title: Conjugation of a TLR7 agonist and antigen enhances protection in the S. pneumoniae murine infection model.
abstract: Next generation vaccine adjuvants include Toll like receptor agonists, which are mostly extracted from microorganisms, but synthetic small molecule TLR agonists have also been identified. However, their delivery systems have not been optimized for effective administration in conjunction with antigens. Here, we describe a novel approach in which a small molecule TLR agonist was directly conjugated to antigen to ensure effective co-delivery. We describe the conjugation of a recombinant protective antigen from Streptococcus pneumoniae linked to a TLR7 agonist. Following thorough characterization to ensure no aggregation, the conjugate was evaluated in a murine infection model. Results showed that the conjugate extended the animals' survival after lethal challenge with S. pneumoniae. Comparable results were obtained with a dose 10-fold lower than that of the native unconjugated antigen. Notably, the animals immunized with the same dose of unconjugated TLR7 agonist and antigen showed no adjuvant effect. The increased immunogenicity was likely a consequence of the co-localization of TLR7 agonist and antigen by chemical binding and was more effective than simple co-administration. This approach can be adopted to increase potency of a broad variety of antigens and reduce the dose of antigen required to induce protective immunity.
authors.affiliation: Novartis Vaccines and Diagnostics, Siena, Italy. Electronic address: simone.vecchi@novartis.com.
authors.forename: S
authors.initials: S
authors.lastname: Vecchi
authors.affiliation: Novartis Vaccines and Diagnostics, Siena, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Bufali
authors.affiliation: Genomics Institute of Novartis Research Foundation, San Diego, CA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Uno
authors.affiliation: Genomics Institute of Novartis Research Foundation, San Diego, CA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Wu
authors.affiliation: Novartis Vaccines and Diagnostics, Siena, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Arcidiacono
authors.affiliation: Novartis Vaccines and Diagnostics, Siena, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Filippini
authors.affiliation: Novartis Vaccines and Diagnostics, Siena, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Rigat
authors.affiliation: Vaccines Research, Novartis Vaccines, Cambridge, MA, USA.
authors.forename: D
authors.initials: D
authors.lastname: O'Hagan
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D058491:Bacterial Load; D004195:Disease Models, Animal; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D007114:Immunization; D018796:Immunoconjugates / Q000276:immunology / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000819:agonists* / Q000378:metabolism; D008807:Mice, Inbred BALB C; D010586:Phagocytes / Q000187:drug effects / Q000276:immunology; D010587:Phagocytosis / Q000187:drug effects; D011008:Pneumococcal Infections / Q000097:blood / Q000276:immunology / Q000517:prevention & control*; D022242:Pneumococcal Vaccines / Q000276:immunology / Q000494:pharmacology*; D013296:Streptococcus pneumoniae / Q000235:genetics / Q000276:immunology*; D013997:Time Factors; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; D022242:Pneumococcal Vaccines; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7
keywords: Adjuvants; Conjugation; Dose reduction; Immunogenicity; S. pneumoniae; TLR7 agonist