title: The global distribution and diversity of protein vaccine candidate antigens in the highly virulent Streptococcus pnuemoniae serotype 1.
abstract: Serotype 1 is one of the most common causes of pneumococcal disease worldwide. Pneumococcal protein vaccines are currently being developed as an alternate intervention strategy to pneumococcal conjugate vaccines. Pre-requisites for an efficacious pneumococcal protein vaccine are universal presence and minimal variation of the target antigen in the pneumococcal population, and the capability to induce a robust human immune response. We used in silico analysis to assess the prevalence of seven protein vaccine candidates (CbpA, PcpA, PhtD, PspA, SP0148, SP1912, SP2108) among 445 serotype 1 pneumococci from 26 different countries, across four continents. CbpA (76%), PspA (68%), PhtD (28%), PcpA (11%) were not universally encoded in the study population, and would not provide full coverage against serotype 1. PcpA was widely present in the European (82%), but not in the African (2%) population. A multi-valent vaccine incorporating CbpA, PcpA, PhtD and PspA was predicted to provide coverage against 86% of the global population. SP0148, SP1912 and SP2108 were universally encoded and we further assessed their predicted amino acid, antigenic and structural variation. Multiple allelic variants of these proteins were identified, different allelic variants dominated in different continents; the observed variation was predicted to impact the antigenicity and structure of two SP0148 variants, one SP1912 variant and four SP2108 variants, however these variants were each only present in a small fraction of the global population (<2%). The vast majority of the observed variation was predicted to have no impact on the efficaciousness of a protein vaccine incorporating a single variant of SP0148, SP1912 and/or SP2108 from S. pneumoniae TIGR4. Our findings emphasise the importance of taking geographic differences into account when designing global vaccine interventions and support the continued development of SP0148, SP1912 and SP2108 as protein vaccine candidates against this important pneumococcal serotype.
authors.affiliation: Malawi-Liverpool Wellcome Trust Clinical Research Programme, Queen Elizabeth Central Hospital, Blantyre, Malawi; Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool L69 7BE, UK. Electronic address: j.cornick@liv.ac.uk.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Cornick
authors.affiliation: Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Grahamstown, South Africa.
authors.forename: Özlem
authors.initials: Ö
authors.lastname: Tastan Bishop
authors.affiliation: Pathogen Genomics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Feyruz
authors.initials: F
authors.lastname: Yalcin
authors.affiliation: Malawi-Liverpool Wellcome Trust Clinical Research Programme, Queen Elizabeth Central Hospital, Blantyre, Malawi; Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool L69 7BE, UK.
authors.forename: Anmol M
authors.initials: AM
authors.lastname: Kiran
authors.affiliation: Malawi-Liverpool Wellcome Trust Clinical Research Programme, Queen Elizabeth Central Hospital, Blantyre, Malawi.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kumwenda
authors.affiliation: Malawi-Liverpool Wellcome Trust Clinical Research Programme, Queen Elizabeth Central Hospital, Blantyre, Malawi; Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool L69 7BE, UK.
authors.forename: Chrispin
authors.initials: C
authors.lastname: Chaguza
authors.affiliation: Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases, A Division of the National Health Laboratory Service, Johannesburg, South Africa; School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Shanil
authors.initials: S
authors.lastname: Govindpershad
authors.affiliation: Centre de Recherche Médicale et Sanitaire, Niamey, Niger.
authors.forename: Sani
authors.initials: S
authors.lastname: Ousmane
authors.affiliation: Medical Research Council, Banjul, Gambia; Division of Translational and Systems Medicine, Microbiology and Infection Unit, The University of Warwick, UK.
authors.forename: Madikay
authors.initials: M
authors.lastname: Senghore
authors.affiliation: Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases, A Division of the National Health Laboratory Service, Johannesburg, South Africa; School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Mignon
authors.initials: M
authors.lastname: du Plessis
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland.
authors.forename: Gerd
authors.initials: G
authors.lastname: Pluschke
authors.affiliation: Medical Research Council, Banjul, Gambia.
authors.forename: Chinelo
authors.initials: C
authors.lastname: Ebruke
authors.affiliation: Centers for Disease Control and Prevention, Atlanta, USA.
authors.forename: Lesley
authors.initials: L
authors.lastname: McGee
authors.affiliation: Centro de Investigação em Saúde da Manhiça, Maputo, Mozambique.
authors.forename: Beutel
authors.initials: B
authors.lastname: Sigaùque
authors.affiliation: Centre de Recherche Médicale et Sanitaire, Niamey, Niger.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Collard
authors.affiliation: Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Grahamstown, South Africa.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Bentley
authors.affiliation: Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool L69 7BE, UK.
authors.forename: Aras
authors.initials: A
authors.lastname: Kadioglu
authors.affiliation: Medical Research Council, Banjul, Gambia; Division of Translational and Systems Medicine, Microbiology and Infection Unit, The University of Warwick, UK; Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Antonio
authors.affiliation: Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases, A Division of the National Health Laboratory Service, Johannesburg, South Africa; School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Anne
authors.initials: A
authors.lastname: von Gottberg
authors.affiliation: Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool L69 7BE, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: French
authors.affiliation: Hubert Department of Global Health, Rollins School of Public Health, Emory University, USA.
authors.forename: Keith P
authors.initials: KP
authors.lastname: Klugman
authors.affiliation: Malawi-Liverpool Wellcome Trust Clinical Research Programme, Queen Elizabeth Central Hospital, Blantyre, Malawi.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Heyderman
authors.affiliation: PATH, Seattle, WA, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Alderson
authors.affiliation: Malawi-Liverpool Wellcome Trust Clinical Research Programme, Queen Elizabeth Central Hospital, Blantyre, Malawi; Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool L69 7BE, UK.
authors.forename: Dean B
authors.initials: DB
authors.lastname: Everett
mesh_terms: D000349:Africa; D000483:Alleles; D000595:Amino Acid Sequence; D000940:Antigenic Variation; D000942:Antigens, Bacterial / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D001208:Asia; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D005060:Europe; D005843:Geography; D014943:Global Health; D006801:Humans; D008958:Models, Molecular; D011008:Pneumococcal Infections / Q000276:immunology / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D022242:Pneumococcal Vaccines / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D065288:Serogroup; D013020:South America; D013296:Streptococcus pneumoniae / Q000145:classification / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity*; D000073887:Vaccination Coverage / Q000706:statistics & numerical data; D022223:Vaccines, Subunit; D014774:Virulence
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D022242:Pneumococcal Vaccines; D022223:Vaccines, Subunit
keywords: Antigenic diversity; Antigenic profiling; Multi-valent; PCV; Pneumococcal disease; Protein modelling; Structural diversity; Variant