title: Recombinant polymorphic membrane protein D in combination with a novel, second-generation lipid adjuvant protects against intra-vaginal Chlamydia trachomatis infection in mice.
abstract: The development of a chlamydial vaccine that elicits protective mucosal immunity is of paramount importance in combatting the global spread of sexually transmitted Chlamydia trachomatis (Ct) infections. While the identification and prioritization of chlamydial antigens is a crucial prerequisite for efficacious vaccine design, it is likely that novel adjuvant development and selection will also play a pivotal role in the translational potential of preclinical Ct vaccines. Although the molecular nature of the immuno-modulatory component is of primary importance, adjuvant formulation and delivery systems may also govern vaccine efficacy and potency. Our study provides the first preclinical evaluation of recombinant Ct polymorphic membrane protein D (rPmpD) in combination with three different formulations of a novel second-generation lipid adjuvant (SLA). SLA was rationally designed in silico by modification of glucopyranosyl lipid adjuvant (GLA), a TLR4 agonistic precursor molecule currently in Phase II clinical development. We demonstrate robust protection against intra-vaginal Ct challenge in mice, evidenced by significantly enhanced resistance to infection and reduction in mean bacterial load. Strikingly, protection was found to correlate with the presence of robust anti-rPmpD serum and cervico-vaginal IgG titres, even in the absence of adjuvant-induced Th1-type cellular immune responses elicited by each SLA formulation, and we further show that anti-rPmpD antibodies recognize Ct EBs. These findings highlight the utility of SLA and rational molecular design of adjuvants in preclinical Ct vaccine development, but also suggest an important role for anti-rPmpD antibodies in protection against urogenital Ct infection.
authors.affiliation: Centre for Immunology and Infection, University of York, York YO10 5DD, United Kingdom; York Structural Biology Laboratory, University of York, York YO10 5DD, United Kingdom. Electronic address: wayne.paes@ndm.ox.ac.uk.
authors.forename: Wayne
authors.initials: W
authors.lastname: Paes
authors.affiliation: Centre for Immunology and Infection, University of York, York YO10 5DD, United Kingdom.
authors.forename: Naj
authors.initials: N
authors.lastname: Brown
authors.affiliation: York Structural Biology Laboratory, University of York, York YO10 5DD, United Kingdom.
authors.forename: Andrzej M
authors.initials: AM
authors.lastname: Brzozowski
authors.affiliation: Infectious Disease Research Institute, Seattle, WA 98102, United States.
authors.forename: Rhea
authors.initials: R
authors.lastname: Coler
authors.affiliation: Infectious Disease Research Institute, Seattle, WA 98102, United States.
authors.forename: Steve
authors.initials: S
authors.lastname: Reed
authors.affiliation: Infectious Disease Research Institute, Seattle, WA 98102, United States.
authors.forename: Darrick
authors.initials: D
authors.lastname: Carter
authors.affiliation: Department of Health Sciences, University of York, York YO10 5DD, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Bland
authors.affiliation: Centre for Immunology and Infection, University of York, York YO10 5DD, United Kingdom.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Kaye
authors.affiliation: Centre for Immunology and Infection, University of York, York YO10 5DD, United Kingdom.
authors.forename: Charles J N
authors.initials: CJN
authors.lastname: Lacey
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D000907:Antibodies, Bacterial / Q000032:analysis; D001426:Bacterial Proteins / Q000276:immunology*; D001428:Bacterial Vaccines / Q000276:immunology*; D002690:Chlamydia Infections / Q000517:prevention & control*; D002692:Chlamydia trachomatis; D005260:Female; D056724:Immunity, Humoral; D018928:Immunity, Mucosal; D007074:Immunoglobulin G / Q000032:analysis; D008055:Lipids / Q000008:administration & dosage; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000276:immunology; D014621:Vagina / Q000382:microbiology
chemical_list: D000276:Adjuvants, Immunologic; D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D001428:Bacterial Vaccines; D007074:Immunoglobulin G; D008055:Lipids; D008565:Membrane Proteins; D011994:Recombinant Proteins; C542391:polymorphic membrane protein D, Chlamydia trachomatis
keywords: Chlamydia trachomatis; Pmps; TLR4 adjuvant; Vaccine