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

Jacopo Enotarpi, Marta Tontini, Cristiana Balocchi, Daan Es, Ludovic Auberger, Evita Balducci, Filippo Carboni, Daniela Proietti, Daniele Casini, Dmitri V. Filippov, Hermen S. Overkleeft, Gijsbert A. Marel, Cinzia Colombo, Maria Rosaria Romano, Francesco Berti, Paolo Costantino, Jeroen D. C. Codeé (), Luigi Lay () and Roberto Adamo ()
Additional contact information
Jacopo Enotarpi: University of Milan
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

Nature Communications, 2020, vol. 11, issue 1, 1-9

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18279-x

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