title: Neutralizing antibodies elicited by a novel detoxified pneumolysin derivative, PlyD1, provide protection against both pneumococcal infection and lung injury.
abstract: Streptococcus pneumoniae pneumolysin (PLY) is a virulence factor that causes toxic effects contributing to pneumococcal pneumonia. To date, deriving a PLY candidate vaccine with the appropriate detoxification and immune profile has been challenging. A pneumolysin protein that is appropriately detoxified and that retains its immunogenicity is a desirable vaccine candidate. In this study, we assessed the protective efficacy of our novel PlyD1 detoxified PLY variant and investigated its underlying mechanism of protection. Results have shown that PlyD1 immunization protected mice against lethal intranasal (i.n.) challenge with pneumococci and lung injury mediated by PLY challenge. Protection was associated with PlyD1-specific IgG titers and in vitro neutralization titers. Pretreatment of PLY with PlyD1-specific rat polyclonal antiserum prior to i.n. delivery of toxin reduced PLY-mediated lung lesions, interleukin-6 (IL-6) production, and neutrophil infiltration into lungs, indicating that protection from lung lesions induced by PLY is antibody mediated. Preincubation of PLY with a neutralizing monoclonal PLY antibody also specifically reduced the cytotoxic effects of PLY after i.n. inoculation in comparison to nonneutralizing monoclonal antibodies. These results indicate that the induction of neutralizing antibodies against PLY can contribute to protection against bacterial pneumonia by preventing the development of PLY-induced lung lesions and inflammation. Our detoxified PlyD1 antigen elicits such PLY neutralizing antibodies, thus serving as a candidate vaccine antigen for the prevention of pneumococcal pneumonia.
authors.affiliation: Sanofi Pasteur, Analytical Research and Development, Toronto, Ontario, Canada.
authors.forename: Danielle
authors.initials: D
authors.lastname: Salha
authors.forename: Jason
authors.initials: J
authors.lastname: Szeto
authors.forename: Lisa
authors.initials: L
authors.lastname: Myers
authors.forename: Carol
authors.initials: C
authors.lastname: Claus
authors.forename: Anthony
authors.initials: A
authors.lastname: Sheung
authors.forename: Mei
authors.initials: M
authors.lastname: Tang
authors.forename: Belma
authors.initials: B
authors.lastname: Ljutic
authors.forename: David
authors.initials: D
authors.lastname: Hanwell
authors.forename: Karen
authors.initials: K
authors.lastname: Ogilvie
authors.forename: Marin
authors.initials: M
authors.lastname: Ming
authors.forename: Benjamin
authors.initials: B
authors.lastname: Messham
authors.forename: Germie
authors.initials: G
authors.lastname: van den Dobbelsteen
authors.forename: Robert
authors.initials: R
authors.lastname: Hopfer
authors.forename: Martina M
authors.initials: MM
authors.lastname: Ochs
authors.forename: Scott
authors.initials: S
authors.lastname: Gallichan
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood* / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000097:blood* / Q000276:immunology; D000942:Antigens, Bacterial / Q000276:immunology / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry / Q000276:immunology; D001428:Bacterial Vaccines / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid; D005260:Female; D055370:Lung Injury / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D011018:Pneumonia, Pneumococcal / Q000517:prevention & control*; D013296:Streptococcus pneumoniae / Q000378:metabolism; D013301:Streptolysins / Q000737:chemistry / Q000276:immunology*
chemical_list: D000907:Antibodies, Bacterial; D057134:Antibodies, Neutralizing; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D001428:Bacterial Vaccines; D013301:Streptolysins; C032290:plY protein, Streptococcus pneumoniae