title: Fusion of the Mycobacterium tuberculosis antigen 85A to an oligomerization domain enhances its immunogenicity in both mice and non-human primates.
abstract: To prevent important infectious diseases such as tuberculosis, malaria and HIV, vaccines inducing greater T cell responses are required. In this study, we investigated whether fusion of the M. tuberculosis antigen 85A to recently described adjuvant IMX313, a hybrid avian C4bp oligomerization domain, could increase T cell responses in pre-clinical vaccine model species. In mice, the fused antigen 85A showed consistent increases in CD4(+) and CD8(+) T cell responses after DNA and MVA vaccination. In rhesus macaques, higher IFN-γ responses were observed in animals vaccinated with MVA-Ag85A IMX313 after both primary and secondary immunizations. In both animal models, fusion to IMX313 induced a quantitative enhancement in the response without altering its quality: multifunctional cytokines were uniformly increased and differentiation into effector and memory T cell subsets was augmented rather than skewed. An extensive in vivo characterization suggests that IMX313 improves the initiation of immune responses as an increase in antigen 85A specific cells was observed as early as day 3 after vaccination. This report demonstrates that antigen multimerization using IMX313 is a simple and effective cross-species method to improve vaccine immunogenicity with potentially broad applicability.
authors.affiliation: The Jenner Institute, University of Oxford, Oxford, United Kingdom. alex.spencer@ndm.ox.ac.uk
authors.forename: Alexandra J
authors.initials: AJ
authors.lastname: Spencer
authors.forename: Fergal
authors.initials: F
authors.lastname: Hill
authors.forename: Jared D
authors.initials: JD
authors.lastname: Honeycutt
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Cottingham
authors.forename: Migena
authors.initials: M
authors.lastname: Bregu
authors.forename: Christine S
authors.initials: CS
authors.lastname: Rollier
authors.forename: Julie
authors.initials: J
authors.lastname: Furze
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Draper
authors.forename: Karen C
authors.initials: KC
authors.lastname: Søgaard
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Gilbert
authors.forename: David H
authors.initials: DH
authors.lastname: Wyllie
authors.forename: Adrian V S
authors.initials: AV
authors.lastname: Hill
mesh_terms: D000217:Acyltransferases / Q000235:genetics / Q000276:immunology*; D000276:Adjuvants, Immunologic; D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D050716:Complement C4b-Binding Protein / Q000235:genetics / Q000276:immunology*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008253:Macaca mulatta; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D010959:Tissue Plasminogen Activator / Q000235:genetics; D032581:Tuberculosis Vaccines / Q000235:genetics / Q000276:immunology*; D014611:Vaccination; D019444:Vaccines, DNA / Q000276:immunology; D014765:Viral Vaccines / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000942:Antigens, Bacterial; D050716:Complement C4b-Binding Protein; C560489:MVA vaccine; D011993:Recombinant Fusion Proteins; D032581:Tuberculosis Vaccines; D019444:Vaccines, DNA; D014765:Viral Vaccines; D007371:Interferon-gamma; D000217:Acyltransferases; C112580:antigen 85A, Mycobacterium tuberculosis; D010959:Tissue Plasminogen Activator