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A stabilized glycomimetic conjugate vaccine inducing protective antibodies against Neisseria meningitidis serogroup A

Author

Listed:
  • Jacopo Enotarpi

    (University of Milan
    Leiden University)

  • Marta Tontini

    (GSK)

  • Cristiana Balocchi

    (GSK)

  • Daan Es

    (Leiden University)

  • Ludovic Auberger

    (University of Milan)

  • Evita Balducci

    (GSK)

  • Filippo Carboni

    (GSK)

  • Daniela Proietti

    (GSK)

  • Daniele Casini

    (GSK)

  • Dmitri V. Filippov

    (Leiden University)

  • Hermen S. Overkleeft

    (Leiden University)

  • Gijsbert A. Marel

    (Leiden University)

  • Cinzia Colombo

    (University of Milan)

  • Maria Rosaria Romano

    (GSK)

  • Francesco Berti

    (GSK)

  • Paolo Costantino

    (GSK)

  • Jeroen D. C. Codeé

    (Leiden University)

  • Luigi Lay

    (University of Milan)

  • Roberto Adamo

    (GSK)

Abstract

Neisseria meningitidis serogroup A capsular polysaccharide (MenA CPS) consists of (1 → 6)-2-acetamido-2-deoxy-α-D-mannopyranosyl phosphate repeating units, O-acetylated at position C3 or C4. Glycomimetics appear attractive to overcome the CPS intrinsic lability in physiological media, due to cleavage of the phosphodiester bridge, and to develop a stable vaccine with longer shelf life in liquid formulation. Here, we generate a series of non-acetylated carbaMenA oligomers which are proven more stable than the CPS. An octamer (DP8) inhibits the binding of a MenA specific bactericidal mAb and polyclonal serum to the CPS, and is selected for further in vivo testing. However, its CRM197 conjugate raises murine antibodies towards the non-acetylated CPS backbone, but not the natural acetylated form. Accordingly, random O-acetylation of the DP8 is performed, resulting in a structure (Ac-carbaMenA) showing improved inhibition of anti-MenA CPS antibody binding and, after conjugation to CRM197, eliciting anti-MenA protective murine antibodies, comparably to the vaccine benchmark.

Suggested Citation

  • Jacopo Enotarpi & Marta Tontini & Cristiana Balocchi & Daan Es & Ludovic Auberger & Evita Balducci & Filippo Carboni & Daniela Proietti & Daniele Casini & Dmitri V. Filippov & Hermen S. Overkleeft & G, 2020. "A stabilized glycomimetic conjugate vaccine inducing protective antibodies against Neisseria meningitidis serogroup A," Nature Communications, Nature, vol. 11(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18279-x
    DOI: 10.1038/s41467-020-18279-x
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