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Keywords:

  • otitis media;
  • S treptococcus ;
  • vaccine;
  • virulence

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.

Synopsis

Thumbnail image of graphical abstract

Pneumococcal vaccines prevent sepsis and meningitis-induced diseases but not otitis media, sinusitis, or pneumonia. A novel live genetically attenuated pneumococcal vaccine is shown protective against mucosal infections in mice and chinchilla models.

  • A novel, live attenuated pneumococcal vaccine was generated by targeting genes required for microbial adaptation to the host environment
  • The live attenuated vaccine was able to confer effective serotype-independent protection against pneumococcal acute otitis media in the murine model
  • The live attenuated vaccine was able to confer effective protection in the chinchilla model of pneumococcal acute otitis media
  • The live attenuated vaccine induced potent serotype-independent antibody responses and conferred serotype independent protection against pneumococcal colonization and invasive disease
  • The live attenuated vaccine induced antibody subtypes distinct from the current conjugate vaccine and these antibody subtypes were dependent upon CD4+ T-cells during vaccination