title: A live-attenuated pneumococcal vaccine elicits CD4+ T-cell dependent class switching and provides serotype independent protection against acute otitis media.
abstract: Acute otitis media (AOM) caused by Streptococcus pneumoniae remains one of the most common infectious diseases worldwide despite widespread vaccination. A major limitation of the currently licensed pneumococcal vaccines is the lack of efficacy against mucosal disease manifestations such as AOM, acute bacterial sinusitis and pneumonia. We sought to generate a novel class of live vaccines that (1) retain all major antigenic virulence proteins yet are fully attenuated and (2) protect against otitis media. A live vaccine candidate based on deletion of the signal recognition pathway component ftsY induced potent, serotype-independent protection against otitis media, sinusitis, pneumonia and invasive pneumococcal disease. Protection was maintained in animals coinfected with influenza virus, but was lost if mice were depleted of CD4(+) T cells at the time of vaccination. The live vaccine induced a strong serum IgG2a and IgG2b response that correlated with CD4(+) T-cell mediated class switching. Deletion of genes required for microbial adaptation to the host environment is a novel live attenuated vaccine strategy yielding the first experimental vaccine effective against pneumococcal otitis media.
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Rosch
authors.forename: Amy R
authors.initials: AR
authors.lastname: Iverson
authors.forename: Jessica
authors.initials: J
authors.lastname: Humann
authors.forename: Beth
authors.initials: B
authors.lastname: Mann
authors.forename: Geli
authors.initials: G
authors.lastname: Gao
authors.forename: Peter
authors.initials: P
authors.lastname: Vogel
authors.forename: Michael
authors.initials: M
authors.lastname: Mina
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Murrah
authors.forename: Antonia C
authors.initials: AC
authors.lastname: Perez
authors.forename: W
authors.initials: W
authors.lastname: Edward Swords
authors.forename: Elaine I
authors.initials: EI
authors.lastname: Tuomanen
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: McCullers
mesh_terms: D000208:Acute Disease; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002682:Chinchilla; D004195:Disease Models, Animal; D017578:Immunoglobulin Class Switching; D007074:Immunoglobulin G / Q000097:blood; D051379:Mice; D008807:Mice, Inbred BALB C; D010033:Otitis Media / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D022242:Pneumococcal Vaccines / Q000276:immunology*; D012703:Serotyping; D012852:Sinusitis / Q000382:microbiology / Q000401:mortality / Q000517:prevention & control; D013296:Streptococcus pneumoniae / Q000378:metabolism; D015996:Survival Rate; D014613:Vaccines, Attenuated / Q000276:immunology; D037521:Virulence Factors / Q000276:immunology
chemical_list: D007074:Immunoglobulin G; D022242:Pneumococcal Vaccines; D014613:Vaccines, Attenuated; D037521:Virulence Factors