2 research outputs found
A Synthetic Disaccharide Analogue from Neisseria meningitidis A Capsular Polysaccharide Stimulates Immune Cell Responses and Induces Immunoglobulin G (IgG) Production in Mice When Protein-Conjugated
Some
new phosphonoester-linked oligomers, stabilized analogues of the corresponding
phosphate-bridged oligomers of Neisseria meningitidis A (MenA) capsular polysaccharide (CPS), were conjugated to human
serum albumin (HSA), as a protein carrier model, and studied for
immunological activities. We determined (i) in vitro, their biocompatibility
(CAM test) and activity in inducing both T cell proliferation (CFSE
method) and IL-2 release (ELISA), and (ii) in vivo, their ability
to stimulate specific IgG antibody production (ELISA). All HSA-conjugated
compounds induce T cell proliferation (40% of proliferation at 10<sup>2</sup> μM), whereas only the phosphonodisaccharide was effective
(28% of proliferation at 10<sup>2</sup> μM) among the unconjugated
forms. IL-2 release confirmed these results. In addition, the HSA-conjugated
showed in vivo the capacity of eliciting the production of specific
IgG antibodies. In conclusion, we obtained novel biocompatible, water-stable,
and immunoactive MenA CPS analogues. A short disaccharide fragment
showed the unusual behavior of triggering T cell proliferation in
vitro
Immunoactivity of Protein Conjugates of Carba Analogues from <i>Neisseria meningitidis</i> A Capsular Polysaccharide
<i>Neisseria meningitidis</i> type A (MenA) is a Gram-negative
encapsulated bacterium that is a major cause of epidemic meningitis,
especially in the sub-Saharan region of Africa. The development and
manufacture of a liquid glycoconjugate vaccine against MenA are hampered
by the poor hydrolytic stability of its capsular polysaccharide (CPS),
consisting of (1→6)-linked 2-acetamido-2-deoxy-α-d-mannopyranosyl phosphate repeating units. The replacement
of the ring oxygen with a methylene group to generate a carbocyclic
analogue leads to enhancement of its chemical stability. Herein, we
report conjugation of carbocyclic analogue monomer, dimer, and trimer
to the protein carrier CRM<sub>197</sub>. After immunization in mice,
only the conjugated trimer was able to induce specific anti-MenA polysaccharide
IgG antibodies with <i>in vitro</i> bactericidal activity,
although to a lesser extent than pentadecamer and hexamer oligomers
obtained from mild acid hydrolysis of the native polysaccharide conjugated
to the same protein carrier. This study represents the first proof-of-concept
that hydrolytically stable structural analogues of saccharide antigens
can be used for the development of efficacious antimicrobial preventative
therapies. Conjugates with longer carbocyclic oligomers and/or precise
acetylation patterns could further increase the induced immune response
to a level comparable with those of commercially available anti-meningococcal
glycoconjugate vaccines