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

ABSTRACT: Neisseria meningitidis serogroup A capsular polysaccharide (MenA CPS) consists of (1???6)-2-acetamido-2-deoxy-?-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.

SUBMITTER: Enotarpi J

PROVIDER: S-EPMC7477203 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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

Enotarpi Jacopo J Tontini Marta M Balocchi Cristiana C van der Es Daan D Auberger Ludovic L Balducci Evita E Carboni Filippo F Proietti Daniela D Casini Daniele D Filippov Dmitri V DV Overkleeft Hermen S HS van der Marel Gijsbert A GA Colombo Cinzia C Romano Maria Rosaria MR Berti Francesco F Costantino Paolo P Codeé Jeroen D C JDC Lay Luigi L Adamo Roberto R

Nature communications 20200907 1

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 sta ...[more]

PMID: 32895393

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Project description:ObjectiveThe optimal long-term vaccination strategies to provide population-level protection against serogroup A Neisseria meningitidis (MenA) are unknown. We developed an age-structured mathematical model of MenA transmission, colonization, and disease in the African meningitis belt, and used this model to explore the impact of various vaccination strategies.MethodsThe model stratifies the simulated population into groups based on age, infection status, and MenA antibody levels. We defined the model parameters (such as birth and death rates, age-specific incidence rates, and age-specific duration of protection) using published data and maximum likelihood estimation. We assessed the validity of the model by comparing simulated incidence of invasive MenA and prevalence of MenA carriage to observed incidence and carriage data.ResultsThe model fit well to observed age- and season-specific prevalence of carriage (mean pseudo-R2 0.84) and incidence of invasive disease (mean R2 0.89). The model is able to reproduce the observed dynamics of MenA epidemics in the African meningitis belt, including seasonal increases in incidence, with large epidemics occurring every eight to twelve years. Following a mass vaccination campaign of all persons 1-29 years of age, the most effective modeled vaccination strategy is to conduct mass vaccination campaigns every 5 years for children 1-5 years of age. Less frequent campaigns covering broader age groups would also be effective, although somewhat less so. Introducing conjugate MenA vaccine into the EPI vaccination schedule at 9 months of age results in higher predicted incidence than periodic mass campaigns.DiscussionWe have developed the first mathematical model of MenA in Africa to incorporate age structures and progressively waning protection over time. Our model accurately reproduces key features of MenA epidemiology in the African meningitis belt. This model can help policy makers consider vaccine program effectiveness when determining the feasibility and benefits of MenA vaccination strategies.

Dataset Information

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

Publications

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

Similar Datasets

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