title: Trivalent pneumococcal protein recombinant vaccine protects against lethal Streptococcus pneumoniae pneumonia and correlates with phagocytosis by neutrophils during early pathogenesis.
abstract: OBJECTIVE
  Due to the fact that current polysaccharide-based pneumococcal vaccines have limited serotype coverage, protein-based vaccine candidates have been sought for over a decade to replace or complement current vaccines. We previously reported that a trivalent Pneumococcal Protein recombinant Vaccine (PPrV), showed protection against pneumonia and sepsis in an infant murine model. Here we investigated immunological correlates of protection of PPrV in the same model.
  
  
  METHODS
  C57BL/6J infant mice were intramuscularly vaccinated at age 1-3 weeks with 3 doses of PPrV, containing pneumococcal histidine triad protein D (PhtD), pneumococcal choline binding protein A (PcpA), and detoxified pneumolysin mutant PlyD1. 3-4 weeks after last vaccination, serum and lung antibody levels to PPrV components were measured, and mice were intranasally challenged with a lethal dose of Streptococcus pneumoniae (Spn) serotype 6A. Lung Spn bacterial burden, number of neutrophils and alveolar macrophages, phagocytosed Spn by granulocytes, and levels of cytokines and chemokines were determined at 6, 12, 24, and 48h after challenge.
  
  
  RESULTS
  PPrV vaccination conferred 83% protection against Spn challenge. Vaccinated mice had significantly elevated serum and lung antibody levels to three PPrV components. In the first stage of pathogenesis of Spn induced pneumonia (6-24h after challenge), vaccinated mice had lower Spn bacterial lung burdens and more phagocytosed Spn in the granulocytes. PPrV vaccination led to lower levels of pro-inflammatory cytokines IL-6, IL-1β, and TFN-α, and other cytokines and chemokines (IL-12, IL-17, IFN-γ, MIP-1b, MIP-2 and KC, and G-CSF), presumably due to a lower lung bacterial burden.
  
  
  CONCLUSIONS
  Trivalent PPrV vaccination results in increased serum and lung antibody levels to the vaccine components, a reduction in Spn induced lethality, enhanced early clearance of Spn in lungs due to more rapid and thorough phagocytosis of Spn by neutrophils, and correspondingly a reduction in lung inflammation and tissue damage.
authors.affiliation: Rochester General Hospital Research Institute, Rochester General Hospital, Rochester, NY 14621, USA.
authors.forename: Qingfu
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Rochester General Hospital Research Institute, Rochester General Hospital, Rochester, NY 14621, USA.
authors.forename: Naveen
authors.initials: N
authors.lastname: Surendran
authors.affiliation: Rochester General Hospital Research Institute, Rochester General Hospital, Rochester, NY 14621, USA.
authors.forename: David
authors.initials: D
authors.lastname: Verhoeven
authors.affiliation: Rochester General Hospital Research Institute, Rochester General Hospital, Rochester, NY 14621, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Klapa
authors.affiliation: Sanofi Pasteur, 1541 Ave Marcel Merieux, 69280 Marcy L'Etoile, France.
authors.forename: Martina
authors.initials: M
authors.lastname: Ochs
authors.affiliation: Rochester General Hospital Research Institute, Rochester General Hospital, Rochester, NY 14621, USA. Electronic address: Michael.Pichichero@rochestergeneral.org.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Pichichero
mesh_terms: D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D006098:Granulocytes / Q000276:immunology; D006801:Humans; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000276:immunology; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000276:immunology*; D010587:Phagocytosis / Q000276:immunology*; D022242:Pneumococcal Vaccines / Q000276:immunology*; D011018:Pneumonia, Pneumococcal / Q000276:immunology* / Q000378:metabolism / Q000401:mortality / Q000517:prevention & control*; D013296:Streptococcus pneumoniae / Q000276:immunology*; D014611:Vaccination
chemical_list: D016207:Cytokines; D022242:Pneumococcal Vaccines
keywords: Alveolar macrophages; Infant murine model; Neutrophils; Phagocytosis; Pneumococcal protein vaccine; Streptococcus pneumoniae