to all epidemiologically important M types, this algorithm should enable the selection of a minimal number of M peptide-based vaccine candidates that elicit broadly protective immunity against Strep A.","journal":"Journal of Biological Chemistry","year":2020,"id":82534,"datarank":0.5184752584077459,"base_score":2.5649493574615367,"endowment":2.5649493574615367,"self_citation_contribution":0.38474240361923057,"citation_network_contribution":0.13373285478851538,"self_endowment_contribution":0.38474240361923057,"citer_contribution":0.13373285478851538,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":8,"citers_with_citation_signal":6,"citers_with_endowment":6,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9584,"is_data_producer":true,"deposit_databanks":{"PDB":["2OTO","5HZP","5HYT"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":427164,"name":"Thomas A. Penfound","orcid":null,"position":1,"is_corresponding":false},{"id":425861,"name":"Jay Spencer","orcid":"0000-0003-1634-8100","position":2,"is_corresponding":false},{"id":425862,"name":"Rupesh Agarwal","orcid":"0000-0003-1029-2281","position":3,"is_corresponding":false},{"id":427165,"name":"Jerome Baudry","orcid":null,"position":4,"is_corresponding":false},{"id":406546,"name":"James B. Dale","orcid":"0000-0001-9860-9233","position":5,"is_corresponding":false},{"id":56176,"name":"Jeremy C. Smith","orcid":"0000-0002-2978-3227","position":6,"is_corresponding":false},{"id":425860,"name":"Michelle P. Aranha","orcid":"0000-0002-8230-5726","position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":null,"created_at":"2026-07-18T21:53:48.608934Z","pmid":"32029479","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":[]}