A live‐attenuated pneumococcal vaccine elicits CD 4 + T ‐cell dependent class switching and provides serotype independent protection against acute otitis media

• Published in: EMBO molecular medicine 2014-01, Vol.6 (1), p.141-154
• Main Authors: Rosch, Jason W, Iverson, Amy R, Humann, Jessica, Mann, Beth, Gao, Geli, Vogel, Peter, Mina, Michael, Murrah, Kyle A, Perez, Antonia C, Edward Swords, W, Tuomanen, Elaine I, McCullers, Jonathan A
• Format: Article
• Language: English
• Subjects: Candidates; CD4 antigen; Class switching; Clonal deletion; Ear diseases; Experiments; Gene deletion; Immunoglobulin G; Immunoglobulins; Infectious diseases; Influenza; Lymphocytes; Lymphocytes T; Meningitis; Mucosa; Otitis media; Pneumonia; Sepsis; Sinusitis; Streptococcus infections; Vaccines; Variance analysis; Virulence
• ISSN: 1757-4676; 1757-4684
• DOI: 10.1002/emmm.201202150

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 CD 4 + T cells at the time of vaccination. The live vaccine induced a strong serum IgG2a and IgG2b response that correlated with CD 4 + 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. image 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