Fully synthetic carbohydrate-based cancer vaccine is an attractive concept, while an important topic in the area is to develop proper vaccine carriers that can improve the immunogenicity and other immunological properties of tumor-associated carbohydrate antigens (TACAs). In this context, four monophosphoryl derivatives of Neisseria meningitidis lipid A were synthesized via a highly convergent and effective strategy and evaluated as vaccine carriers and adjuvants. The conjugates of these monophosphoryl lipid A (MPLA) derivatives with a modified form of the sTn antigen were found to elicit high titers of antigen-specific IgG antibodies, indicating T cell-dependent immune response, in the absence of an external adjuvant. It was concluded that MPLA’s could be utilized as potent vaccine carriers and built-in adjuvants to create fully synthetic self-adjuvanting carbohydrate-based cancer vaccines. The lipid composition and structure of MPLA were shown to have a significant influence on its immunological activity, and among the MPLA’s examined, natural N. meningitidis MPLA exhibited the most promising properties. Moreover, Titermax Gold, a conventional vaccine adjuvant, was revealed to inhibit, rather than promote, the immunological activity of MPLA conjugates, maybe via interacting with MPLA text goes here.
α-2,9-Polysialic acid is an
important capsular polysaccharide
expressed by serotype C Neisseria meningitidis. Its
protein conjugates are current vaccines against group C meningitis.
To address some concerns about traditional protein conjugate vaccines,
a new type of fully synthetic vaccines composed of oligosialic acids
and glycolipids was explored. In this regard, α-2,9-linked di-,
tri-, tetra-, and pentasialic acids were prepared and conjugated with
monophosphoryl lipid A (MPLA). Immunological studies of the conjugates
in C57BL/6J mouse revealed that they alone elicited robust immune
responses comparable to that induced by corresponding protein conjugates
plus adjuvant, suggesting the self-adjuvanting properties of MPLA
conjugates. The elicited antibodies were mainly IgG2b and IgG2c, suggesting
T cell dependent immunities. The antisera had strong and specific
binding to α-2,9-oligosialic acids and to group C meningococcal
polysaccharide and cell, indicating the ability of antibodies to selectively
target the bacteria. The antisera also mediated strong bactericidal
activities. Structure–activity relationship analysis of the
MPLA conjugates also revealed that the immunogenicity of oligosialic
acids decreased with elongated sugar chain, but all tested MPLA conjugates
elicited robust immune responses. It is concluded that tri- and tetrasialic
acid–MPLA conjugates are worthy of further investigation as
the first fully synthetic and self-adjuvanting vaccines against group
C meningitis.
The structure of the capsular polysaccharide (CPS) of serotype Ia group B Streptococcus (GBS) has been characterized for years, but its repeating unit, which is a challenging pentasaccharide with a branch and a difficult α-sialic acid linkage, has not been synthesized yet. In this report, an effective synthesis was developed for the serotype Ia GBS CPS repeating unit, which had a reactive functionality linked to its main chain reducing end to enable further elaboration, such as coupling with carrier proteins. The target molecule was accomplished by a convergent [2+3] glycosylation strategy employing a sialo-disaccharide as donor and a branched trisaccharide as acceptor. The strategy was designed to suit the synthesis of oligomers of the repeating unit.
The total syntheses of stagonolide B and its 4-epimer were carried out to probe into how the relative stereochemistry of allylic hydroxy groups and their protecting groups influence the efficiency of the ring closing metathesis.
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