title: Options for inactivation, adjuvant, and route of topical administration of a killed, unencapsulated pneumococcal whole-cell vaccine.
abstract: We previously reported that ethanol-killed cells of a noncapsulated strain of Streptococcus pneumoniae, given intranasally with cholera toxin as an adjuvant, protect rats against pneumonia and mice against colonization of the nasopharynx and middle ear by capsulated pneumococci of various serotypes. The acceleration of pneumococcal clearance from the nasopharynx in mice is CD4+ T cell-dependent and interleukin 17A (IL-17A) mediated and can be antibody independent. Here, anticipating human studies, we have demonstrated protection with a new vaccine strain expressing a nonhemolytic derivative of pneumolysin and grown in bovine-free culture medium. Killing the cells with chloroform, trichloroethylene, or beta-propiolactone--all used without postinactivation washing--produced more-potent immunogens than ethanol, and retention of soluble components released from the cells contributed to protection. Two sequential intranasal administrations of as little as 1 microg of protein (total of cellular and soluble combined) protected mice against nasopharyngeal challenge with pneumococci. Nontoxic single and double mutants of Escherichia coli heat-labile toxin were effective as mucosal adjuvants. Protection was induced by the sublingual and buccal routes, albeit requiring larger doses than when given intranasally. Protection was likewise induced transdermally with sonicates of the killed-cell preparation. Thus, this whole-cell antigen can be made and administered in a variety of ways to suit the manufacturer and the vaccination program and is potentially a solution to the need for a low-cost vaccine to reduce the burden of childhood pneumococcal disease in low-income countries.
authors.affiliation: Division of Infectious Diseases, Children's Hospital, and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ying-Jie
authors.initials: YJ
authors.lastname: Lu
authors.forename: Puja
authors.initials: P
authors.lastname: Yadav
authors.forename: John D
authors.initials: JD
authors.lastname: Clements
authors.forename: Sophie
authors.initials: S
authors.lastname: Forte
authors.forename: Amit
authors.initials: A
authors.lastname: Srivastava
authors.forename: Claudette M
authors.initials: CM
authors.lastname: Thompson
authors.forename: Robert
authors.initials: R
authors.lastname: Seid
authors.forename: Jee
authors.initials: J
authors.lastname: Look
authors.forename: Mark
authors.initials: M
authors.lastname: Alderson
authors.forename: Andrea
authors.initials: A
authors.lastname: Tate
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Maisonneuve
authors.forename: George
authors.initials: G
authors.lastname: Robertson
authors.forename: Porter W
authors.initials: PW
authors.lastname: Anderson
authors.forename: Richard
authors.initials: R
authors.lastname: Malley
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000278:Administration, Buccal; D000281:Administration, Intranasal; D000286:Administration, Sublingual; D000818:Animals; D001426:Bacterial Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D001427:Bacterial Toxins / Q000235:genetics / Q000276:immunology; D002772:Cholera Toxin / Q000235:genetics / Q000276:immunology; D004768:Enterotoxins / Q000235:genetics / Q000276:immunology; D029968:Escherichia coli Proteins / Q000235:genetics / Q000276:immunology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D011008:Pneumococcal Infections / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D022242:Pneumococcal Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D013296:Streptococcus pneumoniae / Q000166:cytology / Q000276:immunology*; D013301:Streptolysins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D015164:Vaccines, Inactivated / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D022242:Pneumococcal Vaccines; D013301:Streptolysins; D015164:Vaccines, Inactivated; C032290:plY protein, Streptococcus pneumoniae; D002772:Cholera Toxin; C027538:heat-labile enterotoxin, E coli