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A semisynthetic carbohydrate-lipid vaccine that protects against S. pneumoniae in mice

Abstract

Severe forms of pneumococcal meningitis, bacteraemia and pneumonia result in more than 1 million deaths each year despite the widespread introduction of carbohydrate-protein conjugate vaccines against Streptococcus pneumoniae. Here we describe a new and highly efficient antipneumococcal vaccine design based on synthetic conjugation of S. pneumoniae capsule polysaccharides to the potent lipid antigen α-galactosylceramide, which stimulates invariant natural killer T (iNKT) cells when presented by the nonpolymorphic antigen-presenting molecule CD1d. Mice injected with the new lipid-carbohydrate conjugate vaccine produced high-affinity IgG antibodies specific for pneumococcal polysaccharides. Vaccination stimulated germinal center formation; accumulation of iNKT cells with a T follicular helper cell phenotype; and increased frequency of carbohydrate-specific, long-lived memory B cells and plasmablasts. This new lipid-carbohydrate vaccination strategy induced potent antipolysaccharide immunity that protected against pneumococcal disease in mice and may also prove effective for the design of carbohydrate-based vaccines against other major bacterial pathogens.

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Figure 1: iNKT cells are stimulated by CPS-αGC only in the presence of CD1d+ APC.
Figure 2: CD1d-dependent enhancement of antibody responses by CPS-αGC immunization.
Figure 3: Vaccination with CPS-αGC induced expansion of germinal centers.
Figure 4: Binding kinetics of S. pneumoniae CPS4 to specific monoclonal antibodies.
Figure 5: Both passive and active immunizations protect mice from S. pneumoniae.
Figure 6: CPS-αGC–induced generation of CPS-specific memory B cells and iNKTFH cells in vaccinated mice.

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Acknowledgements

We thank A.G. Rolink and D. Finke for materials and helpful discussions, R. Lange and S. Hammerschmidt for S. pneumoniae strains and C. Gärtner for help in preparing the tissue sections. We acknowledge the US National Institutes of Health Tetramer Core Facility (contract HHSN272201300006C) for provision of CD1d tetramers. This study was supported by European Union Framework Programme 7 grant CAREPNEUMO 223111 (to R.L. and G.D.L.), the Swiss National Science Foundation (310030_149571 and Sinergia CRS133-124819 to G.D.L.), a Scholarship of the Studienstiftung des deutschen Volkes (to P.S.), the Alexander von Humboldt Foundation for a postdoctoral research fellowship (to D.C.K.R.), Peter and Traudl Engerlhorn-Stiftung (to A.K.) and funding of the Max Planck Society (P.H.S.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The authors wish to thank L. Robinson and N. McCarthy of Insight Editing London for critical review and manuscript editing and A. K. for the artwork.

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M.C., P.S., R.L. P.H.S. and G.D.L. designed the experiments; M.C., P.S., A.K., D.C.K.R., T.M.A.G. and A.A. performed the research; M.C., P.S., D.C.K.R., A.K. and T.M.A.G. analyzed the data; and M.C., P.S., L.M., P.H.S. and G.D.L. wrote the paper.

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Correspondence to Peter H Seeberger or Gennaro De Libero.

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T.M.A.G. is an employer of SAW Instruments, Bonn. The other authors declare no competing financial interests.

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Supplementary Results, Supplementary Tables 1–4, Supplementary Figures 1–5 and Supplementary Note. (PDF 11157 kb)

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Cavallari, M., Stallforth, P., Kalinichenko, A. et al. A semisynthetic carbohydrate-lipid vaccine that protects against S. pneumoniae in mice. Nat Chem Biol 10, 950–956 (2014). https://doi.org/10.1038/nchembio.1650

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